Asperosaponin VI inhibits LPS-induced inflammatory response by activating PPAR-γ pathway in primary microglia

Zhang, Jinqiang; Yi, Saini; Xiao, Chao; Li, Yahui; Liu, Chan; Jiang, Wei-Ke; Yang, Chun-Lin; Zhou, Tao

doi:10.1101/2020.03.15.992453

Cited by 3 publications

(7 citation statements)

References 21 publications

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“…Consistent with that study, we found here that the PPAR-γ agonist pioglitazone, like ASD, induced an anti-in ammatory microglial phenotype. Our ndings here may help explain how ASD can attenuate microglia-mediated in ammation in animal models of depression [31,32].…”

Section: Discussionmentioning

confidence: 71%

“…PPAR-γ regulates the expression of anti-in ammatory cytokines [56], and the PPAR-γ agonists pioglitazone or rosiglitazone can switch activated microglia cells from a pro-in ammatory to antiin ammatory state [57]. Our previous research showed that ASD acts via PPAR-γ to switch activated microglia from a pro-in ammatory to anti-in ammatory phenotype in vitro [32]. In present study, we further demonstrated that ASD acts via PPAR-γ to induce a pro-neurogenic microglial phenotype in dentate gyrus of CMS-exposed mice and mitigate depressive-like mouse behaviors.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the akebia saponin D (ASD), from the herb Dipsacus asper Wall., e ciently crosses the blood-brain barrier and exerts anti-in ammatory and neuroprotective effects [28][29][30]. We have shown that ASD regulates microglial function to ameliorate neuroin ammation and depression-like behaviors of mice exposed to lipopolysaccharide (LPS) [31,32]. However, we are unaware of studies exploring whether ASD in uences hippocampal neurogenesis, which may thereby help explain its antidepressant effects.…”

Section: Introductionmentioning

confidence: 99%

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Akebia saponin D acts via the PPAR-gamma pathway to reprogramme a pro-neurogenic microglia that can restore hippocampal neurogenesis in mice exposed to chronic mild stress

Liu

et al. 2022

Preprint

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Using drugs to modulate microglial function may be an effective way to treat disorders such as depression that involve impaired neurogenesis. Akebia saponin D (ASD) can cross the blood-brain barrier and exert anti-inflammatory and neuroprotective effects, so we wondered whether it might influence adult hippocampal neurogenesis to treat depression. We exposed C57BL/6 male mice to chronic mild stress (CMS) as a model of depressive-like behaviors, then gave them ASD (40 mg/kg) intraperitoneally once daily for 3 weeks. We investigated the effects of ASD on microglial phenotype, hippocampal neurogenesis, and animal behavior. We found that CMS upregulated pro-inflammatory factors and downregulated anti-inflammatory factors in dentate gyrus of mice, while decreasing sucrose preference and prolonging immobility time in the forced swimming test. CMS also inhibited hippocampal neurogenesis. ASD treatment induced Arg-1+ microglia and increases brain-derived neurotrophic factor (BDNF) expression in the dentate gyrus of CMS mice, and partially reversed all these stress effects. Conditioned medium from microglia treated with ASD and lipopolysaccharide (LPS) strongly increased levels of phospho-TrkB in neural stem/progenitor cells (NSPCs), while promoting their proliferation, survival and neuronal differentiation. An antagonist of TrkB blocked the pro-neurogenic, anti-depressant effects of ASD. Furthermore, ASD activated peroxisome proliferator-activated receptor-gamma (PPAR-γ) in dentate gyrus of CMS mice as well as in primary microglial cultures treated with LPS. Blocking the PPAR-γ using GW9962 suppressed the ASD-reprogrammed Arg-1+ microglia and BDNF expression in dentate gyrus of CMS mice. Such blockade abolished the promoted effects of ASD-treated microglia on NSPC proliferation, survival and neurogenesis. The pro-neurogenic and anti-depressant effects of ASD were blocked by GW9962. These results suggested that ASD acts via the PPAR-γ pathway to induce a pro-neurogenic microglia in dentate gyrus of CMS mice that can increase BDNF expression and promote NSPC proliferation, survival, and neurogenesis. Our results justify further studies of ASD as a potential treatment for depression and may inspire new lines of research targeting the PPAR-γ pathway in disorders involving impaired neurogegammnesis.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Akebia saponin D acts via the PPAR-gamma pathway to reprogramme a pro-neurogenic microglia that can restore hippocampal neurogenesis in mice exposed to chronic mild stress

Liu

et al. 2022

Preprint

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“…Endometrial angiogenesis disorders and infection exert key functions in RSA, and it has been shown that AS6 can effectively accelerate the angiogenesis of regenerated tissues and promote wound healing, and promote the vascularization of HUVECs [18]. AS6 can also inhibit the morphological expansion of microglia, reduce the expression of pro-inflammatory cytokines such as IL-1B, iNOS, TNF-α, IL-6, IL-1B, and TNF-α in a dose-dependent manner [19].…”

Section: Discussionmentioning

confidence: 99%

“…e angiogenesis disorders of the endometrium and infection play important part in RSA, and existing evidence has shown that AS6 efficiently accelerates the angiogenesis of regenerated tissue and facilitates wound healing in vivo, and improves vascularization of human umbilical vein endothelial cells (HUVECs) in vitro by the upregulation of HIF-1α/VEGF pathway [18]. Moreover, it has been revealed that AS6 also inhibits the morphological expansion of microglia cells, decreases the expression, and releases of proinflammatory cytokines, such as IL-1B, iNOS, IL-6, and TNF-a in a dosedependent manner [19]. However, whether AS6 can treat RSA through these pathways needs further research.…”

Section: Introductionmentioning

confidence: 99%

Research on the Mechanism of Asperosaponin VI for Treating Recurrent Spontaneous Abortion by Bioinformatics Analysis and Experimental Validation

Xia

Zhang

Lai

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Asperosaponin VI (AS6), as the quality marker of Dipsaci Radix, is verified to exert therapeutic effect on alleviating recurrent spontaneous abortion (RSA). However, due to the lack of relevant research, its molecular mechanism is still unclear. We retrieved targets for AS6 and RSA, and then used their overlapped targets for PPI analysis. In addition, we used GO and KEGG enrichment analyses, and molecular docking to investigate the anti-RSA mechanisms of AS6. Furthermore, we conducted in vitro experiments to validate the predictions of network pharmacology. Results showed that a total of 103 AS6-associated targets and 2084 RSA-associated targets, with 49 targets overlapped. GO enrichment analysis showed 845 significant biological processes like decidualization, while KEGG pathway enrichment analysis revealed 76 significant entries including 18 signaling pathways, which were closely linked to PI3K-Akt, HIF-1, TNF, IL-17, and VEGF signaling pathways, etc. Molecular docking findings verified that AS6 had tight link with the key targets including JUN, CASP3, STAT3, SRC, and PTGS2. Notably, in vitro experiments revealed that AS6 treatment could exert lower expressions of JUN, pro-CASP3, CASP3, STAT3, SRC, and PTGS2 in decidual cells compared with progesterone despite the expressions of STAT3, SRC, and PTGS2 with no significant difference, and mifepristone could interfere with the effects. In general, numerous targets and multiple pathways involve during the process of AS6 treatment against RSA. Moreover, our in vitro research first reported that AS6 may regulate the expressions of key targets (JUN, CASP3, STAT3, SRC, and PTGS2) in decidual cells to promote decidualization, thus treating RSA.

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Ferulic Acid reduces amyloid beta mediated neuroinflammation through modulation of Nurr1 expression in microglial cells

Moghimi-Khorasgani,

Homayouni Moghadam,

Nasr-Esfahani

2023

PLoS ONE

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Microglial cells (MGCs) serve as the resident macrophages in the brain and spinal cord, acting as the first line of immune defense against pathological changes. With various phenotypes, they can shift from a homeostatic state to a reactive state or transit from a reactive to a non-inflammatory reactive state (alternative homeostatic). A well-timed transit is crucial in limiting excessive microglial reaction and promoting the healing process. Studies indicate that increased Nurr1 expression promotes anti-neuroinflammatory responses in the brain. In this study, we investigated the possible role of ferulic acid (FA) in facilitating microglia transition due to its anti-inflammatory and Nurr1-inducing effects. MGCs were extracted from the brains of male NMRI mice at postnatal day 2 (P2) and cultured with or without FA and beta-amyloid (Aβ). Real-time qRT-PCR was conducted to measure the expressions of Nurr1, IL-1β, and IL-10 genes. Immunostaining was performed to determine the number of NURR1-positive cells, and the ramification index (RI) of MGCs was calculated using Image J software. Treating MGCs with FA (50 μg/ml) induced Nurr1 and IL-10 expressions, while reducing the level of IL-1β in the absence of Aβ-stress. Further assessments on cells under Aβ-stress showed that FA treatment restored the IL-10 and Nurr1 levels, increased the RI of cells, and the number of NURR1-positive cells. Morphological assessments and measurements of the RI revealed that FA treatment reversed amoeboid and rod-like cells to a ramified state, which is specific morphology for non-inflammatory reactive microglia. To conclude, FA can provide potential alternative homeostatic transition in Aβ-reactive microglia by recruiting the NURR1 dependent anti-inflammatory responses. This makes it a promising therapeutic candidate for suppressing Aβ-induced neuroinflammatory responses in MGCs. Furthermore, given that FA has the ability to increase NURR1 levels in homeostatic microglia, it could be utilized as a preventative medication.

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Asperosaponin VI inhibits LPS-induced inflammatory response by activating PPAR-γ pathway in primary microglia

Cited by 3 publications

References 21 publications

Akebia saponin D acts via the PPAR-gamma pathway to reprogramme a pro-neurogenic microglia that can restore hippocampal neurogenesis in mice exposed to chronic mild stress

Akebia saponin D acts via the PPAR-gamma pathway to reprogramme a pro-neurogenic microglia that can restore hippocampal neurogenesis in mice exposed to chronic mild stress

Research on the Mechanism of Asperosaponin VI for Treating Recurrent Spontaneous Abortion by Bioinformatics Analysis and Experimental Validation

Ferulic Acid reduces amyloid beta mediated neuroinflammation through modulation of Nurr1 expression in microglial cells

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