Immunometabolic modulation of retinal inflammation by CD36 ligand

Abstract In subretinal inflammation, activated mononuclear phagocytes (MP) play a key role in the progression of retinopathies. Little is known about the mechanism involved in the loss of photoreceptors leading to vision impairment. Studying retinal damage induced by photo-oxidative stress, we observed that cluster of differentiation 36 (CD36)-deficient mice featured less subretinal MP accumulation and attenuated photoreceptor degeneration. Moreover, treatment with a CD36-selective azapeptide ligand (MPE-001) reduced subretinal activated MP accumulation in wild type mice and preserved photoreceptor layers and function as assessed by electroretinography in a CD36-dependent manner. The azapeptide modulated the transcriptome of subretinal activated MP by reducing pro-inflammatory markers. In isolated MP, MPE-001 induced dissociation of the CD36-Toll-like receptor 2 (TLR2) oligomeric complex, decreasing nuclear factor-kappa B (NF-κB) and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. In addition, MPE-001 caused an aerobic metabolic shift in activated MP, involving peroxisome proliferator-activated receptor-γ (PPAR-γ) activation, which in turn mitigated inflammation. Accordingly, PPAR-γ inhibition blocked the cytoprotective effect of MPE-001 on photoreceptor apoptosis elicited by activated MP. By altering activated MP metabolism, MPE-001 decreased immune responses to alleviate subsequent inflammation-dependent neuronal injury characteristic of various vision-threatening retinal disorders.

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Andrographis paniculata and Its Main Bioactive Ingredient Andrographolide Decrease Alcohol Drinking and Seeking in Rats Through Activation of Nuclear PPARγ Pathway

Alcohol and Alcoholism ◽

10.1093/alcalc/agaa136 ◽

2021 ◽

Author(s):

Serena Stopponi ◽

Yannick Fotio ◽

Carlo Cifani ◽

Hongwu Li ◽

Carolina L Haass-Koffler ◽

...

Keyword(s):

Oral Administration ◽

Alcohol Drinking ◽

Andrographis Paniculata ◽

Peroxisome Proliferator ◽

Herbaceous Plant ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Treatment Administration ◽

Dried Extract

Abstract Background and aims Andrographis paniculata is an annual herbaceous plant which belongs to the Acanthaceae family. Extracts from this plant have shown hepatoprotective, anti-inflammatory and antidiabetic properties, at least in part, through activation of the nuclear receptor Peroxisome Proliferator-Activated Receptor-gamma (PPAR γ). Recent evidence has demonstrated that activation of PPARγ reduces alcohol drinking and seeking in Marchigian Sardinian (msP) alcohol-preferring rats. Methods The present study evaluated whether A. paniculata reduces alcohol drinking and relapse in msP rats by activating PPARγ. Results Oral administration of an A. paniculata dried extract (0, 15, 150 mg/kg) lowered voluntary alcohol consumption in a dose-dependent manner and achieved ~65% reduction at the dose of 450 mg/kg. Water and food consumption were not affected by the treatment. Administration of Andrographolide (5 and 10 mg/kg), the main active component of A. paniculata, also reduced alcohol drinking. This effect was suppressed by the selective PPARγ antagonist GW9662. Subsequently, we showed that oral administration of A. paniculata (0, 150, 450 mg/kg) prevented yohimbine- but not cues-induced reinstatement of alcohol seeking. Conclusions Results point to A. paniculata-mediated PPARγactivation as a possible therapeutic strategy to treat alcohol use disorder.

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Novel Function of α-Cubebenoate Derived from Schisandra chinensis as Lipogenesis Inhibitor, Lipolysis Stimulator and Inflammasome Suppressor

Molecules ◽

10.3390/molecules25214995 ◽

2020 ◽

Vol 25 (21) ◽

pp. 4995

Author(s):

Su Ji Bae ◽

Ji Eun Kim ◽

Yun Ju Choi ◽

Su Jin Lee ◽

Jeong Eun Gong ◽

...

Keyword(s):

Fatty Acid ◽

Binding Protein ◽

Fatty Acid Synthetase ◽

Inflammasome Activation ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Schisandra Chinensis ◽

Peroxisome Proliferator Activated Receptor ◽

Fatty Acid Binding ◽

Ppar Γ

The efficacy of α-cubebenoate isolated from Schisandra chinensis has been previously studied in three disease areas, namely inflammation, sepsis, and allergy, and its role in other diseases is still being explored. To identify the novel function of α-cubebenoate on lipid metabolism and related inflammatory response, alterations in fat accumulation, lipogenesis, lipolysis, and inflammasome activation were measured in 3T3-L1 preadipocytes and primary adipocytes treated with α-cubebenoate. Lipid accumulation significantly decreased in MDI (3-isobutyl-1-methylxanthine, dexamethasone, and insulin)-stimulated 3T3-L1 adipocytes treated with α-cubebenoate without any significant cytotoxicity. The mRNA levels of peroxisome proliferator-activated receptor (PPAR)γ and CCAAT-enhancer binding protein (C/EBP) α for adipogenesis, as well as adipocyte fatty acid binding protein 2 (aP2) and fatty acid synthetase (FAS) for lipogenesis, were reduced after α-cubebenoate treatment, while cell cycle arrest at G2/M stage was restored in the same group. α-cubebenoate treatment induced glycerol release in primary adipocytes and enhanced expression of lipolytic proteins (HSL, perilipin, and ATGL) expression in MDI-stimulated 3T3-L1 adipocytes. Inflammasome activation and downstream cytokines expression were suppressed with α-cubebenoate treatment, but the expression of insulin receptor signaling factors was remarkably increased by α-cubebenoate treatment in MDI-stimulated 3T3-L1 adipocytes. These results indicate that α-cubebenoate may play a novel role as lipogenesis inhibitor, lipolysis stimulator, and inflammasome suppressor in MDI-stimulated 3T3-L1 adipocytes. Our results provide the possibility that α-cubebenoate can be considered as one of the candidates for obesity management.

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Lipopolysaccharide inhibits the expression of resistin in adipocytes

Journal of Molecular Endocrinology ◽

10.1530/jme-13-0117 ◽

2013 ◽

Vol 51 (3) ◽

pp. 287-299 ◽

Cited By ~ 4

Author(s):

Xinxin Xiang ◽

Wenjiao An ◽

Changtao Jiang ◽

Jing Zhao ◽

Xian Wang ◽

...

Keyword(s):

Lipid A ◽

Ex Vivo ◽

Underlying Mechanism ◽

Inhibitory Effect ◽

Pharmacological Intervention ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Resistin Mrna

Resistin is an adipocytokine leading to insulin resistance. Endotoxin/lipopolysaccharide (LPS) has been reported to decrease the expression of resistin mRNA and protein in both lean and db/db obese mice, although the underlying mechanism remains unclear. Several models such as ex vivo culture of adipose tissues, primary rat adipocytes and 3T3-L1 adipocytes were used to further characterize the effect of LPS on the expression of resistin. LPS attenuated both the resistin mRNA and protein in a time- and dose-dependent manner. In the presence of actinomycin D, LPS failed to reduce the half-life of resistin mRNA, suggesting a transcriptional mechanism. The lipid A fraction is crucial for the inhibition of resistin expression induced by LPS. Pharmacological intervention of c-Jun N-terminal kinase (JNK) reversed the inhibitory effect of LPS. LPS down-regulated CCAAT/enhancer-binding protein α (C/EBP-α; CEBPA) and peroxisome proliferator-activated receptor γ (PPAR-γ; PPARG), while activation of C/EBP-α or PPAR-γ by either over-expressing these transcriptional factors or by rosiglitazone, an agonist of PPAR-γ, blocked the inhibitory effect of LPS on resistin. C/EBP homologous protein (CHOP-10; DDIT3) was up-regulated by LPS, while a CHOP-10 antisense oligonucleotide reversed the decrement of resistin protein induced by LPS. Taken together, these results suggest that LPS inhibits resistin expression through a unique signaling pathway involving toll-like receptor 4, JNK, CHOP-10 and C/EBP-α/PPAR-γ.

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Primary chemoprevention of endometrial hyperplasia with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone in the PTEN heterozygote murine model

International Journal of Gynecological Cancer ◽

10.1111/j.1525-1438.2007.01002.x ◽

2008 ◽

Vol 18 (2) ◽

pp. 329-338 ◽

Cited By ~ 10

Author(s):

W. Wu ◽

J. Celestino ◽

M. R. Milam ◽

K. M. Schmeler ◽

R. R. Broaddus ◽

...

Keyword(s):

Cell Lines ◽

Murine Model ◽

Endometrial Hyperplasia ◽

Terminal Deoxynucleotidyl Transferase ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Wild Type ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Dose Dependent

PTEN mutations have been implicated in the development of endometrial hyperplasia and subsequent cancer. Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists have demonstrated antineoplastic and chemopreventive effects. The purpose of this study was to evaluate the effects of the PPAR-γ agonist rosiglitazone on both PTEN wild type and PTEN null cell lines and in the PTEN heterozygote(+/−) murine model. Hec-1-A (PTEN wild type) and Ishikawa (PTEN null) cells were treated with rosiglitazone. Thirty-five female PTEN+/− mice were genotyped and placed into one of four groups for treatment for 18 weeks: A) PTEN wild type with 4 mg/kg rosiglitazone, B) PTEN+/− mice with vehicle, C) PTEN+/− mice with 4 mg/kg rosiglitazone, and D) PTEN+/− mice with 8 mg/kg rosiglitazone. Proliferation and apoptosis were measured by bromodeoxyuridine (BrdU) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling of DNA fragmentation sites assay. Rosiglitazone caused cell growth inhibition in both Hec-1-A and Ishikawa in a dose-dependent manner (P< 0.02 and P< 0.03, respectively). Rosiglitazone also induced apoptosis in both Hec-1-A (P< .001) and Ishikawa (P< .001) cells in a dose-dependent manner. In the murine model, rosiglitazone decreased proliferation of the endometrial hyperplastic lesions (B vs C; 39.7% vs 9.3% and B vs D; 39.7% vs 4.2%; P< 0.0001) and increased apoptosis of glandular endometrial epithelial cells (B vs C; 2.8% vs 22.4%; P< 0.0001 and B vs D; 2.8% vs 30.2%; P= 0.003). PPAR-γ agonist rosiglitazone inhibits proliferation and induces apoptosis in both PTEN intact and PTEN null cancer cell lines and in hyperplastic endometrial lesions in the PTEN+/− murine model.

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Peroxisome Proliferator-Activated Receptor-γ(PPAR-γ) Agonists Attenuate the Profibrotic Response Induced by TGF-β1 in Renal Interstitial Fibroblasts

Mediators of Inflammation ◽

10.1155/2007/62641 ◽

2007 ◽

Vol 2007 ◽

pp. 1-7 ◽

Cited By ~ 29

Author(s):

Weiming Wang ◽

Feng Liu ◽

Nan Chen

Keyword(s):

Protein Expression ◽

Mrna Expression ◽

Kidney Diseases ◽

Smooth Muscle Actin ◽

Tissue Growth ◽

Time Dependent ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ

Background.Studies have shown that peroxisome proliferator-activated receptor-γ(PPAR-γ) agonists could ameliorate renal fibrotic lesions in both diabetic nephropathy and nondiabetic chronic kidney diseases. In order to elucidate the antifibrotic mechanism of PPAR-γagonists, we investigated the effects of PPAR-γactivation on TGF-β1-induced renal interstitial fibroblasts.Methods.In rat renal interstitial fibroblasts (NRK/49F), the mRNA expression of TGF-β1-inducedα-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), fibronectin (FN) and collagen type III (Col III) were observed by reverse transcriptase-polymerase chain reaction (RT-PCR). The protein expressions of FN and Smads were observed by Western blot.Results.In NRK/49F, TGF-β1 enhanced CTGF, FN and Col III mRNA expression in a dose- and time-dependent manner.α-SMA, CTGF, FN and Col III mRNA and FN protein expression in 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2)-troglitazone- and ciglitazone-pretreated groups, respectively, were significantly decreased compared with the TGF-β1-stimulated group. TGF-β1 (5 ng/mL) enhanced p-Smad2/3 protein expression in a time-dependent manner. Compared with the TGF-β1-stimulated group, p-Smad2/3 protein induced by TGF-β1 in PPAR-γagonists-pretreated groups significantly decreased with no statistical difference amongst the three pretreated groups.Conclusion.PPAR-γagonists could inhibit TGF-β1-induced renal fibroblast activation, CTGF expression and ECM synthesis through abrogating the TGF-β1/Smads signaling pathway.

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Transient Expression of Interferon-Inducible p204 in the Early Stage Is Required for Adipogenesis in 3T3-L1 Cells

Endocrinology ◽

10.1210/en.2009-1381 ◽

2010 ◽

Vol 151 (7) ◽

pp. 3141-3153 ◽

Cited By ~ 16

Author(s):

Jing Xiao ◽

Bing Sun ◽

Guo-ping Cai

Keyword(s):

Transient Expression ◽

Adipocyte Differentiation ◽

Early Stage ◽

Expression Patterns ◽

Immunofluorescence Assay ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Irreversible Damage ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ

A member of the interferon-inducible p200 family of proteins, p204, has recently been reported to function in the development of many mesoderm-derived tissues, such as bone, muscle, and cartilage. However, no published study has yet investigated the role of p204 in adipogenesis. Our preliminary experiments showed that p204 can be found in 3T3-L1 preadipocytes, and its expression was up-regulated in a differentiation-dependent manner. As such, we hypothesized that p204 is associated with adipogenesis and focused on the influence of p204 on adipogenesis. In the present study, we investigated the transient elevated expression and cytoplasm-to-nucleus translocation of p204 in the early stage of adipogenesis. To determine the effect of p204 on adipogenesis, p204-siRNA and expression vector were produced for p204 suppression and overexpression, respectively. The knockdown of p204 resulted in a significantly depressed adipocyte differentiation, whereas p204 overexpression promoted adipocyte differentiation. The mRNA expression of adipogenic markers, such as peroxisome-proliferator-activated receptor (PPAR)γ, CCAAT/enhancer-binding-protein (C/EBP)α, lipoprotein lipase, and adipsin, was decreased by p204 suppression and increased by p204 overexpression. A coimmunoprecipitation assay coupled with an indirect immunofluorescence assay also indicated that p204 interacted and colocalized with C/EBPδ in the nucleus. Furthermore, the knockdown of p204 disrupted the interaction between p204 and C/EBPδ and partially suppressed the PPARγ transcriptional activity by dissociating C/EBPδ with the PPARγ promoter element. Collectively, our data indicate that the transient expression of p204 in the early stage is indispensable for adipocyte differentiation. Disruption of p204 expression patterns at this stage leads to irreversible damage in fat formation.

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CBD Promotes Oral Ulcer Healing via Inhibiting CMPK2-Mediated Inflammasome

Journal of Dental Research ◽

10.1177/00220345211024528 ◽

2021 ◽

pp. 002203452110245

Author(s):

X. Qi ◽

W. Lin ◽

Y. Wu ◽

Q. Li ◽

X. Zhou ◽

...

Keyword(s):

Ulcer Healing ◽

Nlrp3 Inflammasome ◽

Therapeutic Potential ◽

Inflammatory Lesion ◽

Oral Ulcer ◽

Inflammasome Activation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Oral Ulcers ◽

Pyrin Domain

Oral ulcer is a common oral inflammatory lesion accompanied by severe pain but with few effective treatments. Cannabidiol (CBD) is recently emerging for its therapeutic potential in a range of diseases, including inflammatory conditions and cancers. Here we show that CBD oral spray on acid- or trauma-induced oral ulcers on mice tongue inhibits inflammation, relieves pain, and accelerates lesion closure. Notably, the enrichment of genes associated with the NOD, LRR, and NLRP3 pyrin domain–containing protein 3 (NLRP3) inflammasome pathway is downregulated after CBD treatment. The expression of cleaved-gasdermin D (GSDMD) and the percentage of pyroptotic cells are reduced as well. In addition, CBD decreases the expression of cytidine/uridine monophosphate kinase 2 (CMPK2), which subsequently inhibits the generation of oxidized mitochondria DNA and suppresses inflammasome activation. These immunomodulating effects of CBD are mostly blocked by peroxisome proliferator activated receptor γ (PPARγ) antagonist and partially antagonized by CB1 receptor antagonist. Our results demonstrate that CBD accelerates oral ulcer healing by inhibiting CMPK2-mediated NLRP3 inflammasome activation and pyroptosis, which are mediated mostly by PPARγ in the nucleus and partially by CB1 in the plasma membrane.

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PPAR-γ agonist rosiglitazone ameliorates peritoneal deterioration in peritoneal dialysis rats with LPS-induced peritonitis through up-regulation of AQP-1 and ZO-1

Bioscience Reports ◽

10.1042/bsr20180009 ◽

2018 ◽

Vol 38 (3) ◽

Cited By ~ 2

Author(s):

Yunfang Zhang ◽

Junxia Feng ◽

Qi Wang ◽

Shili Zhao ◽

Jiaqi Xu ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Therapeutic Potential ◽

Cell Monolayer ◽

Mesothelial Cell ◽

Structure And Function ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

And Function ◽

Lps Treatment

Peritonitis is still a major cause of the death in peritoneal dialysis (PD) patients despite the significant decline of the peritonitis rates in recent years. The present study is designed to evaluate the therapeutic potential of peroxisome proliferator-activated receptor-γ agonist, rosiglitazone, on the structure and function of the peritoneum in a PD rat accompanied with peritonitis induced by lipopolysaccharide (LPS). Our data showed that the peritoneal membrane in the LPS-only group showed increased peritoneal thickness, vessel density, and hypercellularity compared with the PD-only group. Rosiglitazone administration significantly inhibited increase of the three indicators in PD rats with LPS treatment. In line with this, rosiglitazone improved function of the peritoneum in LPS-induced PD rats receiving rosiglitazone, which was reflected by decreased D/P urea and D/P albumin. Mechanistically, rosiglitazone-mediated improvements in the damaged structure and function of the peritoneum in PD rats with LPS treatment were associated with reduced inflammation and preserving mesothelial cell monolayer resulted from up-regulation of AQP-1 and ZO-1. Our findings thus suggest that peroxisome proliferator-activated receptor γ (PPAR-γ) activation might be a reasonable strategy to prevent and ameliorate peritoneal deterioration in PD patients, especially with peritonitis.

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