Gabapentin Reduces Alcohol Intake in Rats by Regulating NF-κB Signaling Pathway Via PPAR γ

2021 ◽  
Author(s):  
Jing Li ◽  
Kewei Xu ◽  
Hao Ding ◽  
Qiaozhen Xi
Keyword(s):  
Locomotor Activity ◽  
Signaling Pathway ◽  
Specific Inhibitor ◽  
Underlying Mechanism ◽  
Ethanol Consumption ◽  
Diglycidyl Ether ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Tnf Α

Abstract Aims Increasing preclinical and clinical reports have demonstrated the efficacy of gabapentin (GBP) in treating alcohol use disorder (AUD). However, the mechanism of the effects of GBP in AUD is largely unknown. Herein, we sought to investigate the effect of GBP in a rat model of AUD and explore the underlying mechanism. Methods The intermittent access to 20% ethanol in a 2-bottle choice (IA2BC) procedure was exploited to induce high voluntary ethanol consumption in rats. The rats were treated daily for 20 days with different doses of GBP, simultaneously recording ethanol/water intake. The locomotor activity and grooming behavior of rats were also tested to evaluate the potential effects of GBP on confounding motor in rats. The levels of IL-1β and TNF-α in serum and hippocampus homogenate from the rats were detected by using ELISA. The expressions of peroxisome proliferator-activated-receptor γ (PPAR-γ) and nuclear factor-κB (NF-κB) in the hippocampus were determined by immunofluorescence and western blot. Results GBP reduced alcohol consumption, whereas increased water consumption and locomotor activity of rats. GBP was also able to decrease the levels of IL-1β and TNF-α in both serum and hippocampus, in addition to the expression of NF-κB in the hippocampus. Furthermore, these effects attributed to GBP were observed to disappear in the presence of bisphenol A diglycidyl ether (BADGE), a specific inhibitor of PPAR-γ. Conclusions Our findings revealed that GBP could activate PPAR-γ to suppress the NF-κB signaling pathway, contributing to the decrease of ethanol consumption and ethanol-induced neuroimmune responses.

15 Deoxy Δ12,14 PGJ2 Induces Procoagulant Activity in Cultured Human Endothelial Cells

2002 ◽  
Vol 87 (03) ◽  
pp. 523-529 ◽  
Author(s):  
Shaoping Xie ◽  
David O’Regan ◽  
Vijay Kakkar ◽  
Michael Scully
Keyword(s):  
Endothelial Cells ◽  
Peroxisome Proliferator ◽  
Endothelial Protein C Receptor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Affinity Ligand ◽  
Ppar Γ ◽  
Tnf Α ◽  
Ea.Hy926 Cells ◽  
High Affinity Ligand ◽  
Feedback Regulator

Summary15 deoxy Δ12,14 PGJ2 (15d-PGJ2), a high affinity ligand of peroxisome proliferator-activated receptor γ (PPAR γ has been proposed to act as a negative feedback regulator of the inflammatory response. We investigated the effect of 15d-PGJ2 on the anticoagulant property of endothelial cells. 15d-PGJ2 stimulated a moderate but sustained increase in tissue factor (TF) activity in HUVECs and EA.hy926 cells while causing a partial loss of thrombomodulin (TM) activity. When cells were co-treated with 15d-PGJ2 and TNF-α, the subsequent elevation of TF activity was synergistically increased over that of cells treated with TNF-α, alone and the decline of TF activity after 24 h was less marked than TNF-α, alone. The induction of TF by 15d-PGJ2 alone and in combination with TNF-α, was reduced in the presence of PD 98059, suggesting the participation of the MEK/ERK pathway. The thiazolidinedione PPAR γ agonist ciglitazone had no effect on TF levels but reduced the expression of endothelial protein C receptor. The ability of 15d-PGJ2 to enhance a procoagulant phenotype arising from TNF-α, suggests a pro-inflammatory role for the prostaglandin.

scholarly journals Apple Flavonols Mitigate Adipocyte Inflammation and Promote Angiogenic Factors in LPS- and Cobalt Chloride-Stimulated Adipocytes, in Part by a Peroxisome Proliferator-Activated Receptor-γ-Dependent Mechanism

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1386 ◽  
Author(s):  
Danyelle M. Liddle ◽  
Meaghan E. Kavanagh ◽  
Amanda J. Wright ◽  
Lindsay E. Robinson
Keyword(s):  
Mrna Expression ◽  
Cobalt Chloride ◽  
Nuclear Factor Κb ◽  
Diglycidyl Ether ◽  
Low Grade ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Anti Inflammatory

Adipose tissue (AT) expansion induces local hypoxia, a key contributor to the chronic low-grade inflammation that drives obesity-associated disease. Apple flavonols phloretin (PT) and phlorizin (PZ) are suggested anti-inflammatory molecules but their effectiveness in obese AT is inadequately understood. Using in vitro models designed to reproduce the obese AT microenvironment, 3T3-L1 adipocytes were cultured for 24 h with PT or PZ (100 μM) concurrent with the inflammatory stimulus lipopolysaccharide (LPS; 10 ng/mL) and/or the hypoxia mimetic cobalt chloride (CoCl2; 100 μM). Within each condition, PT was more potent than PZ and its effects were partially mediated by peroxisome proliferator-activated receptor (PPAR)-γ (p < 0.05), as tested using the PPAR-γ antagonist bisphenol A diglycidyl ether (BADGE). In LPS-, CoCl2-, or LPS + CoCl2-stimulated adipocytes, PT reduced mRNA expression and/or secreted protein levels of inflammatory and macrophage chemotactic adipokines, and increased that of anti-inflammatory and angiogenic adipokines, which was consistent with reduced mRNA expression of M1 polarization markers and increased M2 markers in RAW 264.7 macrophages cultured in media collected from LPS + CoCl2-simulated adipocytes (p < 0.05). Further, within LPS + CoCl2-stimulated adipocytes, PT reduced reactive oxygen species accumulation, nuclear factor-κB activation, and apoptotic protein expression (p < 0.05). Overall, apple flavonols attenuate critical aspects of the obese AT phenotype.

scholarly journals Endogenously produced adiponectin protects cardiomyocytes from hypertrophy by a PPARγ-dependent autocrine mechanism

2010 ◽  
Vol 299 (3) ◽  
pp. H690-H698 ◽  
Author(s):  
Rajesh H. Amin ◽  
Suresh T. Mathews ◽  
Adebisi Alli ◽  
Todd Leff
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Receptor Gene ◽  
Peroxisome Proliferator ◽  
Adrenergic Stimulation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Ppar Γ ◽  
Culture Models

In experimental animal and cell culture models, activation of peroxisome proliferator-activated receptor (PPAR) γ in heart has been shown to have beneficial effects on cardiac function and cardiomyocyte physiology. The goal of this study was to identify the signaling pathway by which PPARγ activation protects cardiomyocytes from the deleterious effects of hypertrophic stimuli. In primary cardiomyocyte cultures, we found that genetic or pharmacological activation of PPARγ protected cells from cardiac hypertrophy induced by α-adrenergic stimulation. Examination of gene expression in these cells revealed a surprising increase in the expression of adiponectin in cardiomyocytes and secretion of the high-molecular-weight form of the hormone into media. Using RNAi to block PPARγ-induced adiponectin production or adiponectin receptor gene expression, we found that the PPARγ-mediated anti-hypertrophic effect required cardiomyocyte-produced adiponectin, as well as an intact adiponectin signaling pathway. Furthermore, mice expressing constitutive-active PPARγ and cardiomyocyte specific adiponectin expression were protected from high-fat diet-induced cardiac hypertrophy and remodeling. These findings demonstrate that functional adiponectin hormone can be produced from the heart and raise the possibility that beneficial effects of PPARγ activation in heart could be due in part to local production of adiponectin that acts on cardiomyocytes in an autocrine manner.

Effect of vitamin D on isoprenaline-induced myocardial infarction in rats: possible role of peroxisome proliferator-activated receptor-γ

2017 ◽  
Vol 95 (6) ◽  
pp. 641-646 ◽  
Author(s):  
Ola Ahmed El-Gohary ◽  
Mona Maher Allam
Keyword(s):  
Myocardial Infarction ◽  
Vitamin D ◽  
Diglycidyl Ether ◽  
Peroxisome Proliferator ◽  
Oxidative Stress Biomarkers ◽  
Cardiac Damage ◽  
Necrosis Factor Alpha ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Infarct-like lesion induced by isoprenaline is a well-known model to study myocardial infarction (MI). Vitamin D has been shown to have anti-inflammatory and antioxidant effects. Recent studies highlighted cross talk between vitamin D and peroxisome proliferator-activated receptor gamma (PPAR-γ). The present study was designed to investigate the effect of pretreatment with vitamin D on the isoprenaline-induced infarct-like lesion in rats and the role of PPAR-γ as a novel mechanism in vitamin-D-mediated cardioprotective effect. Markers chosen to assess cardiac damage included serum level of creatine kinase (CK), lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Cardiac contents of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH) were also assessed. Furthermore, ECG monitoring and measurement of injury extension were carried out. Isoprenaline increased the level of cardiac enzymes, as well as inflammatory and oxidative stress biomarkers. In addition, it produced ST-segment elevation. Pretreatment with vitamin D significantly improved previous parameters. The prior treatment with bisphenol A diglycidyl ether (BADGE), a PPAR-γ antagonist, significantly attenuated the protective effect of vitamin D. In conclusion, vitamin D can be demonstrated as a promising cardioprotective agent in MI and PPAR-γ significantly contributes toward vitamin-D-mediated protection.

scholarly journals PPARγ1 attenuates cytosol to membrane translocation of PKCα to desensitize monocytes/macrophages

2007 ◽  
Vol 176 (5) ◽  
pp. 681-694 ◽  
Author(s):  
Andreas von Knethen ◽  
Mathias Soller ◽  
Nico Tzieply ◽  
Andreas Weigert ◽  
Axel M. Johann ◽  
...  
Keyword(s):  
Human Monocyte ◽  
Underlying Mechanism ◽  
Nuclear Factor Κb ◽  
Peroxisome Proliferator ◽  
Membrane Translocation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Protein Interaction ◽  
Tnf Α ◽  
Dependent Inhibition ◽  
Pparγ Agonists

Recently, we provided evidence that PKCα depletion in monocytes/macrophages contributes to cellular desensitization during sepsis. We demonstrate that peroxisome proliferator–activated receptor γ (PPARγ) agonists dose dependently block PKCα depletion in response to the diacylglycerol homologue PMA in RAW 264.7 and human monocyte–derived macrophages. In these cells, we observed PPARγ-dependent inhibition of nuclear factor-κB (NF-κB) activation and TNF-α expression in response to PMA. Elucidating the underlying mechanism, we found PPARγ1 expression not only in the nucleus but also in the cytoplasm. Activation of PPARγ1 wild type, but not an agonist-binding mutant of PPARγ1, attenuated PMA-mediated PKCα cytosol to membrane translocation. Coimmunoprecipitation assays pointed to a protein–protein interaction of PKCα and PPARγ1, which was further substantiated using a mammalian two-hybrid system. Applying PPARγ1 mutation and deletion constructs, we identified the hinge helix 1 domain of PPARγ1 that is responsible for PKCα binding. Therefore, we conclude that PPARγ1-dependent inhibition of PKCα translocation implies a new model of macrophage desensitization.

PPAR-γ ligands modulate effects of LPS in stimulated rat synovial fibroblasts

2002 ◽  
Vol 282 (1) ◽  
pp. C125-C133 ◽  
Author(s):  
Marie-Agnès Simonin ◽  
Karim Bordji ◽  
Sandrine Boyault ◽  
Arnaud Bianchi ◽  
Elvire Gouze ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Constitutive Expression ◽  
Synovial Fibroblasts ◽  
Binding Activity ◽  
Inos Mrna ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Tnf Α ◽  
Cox 2

This work demonstrated the constitutive expression of peroxisome proliferator-activated receptor (PPAR)-γ and PPAR-α in rat synovial fibroblasts at both mRNA and protein levels. A decrease in PPAR-γ expression induced by 10 μg/ml lipopolysaccharide (LPS) was observed, whereas PPAR-α mRNA expression was not modified. 15-Deoxy-Δ12,14-prostaglandin J2(15d-PGJ2) dose-dependently decreased LPS-induced cyclooxygenase (COX)-2 (−80%) and inducible nitric oxide synthase (iNOS) mRNA expression (−80%), whereas troglitazone (10 μM) only inhibited iNOS mRNA expression (−50%). 15d-PGJ2 decreased LPS-induced interleukin (IL)-1β (−25%) and tumor necrosis factor (TNF)-α (−40%) expression. Interestingly, troglitazone strongly decreased TNF-α expression (−50%) but had no significant effect on IL-1β expression. 15d-PGJ2 was able to inhibit DNA-binding activity of both nuclear factor (NF)-κB and AP-1. Troglitazone had no effect on NF-κB activation and was shown to increase LPS-induced AP-1 activation. 15d-PGJ2 and troglitazone modulated the expression of LPS-induced iNOS, COX-2, and proinflammatory cytokines differently. Indeed, troglitazone seems to specifically target TNF-α and iNOS pathways. These results offer new insights in regard to the anti-inflammatory potential of the PPAR-γ ligands and underline different mechanisms of action of 15d-PGJ2 and troglitazone in synovial fibroblasts.

Endotoxin downregulates peroxisome proliferator-activated receptor-γ via the increase in TNF-α release

2008 ◽  
Vol 294 (1) ◽  
pp. R84-R92 ◽  
Author(s):  
Mian Zhou ◽  
Rongqian Wu ◽  
Weifeng Dong ◽  
Asha Jacob ◽  
Ping Wang
Keyword(s):  
Gene Expression ◽  
Neutralizing Antibodies ◽  
Cecal Ligation ◽  
Polymyxin B ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Ppar Γ ◽  
Tnf Α ◽  
A Cell

The nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) is anti-inflammatory in a cell-based system and in animal models of endotoxemia. We have shown that PPAR-γ gene expression is downregulated in macrophages after lipopolysaccharide (LPS) stimulation. However, it remains unknown whether hepatic PPAR-γ is altered in sepsis and, if so, whether LPS directly downregulates PPAR-γ. To study this, rats were subjected to sepsis by cecal ligation and puncture (CLP). Hepatic tissues were harvested at 5, 10, and 20 h after CLP. PPAR-γ gene expression and protein levels were determined by RT-PCR and Western blot analysis, respectively. The results showed that PPAR-γ gene expression decreased at 10 and 20 h and that its proteins levels were reduced at 20 h after CLP. PPAR-γ levels were also decreased in animals that were administered LPS. To determine the direct effects of LPS on PPAR-γ downregulation, LPS binding agent polymyxin B (PMB) was administered intramuscularly after CLP. The administration of PMB significantly reduced plasma levels of endotoxin, but it did not prevent the downregulation of PPAR-γ expression. We found that circulating levels of TNF-α still remained significantly elevated in PMB-treated septic animals. We, therefore, hypothesize that the decrease of PPAR-γ expression is TNF-α dependent. To investigate this, Kupffer cells (KCs) were isolated from normal rats and stimulated with LPS or TNF-α. TNF-α significantly attenuated PPAR-γ gene expression in KCs. Although LPS decreased PPAR-γ in KCs, the downregulatory effect of LPS was blocked by the addition of TNF-α-neutralizing antibodies. Furthermore, the administration of TNF-α-neutralizing antibodies to animals before the onset of sepsis prevented the downregulation of PPAR-γ in sepsis. We, therefore, conclude that LPS downregulates PPAR-γ expression during sepsis via an increase in TNF-α release.

scholarly journals MAR1 suppresses inflammatory response in LPS-induced RAW 264.7 macrophages and human primary peripheral blood mononuclear cells via the SIRT1/PGC-1α/PPAR-γ pathway

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Wei Wang ◽  
Rong-Li Xu ◽  
Ping He ◽  
Rui Chen
Keyword(s):  
Inflammatory Response ◽  
Mononuclear Cells ◽  
Raw 264.7 ◽  
Peroxisome Proliferator ◽  
Peripheral Blood Mononuclear ◽  
Peroxisome Proliferator Activated Receptor ◽  
Raw 264.7 Macrophages ◽  
Ppar Γ ◽  
Tnf Α ◽  
Blood Mononuclear Cells

Abstract Background Sepsis is a complex syndrome characterized by a dysregulated inflammatory response to systemic infection and leads to shock, multiple organ failure and death especially if not recognized early and treated promptly. Previous studies have suggested Maresin 1 (MAR1) can alleviate systemic inflammation in sepsis, but its mechanism has not been clarified. Methods RAW 264.7 cells and human primary peripheral blood mononuclear cells (hPBMCs) were pretreated with LPS and MAR1. The mRNA expression and supernatant levels of pro-inflammatory cytokines, tumor necrosis factor (TNF-α), interleukin (IL)-1β and IL-6 were evaluated by RT-qPCR and ELISA, respectively. The expression levels of Sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and Peroxisome proliferator-activated receptor gamma (PPAR-γ) were determined by RT-qPCR and Western blot analysis, respectively. Results Our results show that LPS-induced inflammation increased the expression and secretion of proinflammatory cytokines TNF-α, IL-1β and IL-6 and induced suppression of SIRT1, PGC-1α, and PPAR-γ expression, which could be reversed by MAR1. And the effect of MAR1 was eliminated by repression of SIRT1/PPAR-γ and enhanced by PGC-1α overexpression. Conclusions MAR1 suppressed inflammatory response in LPS-induced RAW 264.7 macrophages and hPBMCs via the SIRT1/PGC-1α/PPAR-γ pathway.

Suppression of PPAR-γ attenuates insulin-stimulated glucose uptake by affecting both GLUT1 and GLUT4 in 3T3-L1 adipocytes

2007 ◽  
Vol 293 (1) ◽  
pp. E219-E227 ◽  
Author(s):  
Wei Liao ◽  
M. T. Audrey Nguyen ◽  
Takeshi Yoshizaki ◽  
Svetlana Favelyukis ◽  
David Patsouris ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Insulin Signaling ◽  
Adipocyte Differentiation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Tnf Α ◽  
Interfering Rna

Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays a critical role in regulating insulin sensitivity and glucose homeostasis. In this study, we identified highly efficient small interfering RNA (siRNA) sequences and used lentiviral short hairpin RNA and electroporation of siRNAs to deplete PPAR-γ from 3T3-L1 adipocytes to elucidate its role in adipogenesis and insulin signaling. We show that PPAR-γ knockdown prevented adipocyte differentiation but was not required for maintenance of the adipocyte differentiation state after the cells had undergone adipogenesis. We further demonstrate that PPAR-γ suppression reduced insulin-stimulated glucose uptake without affecting the early insulin signaling steps in the adipocytes. Using dual siRNA strategies, we show that this effect of PPAR-γ deletion was mediated by both GLUT4 and GLUT1. Interestingly, PPAR-γ-depleted cells displayed enhanced inflammatory responses to TNF-α stimulation, consistent with a chronic anti-inflammatory effect of endogenous PPAR-γ. In summary, 1) PPAR-γ is essential for the process of adipocyte differentiation but is less necessary for maintenance of the differentiated state, 2) PPAR-γ supports normal insulin-stimulated glucose transport, and 3) endogenous PPAR-γ may play a role in suppression of the inflammatory pathway in 3T3-L1 cells.

Lipopolysaccharide inhibits the expression of resistin in adipocytes

2013 ◽  
Vol 51 (3) ◽  
pp. 287-299 ◽  
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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