JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2019
·
IF 3.571
Juan Sun,Han-Yu Liu,Cheng-Zhi Lv,Jie Qin,Yuan-Feng Wu
Licorice is a traditional Chinese medicine, which is often used as sweetener and cosmetic ingredients in food and pharmaceutical industries. Among them, glycyrrhetic acid is one of the most important agents. Studies have shown that glycyrrhetic acid exhibited antitumor activities as PPARγ agonist. However, the limited number of PPARγ glycyrrhetinic agonists and their high toxicity greatly limit the design based on the structure. Therefore, clarifying the binding mode between PPARγ and small molecules, we focused on the introduction of a natural active piperazine skeleton in the position of glycyrrhetinic acid C-3. According to the Combination Principle and the Structure-Based Drug Design, 19 glycyrrhetic acid derivatives were designed and synthesized as potential PPARγ agonists. Compounds 4c and 4q were screened as high-efficiency and low-toxicity lead compounds.
研究领域:
药理学
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药物化学
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肿瘤学
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DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
·
2023
·
IF 3.8
Yushuang Liu,Hanshu Zhao,Nan Chen,Yuelong Li,Zeyang Zheng,Zhiyu Sun,Zhongling Zhang
Mitochondrial dysfunction and endoplasmic reticulum (ER) stress occur in ischemic stroke. The disruption of these two organelles can directly lead to cell death through various signaling pathways. Thus, investigation of the associated molecular mechanisms in cerebral ischemia is a prerequisite for stroke treatment. Pleckstrin homology-like domain family A member 1 (PHLDA1) is a multifunctional protein that can modulate mitochondrial function and ER stress in cardiomyocyte and cancer cells. This work studied the role of PHLDA1 in cerebral ischemic/reperfusion (I/R) injury and explored the underlying mechanisms associated with mitochondrial functions and ER stress. Middle cerebral artery occlusion/reperfusion (MCAO/R)-treated mice and oxygen-glucose deprivation/reoxygenation (OGD/R)-stimulated neurons were used as I/R models in vivo and in vitro, respectively. PHLDA1 was upregulated in ischemic penumbra of MCAO/R-induced mice and OGD/R-exposed neurons. In vitro , PHLDA1 knockdown protected neurons from OGD/R-induced apoptosis. In vivo , PHLDA1 silencing facilitated functional recovery and reduced cerebral infarct volume. Mechanistically, PHLDA1 knockdown promoted PPARγ nuclear translocation, which may mediate the effects on reversion of mitochondrial functions and alleviation of ER stress. In summary, PHLDA1 knockdown alleviates neuronal ischemic injuries in mice. PPARγ activation and mitochondrial dysfunction and endoplasmic reticulum stress attenuation are involved in the underlying mechanisms.
研究领域:
神经科学
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分子生物学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2022
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IF 4.319
Yi Zhang,Xiujin Shi,Jialun Han,Wenxing Peng,Zhenwei Fang,Yang Zhou,Xiaoyu Xu,Jie Lin,Fucheng Xiao,Limin Zhao,Yang Lin
Introduction As the primary immune cells, macrophages play a key role in atherosclerotic progression. M2 macrophage polarization has been reported to promote tissue repair and attenuate plaque formation upon the expression of anti-inflammatory factors. Convallatoxin (CNT) is a natural cardiac glycoside with anti-inflammatory pharmacological properties. However, whether CNT protects against atherosclerosis (AS) and underlying mechanisms is unknown. This work was designed to explore the potential effects of CNT on atherosclerosis.Methods In this study, Apolipoprotein E deficiency (ApoE−/-) mice fed with high-fat diet were established, and CNT (50 or 100 μg/kg) were intragastrically administrated for 12 weeks every day. In vitro, RAW264.7 macrophages stimulated with ox-LDL were treated with CNT (50 or 100 nM) for 24 h. The specific PPARγ antagonist, GW9662, was used to block the PPARγ signaling pathway in vitro. Then, the atherosclerotic lesions, macrophage polarization markers, inflammatory cytokines and PPARγ signaling pathway were examined in further examinations.Results Our results showed that the atherosclerotic lesions were reduced by CNT, as demonstrated by the downregulation of serum lipid level and aortic plaque area in AS mice. Furthermore, we found that CNT treatment promoted the expression of M2 macrophage markers (Arg1, Mrc1, Retnla and Chi3l3), and decreased the levels of pro-inflammatory cytokines (IL-6 and TNF-α), accompanied by the increase of anti-inflammatory factor (IL-10) in aortic vessels of AS mice. In ox-LDL-induced RAW264.7 cells, CNT administration also facilitated macrophages polarizing towards M2 subtype and inhibited inflammatory responses. Furthermore, both the in vivo and in vitro experiments showed CNT could increase the expression of PPARγ, Integrin αv and Integrin β5, and GW9662 could block CNT-induced M2 macrophage polarization.Conclusion Taken together, these data suggest that CNT may promote M2 macrophage polarization to exert an anti-atherosclerotic effect, partially through activating PPARγ-Integrin αvβ5 signaling pathway.
研究领域:
心血管疾病
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免疫学
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2022
·
IF 6.656
Shuang Luo,Jinrong He,Shaowei Huang,Xiaojing Wang,Yulin Su,Yanyang Li,Yanping Chen,Guanghua Yang,Bin Huang,Shaoju Guo,Lian Zhou,Xia Luo
Background Emodin is an active ingredient of traditional Chinese medicine Rheum palmatum L. and Polygonum cuspidatum , which possesses anti-inflammatory and intestinal mucosal protection effects. Our previous study found that emodin significantly alleviated ulcerative colitis induced by sodium dextran sulfate (DSS). In this study, we found the underlying mechanism of emodin on ulcerative colitis (UC). Purpose We aimed to further explore the mechanism of emodin in the treatment of ulcerative colitis from the perspective of metabolism and intestinal flora . Methods Ulcerative colitis was induced by 3% sodium dextran sulfate (DSS) on mice, and the mice were respectively treated with mesalazine , rosiglitazone , emodin, and emodin combined with GW9662 (PPARγ inhibitor) simultaneously. Weight changes , the disease activity index (DAI), colonic length, and pathologic changes in colon were used to evaluate the efficacy of emodin. LC-MS/MS was performed for metabolomics analysis of colon. In addition, intestinal flora was assessed using 16S rDNA sequencing. A vector-based short hairpin RNA (shRNA) method was used to silence PPARγ gene expression in Caco-2 cells. Results Emodin binds to the active site of PPARγ protein and forms hydrogen bond interaction with ARG288 and CYS285 amino acids. Furthermore, Emodin significantly promotes the protein expression of PPARγ, while inhibiting iNOS and NF-kB p65 in UC mice, however, this effect is hardly shown when it is combined with GW9662 (the inhibitor of PPARγ). Meanwhile, emodin suppresses the expression of iNOS in Caco-2 cells induced with IFNγ and IL-22, but has no effect on its expression in shPPARγ-Caco-2 cells. In addition, through activating PPARγ signal pathway , emodin is capable of regulating colonic metabolism including oxidative phosphorylation and citrulline metabolism and effecting luminal availability of oxygen and nitrate. This promotes the recovery of anoxic environment of colon epithelial cells, which strains the growth and expansion of Enterobacteriaceae . Conclusion The mechanism of Emodin in the treatment of ulcerative colitis relies on its regulation of PPARγ signal pathway, which could modulate colonic metabolism and restore intestinal homeostasis .
研究领域:
药理学
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胃肠病学
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分子生物学
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免疫学
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微生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Youyun Liu,Junxi Liu,Rui Xu,Yonglei Yuan,Qiwen Sun,Susu Ding,Feifei Wang,Liping Qu
Ethnopharmacological relevance Ludwigia adscendens (L.) Hara ( L. adscendens ) is a Traditional Chinese Medicine (TCM), first mentioned in Sheng Cao Yao Xing Bei Yao ( Essential Guide to Raw Herbal Properties ). It clears heat, removes dampness, detoxifies, and reduces swelling. In TCM, it is prescribed for acne caused by dampness-heat accumulation. It is also used for cold, fever, sore throat, boils, dermatitis, and snake or dog bites. Research shows it has antioxidant, antibacterial, anti-inflammatory, and anti-lipoxygenase effects. However, studies on its impact on sebaceous gland function (a key factor in acne pathogenesis) are still limited. Aim of the study This study aims to investigate the effects of L. adscendens extract (LHE) on sebaceous gland function and its mechanisms. Materials and methods Active compounds in LHE were identified using high-performance liquid chromatography (HPLC). Its effects on lipid synthesis, sebocyte proliferation, and reactive oxygen species (ROS) were assessed in a 5α-dihydrotestosterone (DHT)-induced sebocyte model. Untargeted lipidomics was used to analyse sebum composition and detect LHE-induced changes. Anti-inflammatory and antioxidant activities were evaluated using zebrafish models and biochemical assays. Sebum-regulatory efficacy was measured to assess LHE's impact on sebum production. Results LHE showed strong biological activity by activating the PPARγ/LXRα/SREBP1 pathway, reducing lipid production, inhibiting sebocyte hyperproliferation, and delivering notable antioxidant and anti-inflammatory effects. Lipidomic analysis revealed that LHE effectively altered lipid composition, especially by lowering triglycerides (TG), diacylglycerols (DG), ceramides (Cer), and hexosyl-1-ceramides (Hex1Cer), with major changes observed in medium- and long-chain TG and phosphatidylethanolamine (PE) levels. Efficacy tests confirmed that LHE reduced sebum production and improved skin texture by shrinking pore size. Conclusions LHE improves sebaceous gland function by reducing lipid overproduction and hyperproliferation through the PPARγ/LXRα/SREBP1 pathway. It also enhances the lipid profile by lowering key lipid molecules like TGs and PEs. Moreover, LHE shows anti-inflammatory and antioxidant effects. These findings suggest its therapeutic potential for sebaceous gland-related conditions and reveal new insights into its mechanism in topical use.
研究领域:
药理学
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民族药理学
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皮肤科学
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分子生物学
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生物化学
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脂质代谢
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植物学
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产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2022
·Vol. 36
·期 10
·3969-3987
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IF 6.388
Yi Chen,Shasha Song,Yongfang Wang,Jia Zhu,Xinyu Li
Psoriasis (PSO), an immune-mediated chronic inflammatory skin disease, has seriously affected the quality of patients' life. It is urgent to find effective medicines with lower costs and less side effects. Baicalin (HQG) is the main bioactive substance from Scutellaria baicalensis with effects of anti-inflammation and immunoregulation. Herein, we explored the effect of oral HQG treating PSO and its potential mechanism. Firstly, network pharmacology was used to predict that HQG may act on Estrogen, TNF-alpha (tumor necrosis factor, TNF), interleukin-17 (IL-17) signaling pathways and Th17 cell differentiation, especially the key targets including TNF, Proto-oncogene tyrosine-protein kinase Src, Peroxisome proliferator-activated receptor gamma and Matrix metalloproteinase-9. Imiquimod (IMQ)-induced mice were then used to study the effects of HQG treating PSO. HQG could significantly ameliorate the skin lesions, decrease the level of inflammatory factors and inhibit Th1/Th17 cell differentiation in IMQ-induced mice. Finally, transcriptome analysis of skin lesions integrated with the prediction of network pharmacology further demonstrated that the potential mechanism may be associated with suppressing Wnt signaling pathway and inhibiting Th17/IL-17 axis by activating PPARγ. In conclusion, this study suggested that HQG may be a promising agent for further studies in the search for therapeutic strategies to treat PSO in the future.
研究领域:
药理学
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免疫学
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皮肤科
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Rongjia Xu,Jiajia Zhang,Xingge Hu,Penghao Xu,Shiqi Huang,Shiyan Cui,Yuxin Guo,Hongtao Yang,Xiangmei Chen,Chen Jiang
Ethnopharmacological relevance Controversy persists regarding the treatment of immunoglobulin A nephropathy (IgAN), thereby highlighting the demand for safer more effective therapeutic drugs. Although supplementary treatment using Yi-Shen-Hua-Shi (YSHS) granules has distinct advantages with respect to improving renal function in IgAN, a lack of clarity regarding the underlying mechanisms limits their clinical application. Aim of the study In this study, we aimed to elucidate the therapeutic mechanisms underlying the efficacy of YSHS granules in the treatment of IgAN. Materials and methods A rat model of IgAN was established based on lipopolysaccharide, carbon tetrachloride, and bovine serum albumin induction. In order to evaluate the effects of YSHS granules, we performed a range of techniques, including immunofluorescence assays, hematoxylin and eosin staining, and flow cytometry, to assess inflammation, immunity, and other relevant factors. Direct data-independent acquisition–mass spectrometry (DIA-MS) analysis and parallel reaction monitoring (PRM) were used for functional characterization and quantitative validation of differentially expressed proteins (DEPs), and Western blot analysis is used to identify downstream proteins associated with DEPs. Results Compared with the model group, the levels of proteinuria, urine red blood cells, serum creatinine, blood urea nitrogen, low-density lipoprotein-cholesterol, triglycerides, and pathological kidney damage were reduced in the YSHS group. A high dose of YSHS granules was found to raise the levels of CD8 T cells and reduce the CD4/CD8 ratio in the peripheral serum. To examine the mechanisms underlying the therapeutic effects YSHS granules, we performed direct DIA-MS analysis to identify proteins that were differentially expressed among the model, YSHS, and control groups. A total of 29 proteins were identified as being commonly expressed in all three groups. Further KEGG and protein–protein interaction (PPI) network analysis revealed that YSHS granules can contribute to the regulation of N -glycosylation-associated proteins, such as ALG3 and STT3A, in rats with IgAN. Detected changes in the expression of ALG3 and STT3A were consistent with the PRM results. We also established that the administration of YSHS granules can contribute to regulation of the ALG3-associated PPAR-γ/NF-κB signaling pathway. Conclusions Our findings in this study provide evidence to indicate the efficacy of YSHS granules in the treatment of IgAN, the putative underlying mechanisms of which involve the modulation of N-glycosylation, mediated via the PPAR-γ/NF-κB pathway.
研究领域:
药理学
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免疫学
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肾病学
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蛋白质组学
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中医药
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产品关联
DOI
PubMed
高影响因子
MOLECULAR IMMUNOLOGY
·
2025
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IF 3
Aiping Li,Mengjiao Wang,Min Guo,Yuetao Liu,Ke Li,Lichao Zhang,Xuemei Qin,Guangzhen Liu
Astragali Radix (AR), a homologous of medicine and food, has been extensively recorded to possess a nephroprotective impact on individuals suffering from chronic kidney disease (CKD). Astragaloside IV (ASIV) is one of the prominent bioactive constituents derived from AR. This study aimed to investigate how ASIV promotes M2 polarization of macrophages and whether this contributes to the protection of podocytes from injury, using a combination of lipidomics and molecular biology techniques.The effect of ASIV on adriamycin (ADR)-induced renal injury in rats was evaluated in vivo, with a particular emphasis on elucidating the potential involvement of macrophages. The M1 polarization model of RAW264.7 cells induced by ADR was established in vitro . The impact of ASIV on ADR-induced macrophage polarization was comprehensively assessed by measuring the expression levels of M1 and M2 macrophage marker proteins, along with their associated mRNA profiles. Flow cytometry was employed to analyze surface marker expression, while Western blot (WB) was used to quantify protein levels, and real-time quantitative PCR (qPCR) allowed for the measurement of gene expression. Notably, we found that the macrophage supernatant intervened by ASIV was found to have a protective effect against podocyte injury, which was evaluated through cell adhesion and apoptosis assays. Innovatively, we explored the mechanism by which ASIV affects macrophage polarization from the perspective of lipid metabolism, using lipidomics methods. During this process, the role of peroxisome proliferator-activated receptor gamma (PPARγ) in macrophage polarization caught our attention. This receptor is closely associated with lipid metabolites, as confirmed by molecular docking. ASIV has been shown to effectively ameliorate kidney injury, with macrophages playing a pivotal role in renal podocyte repair process. The protein and mRNA expressions of ARG-1, CD206 and IL-10, M2 macrophage markers, was increased by ASIV and M2 macrophages polarization was promoted by ASIV (P < 0.05). In addition, it was observed that the supernatant of macrophages intervened by ASIV exerts a protective effect on podocyte injury, which was confirmed through podocyte adhesion assays and cell apoptosis experiments. This study suggests that ASIV enhances the M2 polarization of macrophages, and the supernatant from these polarized macrophages has a protective effect on podocytes. From the perspective of lipid metabolism, the underlying mechanism of this effect may involve the modulation of sphingolipids, arachidonic acid, glycerophospholipids, and other lipid metabolites, which activate the receptor PPARγ, thereby exerting protective effects on podocytes.
研究领域:
药理学
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免疫学
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肾脏病学
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生物化学
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分子生物学
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细胞生物学
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脂质组学
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药物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
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IF 5.811
Liu Tao,Cui Lijuan,Xue Huan,Yang Xiaohua,Liu Mengmeng,Zhi Linping,Yang Huanhuan,Liu Zhihong,Zhang Min,Guo Qing,He Peifeng,Liu Yunfeng,Zhang Yi
Angiotensin II type 1 (AT1) receptor blockers (ARBs), as antihypertensive drugs, have drawn attention for their benefits to individuals with diabetes and prediabetes. However, the direct effects of ARBs on insulin secretion remain unclear. In this study, we aimed to investigate the insulinotropic effect of ARBs and the underlying electrophysiological mechanism. We found that only telmisartan among the three ARBs (telmisartan, valsartan, and irbesartan) exhibited an insulin secretagogue role in rat islets. Independent of AT1 receptor and peroxisome proliferator-activated receptor γ (PPARγ), telmisartan exerted effects on ion channels including voltage-dependent potassium (Kv) channels and L-type voltage-gated calcium channels (VGCCs) to promote extracellular Ca2+ influx, thereby potentiating insulin secretion in a glucose-dependent manner. Furthermore, we identified that telmisartan directly inhibited Kv2.1 channel on a Chinese hamster ovary cell line with Kv2.1 channel overexpression. Acute exposure of db/db mice to a telmisartan dose equivalent to therapeutic doses in humans resulted in lower blood glucose and increased plasma insulin concentration in OGTT. We further observed the telmisartan-induced insulinotropic and electrophysiological effects on pathological pancreatic islets or β-cells isolated from db/db mice. Collectively, our results establish an important insulinotropic function of telmisartan distinct from other ARBs in the treatment of diabetes.
研究领域:
药理学
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内分泌学
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糖尿病
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电生理学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Pan Su,Liming Liu,Yuhang Gong,Shuaijun Peng,Xiangli Yan,Ming Bai,Erping Xu,Yucheng Li
Background The pathogenesis of depression is largely influenced by dyshomeostasis of neuroinflammation regulated by microglia M1/M2 polarization, and NLRP3 inflammasome acts critical roles in shifting microglia polarization. Kaempferol (Kae), a major flavonoid in edible plants, possesses anti-inflammation and anti-depression capacity, but its underlying cellular and molecular mechanisms of antidepressive effect have not yet fully explored. Methods In vivo studies with lipopolysaccharide (LPS)-induced depressive mice were carried out to evaluate antidepressant effect of Kae. In vitro, BV2 microglia cell line stimulated by LPS along with IFN-γ to detect pharmacological effects of Kae on microglia polarization and NLRP3. Based on two depression-related GEO datasets (GSE54570 and GSE54568) and the potential targets of Kae obtained from GeneCards database, enrichment analysis and protein–protein interaction (PPI) network construction reveal potential therapeutic targets of Kae for depression. Then the precise antidepressant mechanisms of Kae were verified by western blot and immunofluorescent staining in vivo and vitro . Results Our results showed that Kae significantly improves LPS-induced depressive behaviors and alleviates neuroinflammation in prefrontal cortex. Moreover, Kae obviously shifted microglia polarization to M2 phenotype, and also suppressed NLRP3 in prefrontal cortex and BV2. Enrichment analysis and PPI network construction suggested PPARγ and STAT1 signaling are related to regulation of NLRP3 in depression. Furtherly, Kae remarkably enhanced PPARγ activation and inhibited nuclear translocation of p-STAT1 in microglia of prefrontal cortex and BV2. Importantly, pre-incubation with PPARγ antagonist T0070907 or overexpression with CA STAT1 (constitutively active STAT1) both prevented pharmacologic effects of Kae on shifting microglia polarization and suppressing NLRP3 in BV2. Noteworthily, T0070907 significantly blocked the inhibitory effect of Kae on STAT1 while overexpression with CA STAT1 abolished the effect of Kae on PPARγ activation in BV2. Above results suggested that pharmacologic effects of Kae on microglia polarization and NLRP3 are dependent on the balance of counter-regulatory PPARγ and STAT1 signaling. Conclusion Our results indicated that the shifting microglia polarization and suppression of NLRP3 via tilting the balance of PPARγ and STAT1 signaling may be the antidepressant mechanism of Kae, which provides a novel perspective for elucidating antidepressive effect of Kae.
研究领域:
药理学
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神经科学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF NEUROSCIENCE
·
2022
·Vol. 56
·期 3
·4045-4059
·
IF 3.698
Huqing Wang,Ming Chen,Tao Zhang,Zhen Gao,Yu Gong,Xiaorui Yu,Haiqin Wu
In vitro cell experiments have suggested that recombinant human erythropoietin (rhEPO) and peroxisome proliferator activated receptor γ (PPARγ) activation exert protective effects on neurons. This study observed the learning and memory ability, antioxidant capacity and the ratio of apoptotic cells after rhEPO intervention and investigated the relationship among rhEPO, PI3K/Akt and PPARγ in the anti-neural oxidative stress injury process in vivo. The results showed that rhEPO significantly improved the learning and memory abilities of rats subjected to oxidative stress, enhanced the antioxidant capacity of cells, and reduced neuronal apoptosis. Then, the PI3K/Akt and PPARγ pathways were inhibited, and TUNEL staining were used to observe the changes in the effect of rhEPO. After the PI3K/Akt and PPARγ pathways were inhibited, the effect of rhEPO on rats subjected to oxidative stress was significantly weakened, suggesting that both the PI3K/Akt and PPARγ pathways are involved in the process by which rhEPO protects neurons. Finally, Western blotting and immunofluorescence staining were used to observe the changes in PI3K/Akt and PPARγ signalling proteins in the neurons after the rhEPO intervention and to explore the relationship among the three. The results showed that rhEPO significantly increased the levels of the p-Akt and PPARγ proteins and the level of the PPARγ protein in the nucleus, indicating that the PI3K/Akt pathway was located upstream of and regulates PPARγ. In conclusion, this study suggested that rhEPO activates the PI3K/Akt to upregulate PPARγ, enhance the cellular antioxidant capacity, and protect neurons in rats subjected to oxidative stress.
研究领域:
神经科学
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药理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2024
·
IF 6.9
Yuan Nai-jun,Zhu Wen-jun,Ma Qing-yu,Huang Min-yi,Huo Rou-rou,She Kai-jie,Pan Jun-ping,Wang Ji-gang,Chen Jia-xu
Accumulating evidence shows that neuroinflammation substantially contributes to the pathology of depression, a severe psychiatric disease with an increasing prevalence worldwide. Although modulating microglial phenotypes is recognized as a promising therapeutic strategy, effective treatments are still lacking. Previous studies have shown that luteolin (LUT) has anti-inflammatory effects and confers benefits on chronic stress-induced depression. In this study, we investigated the molecular mechanisms by which LUT regulates the functional phenotypes of microglia in mice with depressive-like behaviors. Mice were exposed to chronic restraint stress (CRS) for 7 weeks, and were administered LUT (10, 30, 40 mg· kg −1 ·day −1 , i.g.) in the last 4 weeks. We showed that LUT administration significantly ameliorated depressive-like behaviors and decreased hippocampal inflammation. LUT administration induced pro-inflammatory microglia to undergo anti-inflammatory arginase (Arg)-1 + phenotypic polarization, which was associated with its antidepressant effects. Furthermore, we showed that LUT concentration-dependently increased the expression of PPARγ in LPS + ATP-treated microglia and the hippocampus of CRS-exposed mice, promoting the subsequent inhibition of the NLRP3 inflammasome. Molecular dynamics (MD) simulation and microscale thermophoresis (MST) analysis confirmed a direct interaction between LUT and peroxisome proliferator-activated receptor gamma (PPARγ). By using the PPARγ antagonist GW9662, we demonstrated that LUT-driven protection, both in vivo and in vitro, resulted from targeting PPARγ. First, LUT-induced Arg-1 + microglia were no longer detected when PPARγ was blocked. Next, LUT-mediated inhibition of the NLRP3 inflammasome and downregulation of pro-inflammatory cytokine production were reversed by the inhibition of PPARγ. Finally, the protective effects of LUT, which attenuated the microglial engulfment of synapses and prevented apparent synapse loss in the hippocampus of CRS-exposed mice, were eliminated by blocking PPARγ. In conclusion, this study showed that LUT ameliorates CRS-induced depressive-like behaviors by promoting the Arg-1 + microglial phenotype through a PPARγ-dependent mechanism, thereby alleviating microglial pro-inflammatory responses and reversing microglial phagocytosis-mediated synapse loss.
研究领域:
神经科学
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药理学
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精神病学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）