No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Emerging roles of PPARS in inflammation and immunity
Abstract
Lipids and lipid metabolism have well-documented regulatory effects on inflammatory processes. Recent work has highlighted the role of the peroxisome proliferator-activated receptors (PPARs)--a subset of the nuclear-hormone-receptor superfamily that are activated by various lipid species--in regulating inflammatory responses. Here, we describe how the PPARs, through their interactions with transcription factors and other cell-signalling systems, have important regulatory roles in innate and adaptive immunity.
... Transcriptomic analysis revealed that IL-37a can regulate a wide range of proinflammatory genes, including cytokines and those involved in various cell signaling pathways, in response to LPS. Additionally, our investigations demonstrated that nuclear IL-37a can induce the expression of PPARγ, a multifaceted nuclear receptor that plays a crucial role in diverse metabolic and inflammatory conditions [48,[64][65][66]. Evidence from animal studies suggests the beneficial effects of PPARγ on LPS-mediated inflammatory A C B D E Fig. 8 PPARγ plays a critical role in FLIL-37a-mediated protection against LPS shock in vivo. ...
... E Schematic representation of the IL-1R8-dependent and -independent pathways mediated by nuclear and cytokine IL-37a conditions [47,67]. PPARγ exerts its inhibitory effects on the response to LPS by interacting with and suppressing the functions of several key proinflammatory transcription factors, such as NF-κB, STAT, NF-AT, and AP1 [47,[64][65][66][67][68]. Furthermore, PPARγ interferes with the activity of various protein kinases, particularly MAPK [49,52,[66][67][68]. ...
... PPARγ exerts its inhibitory effects on the response to LPS by interacting with and suppressing the functions of several key proinflammatory transcription factors, such as NF-κB, STAT, NF-AT, and AP1 [47,[64][65][66][67][68]. Furthermore, PPARγ interferes with the activity of various protein kinases, particularly MAPK [49,52,[66][67][68]. Our in vitro and in vivo results indicate that IL-37a can downregulate the expression of these transcription factors and protein kinase-related inflammatory effects. ...
Cytokine storms are crucial in the development of various inflammatory diseases, including sepsis and autoimmune disorders. The immunosuppressive cytokine INTERLEUKIN (IL)-37 consists of five isoforms (IL-37a-e). We identified IL-37a as a nuclear cytokine for the first time. Compared to IL-37b, IL-37a demonstrated greater efficacy in protecting against Toll-like receptor-induced cytokine hypersecretion and lethal endotoxic shock. The full-length (FL) form of IL-37a and the N-terminal fragment, which is processed by elastase, could translocate into cell nuclei through a distinctive nuclear localization sequence (NLS)/importin nuclear transport pathway. These forms exerted their regulatory effects independent of the IL-1R8 receptor by transcriptionally upregulating the nuclear receptor peroxisome proliferator-activated receptor (PPARγ). This process involved the recruitment of the H3K4 methyltransferase complex WDR5/MLL4/C/EBPβ and H3K4me1/2 to the enhancer/promoter of Pparg. The receptor-independent regulatory pathway of the nuclear IL-37a-PPARγ axis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases, including sepsis.
... Peroxisome proliferator-activated receptors (PPARs) are a group of ligand-binding transcription factors with pivotal action in regulating pleiotropic signaling pathways of energetic metabolism, immune responses and cell proliferation and differentiation [1][2][3][4][5]. The three members-PPARα, PPARβ/δ and PPARγ-structurally belong to the subfamily 1 group C of the nuclear receptor (NR) superfamily, and hence they are alternatively named NR1C1, NR1C2 and NR1C3, respectively. ...
... PPARs have similar amino acid sequences and, as all NR, possess a modular architecture, based on functional domains [9,10]. Thus, they comprise five parts: (A/B) the The ligand-independent repression corresponds to the unliganded state of the PPAR-RXR heterodimer, which makes complexes with corepressor proteins such as the nuclear receptor corepressor 1 (NCOR1) and the silencing mediator of retinoic acid and The modulatory effects of PPARs on various signaling cascades stem from three main mechanisms: (i) the ligand-independent repression, (ii) the ligand-dependent transactivation and (iii) the nontranscriptional ligand-dependent transrepression (reviewed by Daynes and Jones 2002 [3] and Lamas Bervejillo and Ferreira 2019 [15]). ...
... PPARs have similar amino acid sequences and, as all NR, possess a modular architecture, based on functional domains [9,10]. Thus, they comprise five parts: (A/B) the The ligand-independent repression corresponds to the unliganded state of the PPAR-RXR heterodimer, which makes complexes with corepressor proteins such as the nuclear receptor corepressor 1 (NCOR1) and the silencing mediator of retinoic acid and The modulatory effects of PPARs on various signaling cascades stem from three main mechanisms: (i) the ligand-independent repression, (ii) the ligand-dependent transactivation and (iii) the nontranscriptional ligand-dependent transrepression (reviewed by Daynes and Jones 2002 [3] and Lamas Bervejillo and Ferreira 2019 [15]). ...
Peroxisome proliferator-activated receptors (PPARs) are a group of ligand-binding transcription factors with pivotal action in regulating pleiotropic signaling pathways of energetic metabolism, immune responses and cell proliferation and differentiation. A significant body of evidence indicates that the PPARα receptor is an important modulator of plasma lipid and lipoprotein metabolism, with pluripotent effects influencing the lipid and apolipoprotein cargo of both atherogenic and antiatherogenic lipoproteins and their functionality. Clinical evidence supports an important role of PPARα agonists (fibric acid derivatives) in the treatment of hypertriglyceridemia and/or low high-density lipoprotein (HDL) cholesterol levels, although the effects of clinical trials are contradictory and point to a reduction in the risk of nonfatal and fatal myocardial infarction events. In this manuscript, we provide an up-to-date critical review of the existing relevant literature.
... ALOX15-derived metabolites of free polyenoic fatty acids (PUFAs) have previously been identified as PPAR-γ ligands with strong antiproliferative activity [12]. The anti-inflammatory role of such metabolites has been also reported [13]. However, in different cancer types and in various inflammation models, ALOX15 and its PUFA metabolites exhibit dual functionality. ...
... In contrast, in the presence of compound 2, the AA carboxylate group mainly interacts with Trp145 (d(NH-O1) = 2.01 Å), and forms weaker hydrogen bonds with Arg405, Ser410, and His426 ( Figure 5D). Again, the tail of the substrate fatty acid remains located in the same region, regardless of which inhibitor is present in the cavity of monomer A. However, in the presence of compound 1, the AA becomes more extended and its C 13 and H 13proS atoms are farther away from the OH − group. Instead, in the presence of compound 2 in monomer A, AA adopts an L-shaped conformation and now, its C 13 and H 13proS atoms become somewhat closer to the OH − group and the percentage of well-oriented structures is higher (93.38% vs. 87.90%) ...
... Yield: 1.93 g (87.0%). R f = 0. 13 C NMR (75 MHz, peptone medium and 10.0 g/L NaCl. The starting culture (300 mL) was generated by incubation for 12 h at 32 • C and 180 rpm. ...
Mammalian 15-lipoxygenases (ALOX15) are lipid peroxidizing enzymes that exhibit variable functionality in different cancer and inflammation models. The pathophysiological role of linoleic acid- and arachidonic acid-derived ALOX15 metabolites rendered this enzyme a target for pharmacological research. Several indole and imidazole derivatives inhibit the catalytic activity of rabbit ALOX15 in a substrate-specific manner, but the molecular basis for this allosteric inhibition remains unclear. Here, we attempt to define a common pharmacophore, which is critical for this allosteric inhibition. We found that substituted imidazoles induce weaker inhibitory effects when compared with the indole derivatives. In silico docking studies and molecular dynamics simulations using a dimeric allosteric enzyme model, in which the inhibitor occupies the substrate-binding pocket of one monomer, whereas the substrate fatty acid is bound at the catalytic center of another monomer within the ALOX15 dimer, indicated that chemical modification of the core pharmacophore alters the enzyme-inhibitor interactions, inducing a reduced inhibitory potency. In our dimeric ALOX15 model, the structural differences induced by inhibitor binding are translated to the hydrophobic dimerization cluster and affect the structures of enzyme-substrate complexes. These data are of particular importance since substrate-specific inhibition may contribute to elucidation of the putative roles of ALOX15 metabolites derived from different polyunsaturated fatty acids in mammalian pathophysiology.
... PPAR␥ is a member of the peroxisome proliferator-activated receptors (PPARs) family, which consists of three isoforms: PPAR␣, PPAR/δ, and PPAR␥. PPAR␥ functions in a ligand-dependent manner [19,22]. Endogenous polyunsaturated fatty acids (PUFAs) act as the natural ligand of PPAR␥, with a low affinity. ...
... Third, PPAR␥ inhibits the activation of mitogen-activated protein kinase (MAPK), thereby inhibiting downstream transcription factors. Among them, NF-κB is the main target for PPAR␥, which is involved in the expression of numerous inflammatory factors and pro-inflammatory mediators (Fig. 2) [22]. ...
Alzheimer’s disease (AD) is the main cause of dementia in older age. The prevalence of AD is growing worldwide, causing a tremendous burden to societies and families. Due to the complexity of its pathogenesis, the current treatment of AD is not satisfactory, and drugs acting on a single target may not prevent AD progression. This review summarizes the multi-target pharmacological effects of thiazolidinediones (TZDs) on AD. TZDs act as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and long-chain acyl-CoA synthetase family member 4 (ACSL4) inhibitors. TZDs ameliorated neuroinflammation and ferroptosis in preclinical models of AD. Here, we discussed recent findings from clinical trials of pioglitazone in the treatment of AD, ischemic stroke, and atherosclerosis. We also dissected the major limitations in the clinical application of pioglitazone and explained the potential benefit of pioglitazone in AD. We recommend the use of pioglitazone to prevent cognitive decline and lower AD risk in a specific group of patients.
... These data suggest that glucose oxidation might not be involved in Cav-1-mediated Tfh response. PPARα is also recognized to limit in ammatory responses via transcriptional repression 29 . This is achieved by a conserved mechanism that PPARs could form heterodimer with 9-cis-retinoic acid receptor (RXR), which binds to peroxisome proliferator response element (PPRE) at the promoter region of target genes 40 . ...
... Another pivotal function of PPARs is the inhibition of in ammatory gene expression. Notably, the expression levels of PPARα and PPARγ were diverse in naïve and activated, among which PPARγ was mostly studied 29 . Ligand-mediated PPARγ activation could induce T cell apoptosis, inhibit T cell activation, and suppress Th1 cytokines 52 . ...
T follicular helper (Tfh) cells play a central role in humoral autoimmunity, including primary Sjögren’s syndrome (pSS). However, targeting Tfh cells is challenging in clinical management. Previous studies suggested inducible Tcell costimulator (ICOS) directed Tfh cell motility in engaging bystander B cells. Here, we identified a novel function of caveolin-1 (Cav-1) in restraining Tfh cell motility, in which Icos transcription was repressed by peroxisome proliferator-activated receptor alpha (PPARα), unexpectedly, independence of lipid metabolism. In the context of autoimmunity, Cav-1 and PPARα expressions were decreased in CD4+ T cells from pSS patients and mice with experimental SS (ESS), while Cav-1 deficiency significantly exacerbated Tfh cell response and ESS pathology. Importantly, pharmaceutical activation of PPARα with fenofibrate effectively ameliorated ESS in mice with acute or chronic inflammation. These results revealed an unrecognized role of Cav-1/PPARα axis in Tfh cell tolerance, suggesting PPARα as a promising target in the treatment of humoral autoimmunity.
... It is known that the metabolic products of ALA are antiinflammatory and the metabolic products of GLA are pro-inflammatory. However, GLA has been reported to have anti-inflammatory properties by downregulating inflammatory cytokines (Daynes & Jones, 2002). Yadav et al. study evaluated the comparative treatment of rats with ALA and GLA in a model of autism and observed significant reductions in depression, nociception and oxidative stress parameters. ...
... In contrast to ALA, GLA treatment was more effective in NO production and preserved the cerebellum more significantly against neuronal degeneration neuronal loss and favourably prevented microglial activation (Yadav et al., 2017). The stronger protection of GLA may be explained by its ability to be more permeable to cellular membranes (Daynes & Jones, 2002). The neuroprotective effect of ALA and GLA, which can prevent neurodegeneration and alleviate behavioural disorders in ASD, may be attributed to the reduction of inflammation through the oxidantantioxidant system. ...
Background and aims:
Although the exact cause of autism spectrum disorder, which is a neurodevelopmental disorder, is not known, it is thought that environmental factors are also effective in addition to genetic risk factors. Studies are showing an increase in oxidative stress markers and a decrease in some antioxidant enzymes in individuals with autism. This study aims to try to explain the effect of nutritional interventions that reduce oxidative stress on behavioral and gastrointestinal problems in ASD based on a literature review.
Methods:
All relevant studies from 2000 to 2021 were identified through a systematic search in the PubMed and Web of Science databases by using key search terms. A systematic search of the electronic databases resulted in a total of 3235 potential articles, and data were extracted from 24 studies.
Results:
There were nine clinical trials and 15 animal studies. Most studies find statistically significant results for nutritional supplementation compared to placebo ASD symptoms.
Conclusion:
Most studies on the interventions of nutritional supplements that reduce oxidative stress in individuals with ASD have found improving effects on ASD symptoms, and no serious side effects have been observed. However, more interventional studies are needed to determine the precise effects of oxidative stress-reducing nutritional supplementation.
... Reactive oxygen species promote inflammation and vice versa; inflammation aggravates the production of reactive oxygen species, archetypally creating the self-devouring serpent of Ouroboros which leads to the failure of vital function (9)(10)(11). Several transcription regulators that take part in the inflammatory response have much in common with oxidative stress, including RelA (nuclear factor-κB [NF-κB] p65 subunit), IκB (inhibitor factor-κB), PPARs (peroxisome proliferatoractivated receptors), and CREBs (cAMP responsive element binding proteins), which may connect inflammation to oxidative stress (12)(13)(14). RelA and IκB both play a central role in inflammation. The complex of RelA and IκB remains Copyright © 2022, Author(s). ...
... Likewise, oxidative stress stimulates this pathway by inhibiting IκB and leads to inflammation, but indeed, it is now to make use of RelA-induced antioxidants (17). Meanwhile, PPAR-α and PPAR-γ which possess an anti-inflammatory function through inhibiting RelA are suppressed by both inflammation and oxidative stress (12,18,19). Another inhibitor of RelA signaling is CREB1, also known as CREB, which competes with the co-activator of RelA, namely p300/CBP (20). ...
Background: Hepatic ischemia/reperfusion injury is a major problem that can exacerbate complications, particularly in liver transplantations.
Objectives: This study aimed to investigate the cellular mechanisms of ischemia/reperfusion injury and hepatoprotection by curcumin.
Methods: Wistar albino rats were divided into four groups as Control, Sham, I/R, and Cur+I/R. Hepatic ischemia/reperfusion was
induced in I/R and Cur+I/R animals, the latter of which was also given 50 mg/kg/day of curcumin for 14 days. Liver aminotransferases and the transcription regulators of inflammation (RelA, IκB, PPAR-α, PPAR-γ, CREB1) were examined along with the histological examination.
Results: Hepatic ischemia/reperfusion was found to disrupt hepatic microstructure and downregulate PPAR-α, PPAR-γ, and CREB1 transcripts. Curcumin supplementation in hepatic ischemia/reperfusion recovered the structural organization and promoted the hepatocyte regeneration while increasing expressions of PPARs and CREB1. RelA and IκB were found unaltered, possibly due to the crosstalk between targeted transcripts by ischemia/reperfusion and curcumin.
Conclusions: In sum, PPAR-α/γ and CREB1 were involved in hepatic ischemia/reperfusion and, moreover, were detected to be stimulated by curcumin. PPAR and CREB pathways were found to provide a route to hepatoprotection for curcumin supplementation
as evidenced by the microstructural improvement.
... In addition, besides the energetic effect and being a major component of cell membrane, fatty acids and their metabolites also play a key role as substrates in various biochemical pathways, and are known as immune modulators and cell signaling molecules (Lim et al., 2017;Sugihara et al., 2018). It is also known that CLA shows a high similarity with the ligand of peroxisome proliferator-activated receptor gamma (PPARg) (Yuan et al., 2015), which is involved in the transductions of various inflammatory and nutritional signals (Daynes and Jones, 2002). Our previous study indicated that an isomer specific effect of CLA existed in ruminal epithelial cells, with trans-10, cis-12 CLA showing the best anti-inflammatory effect (Yang et al., 2021). ...
... In addition, we also found the addition of trans-10, cis-12 CLA significantly upregulated the protein expression of PPARg in REC when faced with stimulation, which is consist with its high similarity with the PPARg ligand. The significant role of PPARg in the control of inflammatory response has been suggested to largely rely on its ability to suppress the activities of many transcription factors including NF-kB, STAT and AP1 that are involved in the promotion of pro-inflammatory process (Daynes and Jones, 2002). Thus, trans-10, cis-12 CLA supplementation can alleviate the inflammation in REC via regulating PPARg-dependent downregulation of NF-кB signaling. ...
Developing alternatives to antibiotics for prevention of gastrointestinal dysbiosis in early-weaning farmed animals is urgently needed. This study was to explore the potential effects of trans-10, cis-12 conjugated linoleic acid (CLA) on maintaining ruminal homeostasis of young ruminants during the weaning transition period. Thirty neonatal lambs were selected (6 lambs per group) and euthanized for rumen microbial and epithelial analysis. The lambs were weaned at 28 d and experienced the following 5 treatments: euthanized on d 28 as the pre-weaning control (CON0), fed starter feed for 5 (CON5) or 21 (CON21) d, fed starter feed with 1% of CLA supplemented for 5 (CLA5) or 21 (CLA21) d. Results showed that the average daily weight gain and dry matter intake were significantly higher in CLA5 than CON5 group. As compared with the CON5 and CON21 group, the relative abundances of volatile fatty acid (VFA) producing bacteria including Bacteroides, Treponema, Parabacteroides and Anaerovibrio, as well as the concentrations of acetate, butyrate and total VFA were significantly increased in CLA5 and CLA21 group, respectively. Integrating microbial profiling and epithelial transcriptome results showed that 7 downregulated inflammatory signaling-related host genes IL2RA, CXCL9, CD4, CCR4, LTB, SPP1, and BCL2A1 with CLA supplementation were significantly negatively correlated with both VFA concentration and VFA producing bacteria, while 3 (GPX2, SLC27A2 and ALDH3A1) and 2 (GSTM3 and GSTA1) upregulated metabolism-related genes, significantly positively correlated with either VFA concentration or VFA producing bacteria, respectively. To confirm the effects of CLA on epithelial signal transduction, in vitro experiment was further conducted by treating rumen epithelial cells without or with IL-17A + TNF-α for 12 h after pretreatment of 100 μM CLA or not (6 replicates per treatment). The results demonstrated the anti-inflammatory effect of CLA via suppressing the protein expression of NF-кB p-p65/p65 with the activation of peroxisome proliferator-activated receptor gamma (PPARγ). In conclusion, CLA supplementation enhanced the ruminal microbiota-driven transcriptional regulation in healthy rumen epithelial development via rumen VFA production, and CLA may therefore serve as an alternative way to alleviate early-weaning stress and improve physiological and metabolic conditions of young ruminants.
... Inflammation is at the core of many chronic and infectious conditions, including the severity of coronavirus disease 2019 (COVID- 19) infection (1,2). The SARS-CoV-2 virus, responsible for COVID-19, is classified in the β genus of the Coronaviridae family (3). ...
... PEA is also endogenously produced in human tissues and functions as a lipid mediator targeting ion channels, nuclear hormone receptors, and G protein-coupled receptors, with wide-reaching effects on metabolism (17). One of the direct targets for PEA has been identified as nuclear receptor peroxisome proliferator-activated receptor α (PPAR-α), which is expressed in several cells, including immune cells, and supports PEA's ability for use in modulating inflammatory responses (18,19). PEA's interaction with PPAR-α has been shown to mediate its anti-inflammatory effects, and PEA's binding to PPAR-α on immune cells leads to reductions in proinflammatory and pain signals (20). ...
Background
Inflammation is at the core of many chronic conditions and exacerbates infectious conditions, including the severity of coronavirus disease 2019 (COVID-19) infections.
Objectives
This study aimed to examine the effects of a novel food supplement, palmitoylethanolamide (PEA), specifically Levagen+, as compared with a placebo on proinflammatory biomarkers in adults recently diagnosed with COVID-19 who were unvaccinated and nonhospitalized.
Methods
This study was a double-blind randomized placebo-controlled trial conducted October 2020–March 2021 (clinicaltrials.gov: NCT04912921). Participants aged 19–53 y were unvaccinated and recently infected with COVID-19 as indicated by a positive test result per RT-PCR or antigen test, and they reported to the test site following diagnosis as allowed by the CDC's return-to-work policy. Participants were stratified by age, sex, and BMI and randomly assigned by coin toss to receive 600 mg Levagen+ twice daily (LEV) or placebo tablets twice daily (CON) for 4 wk. At baseline and week 4, participants completed health histories, 24-h dietary recalls, anthropometrics, and nonfasting blood sampling. The primary outcomes were the 4-wk change between groups for IL-6, C-reactive protein, ferritin, intercellular adhesion molecule 1, soluble P-selectin (sP-selectin), and neutrophil/lymphocyte ratio. Multiple linear regression models were utilized to assess treatment effects on outcomes, adjusting for covariates.
Results
A total of 60 participants completed the study (LEV: n = 30; CON: n = 30). After 4 wk of supplementation, sP-selectin (β = −11.5; 95% CI: −19.8, −3.15; P = 0.0078), IL-1β (β = −22.9; 95% CI: −42.4, −3.40; P = 0.0222), and IL-2 (β = −1.73; 95% CI: −3.45, −0.065; P = 0.0492) concentrations were significantly reduced in the LEV group compared with the CON group.
Conclusions
Inflammatory mechanisms are crucial to optimal resolution of infectious conditions, yet unchecked secretion of inflammatory mediators can promote the dysregulated immune response implicated in COVID-19 complications. Overall, PEA supplementation produced anti-inflammatory effects in individuals recently diagnosed with COVID-19 who were nonhospitalized.
... Moreover, PEA plays a central role in the modulation of pain and inflammation pathways by the activation of peroxisome proliferator-activated receptoralpha receptor (PPAR-α) [69,70]. In particular, the activation of PPAR-α induced by PEA, through the interaction with transcriptions factors is involved in the reduction in NF-κB activation and pro-inflammatory enzyme synthesis, thus promoting anti-inflammatory and analgesic effects [71,72]. Moreover, the protective effects of PEA in neurodegeneration and neuroinflammation preclinical models of different pathologies are reversed by the pharmacological modulation of PPAR-α with antagonists or its genetic silencing [73][74][75][76]. ...
... The first in vitro study of the mechanism of PEA in AD model from Scuderi et al. in 2011 demonstrated the ability of PEA to reduce Aβ-induced astrocyte activation and proinflammatory molecules and cytokine release in primary rat astrocytes through a PPARα-dependent mechanism [72]. In line with the same observations, a later study of the same authors showed that PEA reduced reactive gliosis and attenuated neuronal damage in rat models of Aβ-induced neurotoxicity, with a mechanism strictly depending on PPAR-α activation [102,103]. ...
Increasing evidence strongly supports the key role of neuroinflammation in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Neuroinflammation may alter synaptic transmission contributing to the progression of neurodegeneration, as largely documented in animal models and in patients’ studies. In the last few years, palmitoylethanolamide (PEA), an endogenous lipid mediator, and its new composite, which is a formulation constituted of PEA and the well-recognized antioxidant flavonoid luteolin (Lut) subjected to an ultra-micronization process (co-ultraPEALut), has been identified as a potential therapeutic agent in different disorders by exerting potential beneficial effects on neurodegeneration and neuroinflammation by modulating synaptic transmission. In this review, we will show the potential therapeutic effects of PEA in animal models and in patients affected by neurodegenerative disorders.
... Activated PPARs regulate the inflammatory response by controlling the expression of several inflammation-related genes. 19 Therefore, we investigated the anti-inflammation activities associated with PPARs. In a previous study, compound 2d acted as a PPARγ partial agonist (K i = 4.3 μM) and a PPARδ antagonist (K i = 1.0 μM). ...
Inflammatory responses are fundamental protective warning mechanisms. However, in certain instances, they contribute significantly to the development of several chronic diseases such as cancer. Based on previous studies of truncated 1′-homologated adenosine derivatives, l-nucleosides and their nucleobase-modified quinolone analogues were designed, synthesized, and evaluated for anti-inflammatory activities. The target molecules were synthesized via the key intramolecular cyclization of monotosylate and Mitsunobu condensation from the natural product, d-ribose. All compounds tested and showed potent anti-inflammatory activities, as indicated by their inhibition of LPS-induced IL-1β secretion from the RAW 264.7 macrophages. Gene expressions of pro-inflammatory cytokines showed that all compounds, except 3a and 3b, significantly reduced LPS-induced IL-1β and IL-6 mRNA expressions. The half-maximal inhibitory concentrations (IC50) of 2g and 2h against IL-1β were 1.08 and 2.28 μM, respectively. In contrast, only 2d, 2g, and 3d effectively reversed LPS-induced TNFα mRNA expression. Our mechanistic study revealed that LPS-induced phosphorylation of NF-κB was significantly downregulated by all compounds tested, providing evidence that the NF-κB signaling pathway is involved in their anti-inflammatory activities. Among the compounds tested, 2g and 2h had the most potent anti-inflammatory effects, as shown by the extent of decrease in pro-inflammatory gene expression, protein secretion, and NF-κB phosphorylation. These findings suggest that the l-truncated 1′-homologated adenosine skeleton and its nucleobase-modified analogues have therapeutic potential as treatments for various human diseases by mediating inflammatory processes.
... In addition to their role in metabolic regulation, PPARs also contribute to the inactivation of proinflammatory genes. Ligand-dependent transrepression appears to be the predominant mechanism by which PPARγ promotes anti-inflammatory effects by antagonizing NF-κB activation through the stabilization of a co-repressor complex [68][69][70][71][72]. The relevance of this mechanism in the context of AD is supported by the fact that PPARγ agonists limit neuroinflammation in AD cell culture and mouse models Fig. 8 Increased NOS2 immunoreactivity in astrocytes expressing high FABP7 levels. ...
Alzheimer's disease (AD), the most common cause of dementia in the elderly, is characterized by the accumulation of intracellular neurofibrillary tangles, extracellular amyloid plaques, and neuroinflammation. In partnership with microglial cells, astrocytes are key players in the regulation of neuroinflammation. Fatty acid binding protein 7 (FABP7) belongs to a family of conserved proteins that regulate lipid metabolism, energy homeostasis, and inflammation. FABP7 expression is largely restricted to astrocytes and radial glia-like cells in the adult central nervous system. We observed that treatment of primary hippocampal astrocyte cultures with amyloid β fragment 25-35 (Aβ25-35) induces FABP7 upregulation. In addition, FABP7 expression is upregulated in the brain of APP/PS1 mice, a widely used AD mouse model. Co-immunostaining with specific astrocyte markers revealed increased FABP7 expression in astrocytes. Moreover, astrocytes surrounding amyloid plaques displayed increased FABP7 staining when compared to non-plaque-associated astrocytes. A similar result was obtained in the brain of AD patients. Whole transcriptome RNA sequencing analysis of human astrocytes differentiated from induced pluripotent stem cells (i-astrocytes) overexpressing FABP7 identified 500 transcripts with at least a 2-fold change in expression. Gene Ontology enrichment analysis identified (i) positive regulation of cytokine production and (ii) inflammatory response as the top two statistically significant overrepresented biological processes. We confirmed that wild-type FABP7 overexpression induces an NF-κB-driven inflammatory response in human i-astrocytes. On the other hand, the expression of a ligand-binding impaired mutant FABP7 did not induce NF-κB activation. Together, our results suggest that the upregulation of FABP7 in astrocytes could contribute to the neuroinflammation observed in AD.
... Among PPAR family, Pparα, a well-known fatty acid modulator, regulates the T cell immune responses, including the onset of T cell-mediated autoimmune diseases in a gender-specific manner 24,28,29 . Additionally, the role of Pparα has been suggested as an anti-inflammatory mediator in several immune cell types 24,[30][31][32][33] . ...
The helper CD4⁺ T cell-type 17 (Th17) cells and regulatory CD4⁺ T cells (Tregs) are balanced through numerous molecular regulators, particularly metabolic factors, and their alteration causes immune dysregulation. Herein, we report that peroxisome proliferator of activated receptor-alpha (Pparα), a lipid metabolism regulator, suppresses Th17 differentiation. We demonstrated that Pparα ablation improves Th17 and pro-Th17 factor HIF-1α by enhancing the expression and nuclear localization of NFκB-activator IκB kinase-alpha (IKKα). Unexpectedly, we found that IKKα directly interacts with RORγt and enhances the expression of Il17a gene. Meanwhile, IKKα also interacts with Foxp3, leading to the post-translational regulation of Foxp3 by elevating its proteasomal degradation, and influencing Th17 development. Pparα deficiency leads to enhanced Th17 development in vivo and is associated with enhanced pathology in a murine experimental autoimmune encephalomyelitis (EAE) model. Overall, our data indicate that Pparα may serve as a potential therapeutic target for autoimmune and inflammatory diseases.
... Saturated fatty acids have a stimulatory effect on peroxisome proliferator-activated receptors (PPARs) nuclear receptors. [20] PPARs induce mast cell degranulation via immunoglobulin E (IgE) and stimulate allergic asthma by regulating eosinophils, dendritic cells, and epithelial cells. [21][22][23][24][25] ...
Nutrition plays an important role in maintaining a healthy life with a better lifespan. A balanced diet is very important to maintain good health as illustrated in yoga. Pathya and Apathya Ahara (diet) is an important part of almost every treatment of various lifestyle diseases including Asthma. Ayurveda also believes that a proper diet for a particular disease is as effective as medicine. According to the principles of Yoga, the essence of food forms the mind. A healthy diet is essential for a healthy mind and body. However, diet plays an important role in yoga perfection and success. The yoga diet brings peace and spiritual development. Hence, in this article, we discuss the diet required for an asthmatic following the principles illustrated in yoga literature such as Hathayoga Padipika, Gheranda Samhita, and Shrimad Bhagavadgita.
... The regulation of apolipoprotein E and activation of peroxisome proliferated activated receptor (PPAR) by phytosterols along with reduction in interleukins like IL-18 seems to be responsible for its antiinflammatory effects [9] . PPAR regulates inflammation by monitoring the expression of genes involved in inflammation [10] . Phytosterol activates PPAR and thus regulates inflammation. ...
In this article the beneficial effect of phytosterols in the management of neurodegenerative disorders have been discussed with respect to anti-inflammatory effect and antioxidant effect of phytosterols. Regarding the anti-inflammatory effect of phytosterols it is found that they regulate Apolipoprotein-E which activates microglia and regulate PPAR which in turn is necessary for synthesis of interleukins. Phytosterolsexhibit antioxidant effect by eliminating reactive oxygen species (ROS) and multiplying enzymatic antioxidants. A special mention about how phytosterols are useful in Alzeimer's disease has been discussed in this article. Phytosterols inhibit Phytosterols and its neuroprotective effect-an updated review Section A-Research paper 7817 Eur. Chem. Bull. 2023, 12(Special Issue 4), 7816-7832 the formation of amyloid-beta as it arrests the cleavage of amyloid precursor protein (APP) by β-Secretase and prevent the formation of toxic oligomers. Thus this review is a consolidated collection of information regarding the therapeuticpotencies of phytosterols in the area of neurodegenerative disorders.
... Although A/J and B10.A clustered genes in similar categories when using the immune system process GO database, the BMDCs in PCM-resistant mice (A/J) are probably mounting a more controlled and precise response, up-regulating monocyte's and neutrophil's recruitment, apoptotic process, cell killing, response to interferon-beta, and type I interferon and cytokine production. In comparison, PCM-susceptible mice (B10.A) induces an inadequate and disproportionate response by direct or indirectly downregulating several catabolic processes, essential for lysosomal function, and possibly to antigen presentation and the PPAR pathway, important in the modulation of inflammatory processes [70,71], while upregulating macrophage migration but not neutrophil or monocyte recruitment. ...
Most people infected with the fungus Paracoccidioides spp. do not get sick, but approximately 5% develop paracoccidioidomycosis. Understanding how host immunity determinants influence disease development could lead to novel preventative or therapeutic strategies; hence, we used two mouse strains that are resistant (A/J) or susceptible (B10.A) to P. brasiliensis to study how dendritic cells (DCs) respond to the infection. RNA sequencing analysis showed that the susceptible strain DCs remodeled their transcriptomes much more intensely than those from the resistant strain, agreeing with a previous model of more intense innate immunity response in the susceptible strain. Contrastingly, these cells also repress genes/processes involved in antigen processing and presentation, such as lysosomal activity and autophagy. After the interaction with P. brasiliensis, both DCs and macrophages from the susceptible mouse reduced the autophagy marker LC3-II recruitment to the fungal phagosome compared to the resistant strain cells, confirming this pathway's repression. These results suggest that impairment in antigen processing and presentation processes might be partially responsible for the inefficient activation of the adaptive immune response in this model.
... Although A/J and B10.A clustered genes in similar categories when using the immune system process GO database, the BMDCs in PCM-resistant mice (A/J) are probably mounting a more controlled and precise response, up-regulating monocyte's and neutrophil's recruitment, apoptotic process, cell killing, response to interferon-beta, and type I interferon and cytokine production. In comparison, PCM-susceptible mice (B10.A) induces an inadequate and disproportionate response by direct or indirectly downregulating several catabolic processes, essential for lysosomal function, and possibly to antigen presentation and the PPAR pathway, important in the modulation of inflammatory processes [70,71], while upregulating macrophage migration but not neutrophil or monocyte recruitment. ...
... Tissue distribution patterns and expression levels are the main differences between the three isoforms, displaying regulatory activities and modulating specific responses [2]. PPARα is expressed predominantly in skeletal muscle, heart, liver, and brown adipose tissue, all of them are high-energyrequiring tissues. ...
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of lipids and glucose metabolism, and immune response. Therefore, they have been considered pharmacological targets for treating metabolic diseases, such as dyslipidemia, atherosclerosis, and non-alcoholic fatty liver disease. However, the available synthetic ligands of PPARs have mild to significant side effects, generating the necessity to identify new molecules that are selective PPAR ligands with specific biological responses. This study aimed to evaluate some components of the atheroprotective and hepatoprotective HB-ATV-8 nanoparticles [the amphipathic peptide Helix-Y12, thermozeaxanthin, thermozeaxanthin-13, thermozeaxanthin-15, and a set of glycolipids], as possible ligands of PPARs through blind molecular docking. According to the change in free energy upon protein–ligand binding, ∆Gb, thermozeaxanthins show a more favorable interaction with PPARs, followed by Helix-Y12. Moreover, Helix-Y12 interacts with most parts of the Y-shaped ligand-binding domain (LBD), surrounding helix 3 of PPARs, and reaching helix 12 of PPARα and PPARγ. As previously reported for other ligands, Tyr314 and Tyr464 of PPARα interact with Helix-Y12 through hydrogen bonds. Several PPARα’s amino acids are involved in the ligand binding by hydrophobic interactions. Furthermore, we identified additional PPARs’ amino acids interacting with Helix-Y12 through hydrogen bonds still not reported for known ligands. Our results show that, from the studied ligand set, the Helix-Y12 peptide and Tzeaxs have the most significant probability of binding to the PPARs’ LBD, suggesting novel ligands for PPARs.
... This action leads to a reduction in oxidative stress and involves the Wnt/b-catenin pathway [63,64]. The activation of PPARc in AD results in the induction of anti-inflammatory responses [65]. Through the activation of PPARc, CBD can promote neuronal lifespan by inhibiting the process of apoptosis and lowering the levels of amyloid precursor protein [66]. ...
Cannabidiol (CBD), a nonpsychotropic phytocannabinoid that was once largely disregarded, is currently the subject of significant medicinal study. CBD is found in Cannabis sativa, and has a myriad of neuropharmacological impacts on the central nervous system, including the capacity to reduce neuroinflammation, protein misfolding and oxidative stress. On the other hand, it is well established that CBD generates its biological effects without exerting a large amount of intrinsic activity upon cannabinoid receptors. Because of this, CBD does not produce undesirable psychotropic effects that are typical of marijuana derivatives. Nonetheless, CBD displays the exceptional potential to become a supplementary medicine in various neurological diseases. Currently, many clinical trials are being conducted to investigate this possibility. This review focuses on the therapeutic effects of CBD in managing neurological disorders like Alzheimer’s disease, Parkinson’s disease and epilepsy. Overall, this review aims to build a stronger understanding of CBD and provide guidance for future fundamental scientific and clinical investigations, opening a new therapeutic window for neuroprotection.
... PPAR agonists have been reported to block the development of fibrosis in the liver, heart, kidneys, and lungs [16,17]. Furthermore, several studies have reported the antiinflammatory action of peroxisome proliferator-activated receptor (PPAR) agonists [18]. ...
The peroxisome proliferator-activated receptor (PPAR) nuclear receptor has been an interesting target for the treatment of chronic diseases. Although the efficacy of PPAR pan agonists in several metabolic diseases has been well studied, the effect of PPAR pan agonists on kidney fibrosis development has not been demonstrated. To evaluate the effect of the PPAR pan agonist MHY2013, a folic acid (FA)-induced in vivo kidney fibrosis model was used. MHY2013 treatment significantly controlled decline in kidney function, tubule dilation, and FA-induced kidney damage. The extent of fibrosis determined using biochemical and histological methods showed that MHY2013 effectively blocked the development of fibrosis. Pro-inflammatory responses, including cytokine and chemokine expression, inflammatory cell infiltration, and NF-κB activation, were all reduced with MHY2013 treatment. To demonstrate the anti-fibrotic and anti-inflammatory mechanisms of MHY2013, in vitro studies were conducted using NRK49F kidney fibroblasts and NRK52E kidney epithelial cells. In the NRK49F kidney fibroblasts, MHY2013 treatment significantly reduced TGF-β-induced fibroblast activation. The gene and protein expressions of collagen I and α-smooth muscle actin were significantly reduced with MHY2013 treatment. Using PPAR transfection, we found that PPARγ played a major role in blocking fibroblast activation. In addition, MHY2013 significantly reduced LPS-induced NF-κB activation and chemokine expression mainly through PPARβ activation. Taken together, our results suggest that administration of the PPAR pan agonist effectively prevented renal fibrosis in both in vitro and in vivo models of kidney fibrosis, implicating the therapeutic potential of PPAR agonists against chronic kidney diseases.
... PPARs comprise a family of transcription factors that play a central role in lipid metabolism and energy homeostasis. 28 Among the leading-edge genes (Table S1), we found that many of them were specifically associated with PPARg signaling, including FABP4, FABP3, LPL, CD36, and PPARG 16 (Figure S1A). To further evaluate whether this enrichment actually represented a common signature in different tumors, singlecell RNA sequencing (scRNA-seq) data of tumor-infiltrating myeloid cells from 15 different types of cancer were analyzed. ...
Monocytes can differentiate into macrophages (Mo-Macs) or dendritic cells (Mo-DCs). The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the differentiation of monocytes into Mo-Macs, while the combination of GM-CSF/interleukin (IL)-4 is widely used to generate Mo-DCs for clinical applications and to study human DC biology. Here, we report that pharmacological inhibition of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) in the presence of GM-CSF and the absence of IL-4 induces monocyte differentiation into Mo-DCs. Remarkably, we find that simultaneous inhibition of PPARγ and the nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) induces the differentiation of Mo-DCs with stronger phenotypic stability, superior immunogenicity, and a transcriptional profile characterized by a strong type I interferon (IFN) signature, a lower expression of a large set of tolerogenic genes, and the differential expression of several transcription factors compared with GM-CSF/IL-4 Mo-DCs. Our findings uncover a pathway that tailors Mo-DC differentiation with potential implications in the fields of DC vaccination and cancer immunotherapy.
... Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors consisting of the three identified subtypes PPARα, PPARβ/δ, and PPARγ [113,114]. They are expressed in various cells including those of the immune system and they have been described to interact with both the innate as well as the acquired immune system [115]. An excellent overview of the general role of PPARs concerning immune responses is provided by Christofides et al. [114]. ...
Background
Per- and polyfluoroalkyl substances (PFAS) are of public health concern, because of their ubiquitous and extremely persistent occurrence, and depending on their structure, their bio-accumulative, mobile and toxic properties. Human health effects associated with exposure to PFAS include adverse effects on the immune system. In 2020, EFSA (the European Food Safety Authority) defined adverse effects on the immune system as the most critical effect for human health risk assessment, based on reduced antibody responses to childhood vaccines and similar effects observed in experimental animal studies. Likewise, the U.S. EPA (Environmental Protection Agency) considers PFAS-induced immunotoxicity, especially in children, as the critical effect for risk assessment. However, the mechanisms by which antibody concentrations are impacted are not completely understood. Furthermore, other targets of the immune system functions have been reported in the literature.
Objective
The aim of this review is to explore PFAS-associated immune-related effects. This includes, relevant mechanisms that may underlie the observed effects on the immune system, immunosuppression as well as immunoenhancement, such as i) modulation of cell signalling and nuclear receptors, such as NF-κB and PPARs; ii) alteration of calcium signalling and homoeostasis in immune cells; iii) modulation of immune cell populations; iv) oxidative stress and v) impact on fatty acid metabolism & secondary effects on the immune system.
Methods
A literature research was conducted using three databases (Web of Science, PubMed, and Scopus), which were searched in July 2021 for relevant studies published in the time frame from 2018 to 2021. In total, 487 publications were identified as potentially eligible and following expert-based judgement, articles relevant for mechanisms of PFAS induced immunotoxicity are discussed.
Conclusions
Taken together, we show that there is substantial evidence from both in vitro and in vivo experimental as well as epidemiological studies, supporting that various PFAS, not only PFOA and PFOS, affect multiple aspects of the immune system. Timing of exposure is critical, because the developing immune system is especially vulnerable to toxic insults, resulting in a higher risk of particularly adverse immune effects but also other organs later in life.
... PPARγ is expressed in a variety of tissues, including adipose tissue, muscle, and the liver [33,34,55], and is activated by diverse ligands, including fatty acids and their derivatives, as well as synthetic chemicals known as thiazolidinediones [4,7]. PPARγ is responsible for regulating lipid metabolism, glucose homeostasis, and inflammation [63,64]. Numerous inflammatory mediators and cytokines are inhibited by PPARγ ligands in various cell types, including monocytes/macrophages, epithelial cells, smooth muscle cells, endothelial cells, dendritic cells, and lymphocytes. ...
Peroxisome proliferator-activated receptors (PPARs) α, β, and γ are nuclear receptors that orchestrate the transcriptional regulation of genes involved in a variety of biological responses, such as energy metabolism and homeostasis, regulation of inflammation, cellular development, and differentiation. The many roles played by the PPAR signaling pathways indicate that PPARs may be useful targets for various human diseases, including metabolic and inflammatory conditions and tumors. Accumulating evidence suggests that each PPAR plays prominent but different roles in viral, bacterial, and parasitic infectious disease development. In this review, we discuss recent PPAR research works that are focused on how PPARs control various infections and immune responses. In addition, we describe the current and potential therapeutic uses of PPAR agonists/antagonists in the context of infectious diseases. A more comprehensive understanding of the roles played by PPARs in terms of host-pathogen interactions will yield potential adjunctive personalized therapies employing PPAR-modulating agents.
... Studies also showed that TZDs could increase IL-10 levels, enhance neutrophil recruitment to the infection foci, raise fibroblast growth factor (FGF) 21 levels, and improve survival in animals with sepsis (Trevelin et al., 2017;Pearson-Stuttard et al., 2022). PPARγ may play a role in the differentiation of naive T cells to effector T cells and improve adaptive immunity (Daynes and Jones, 2002;Wang et al., 2019). Preclinical studies demonstrated that TZDs could have direct antibacterial activity (Stegenga et al., 2009;Masadeh et al., 2011;Li et al., 2019). ...
IntroductionWe conducted this study to compare the risk of pneumonia between thiazolidinedione (TZD) use and nonuse in persons with type 2 diabetes (T2D).Methods
We identified 46,763 propensity-score matched TZD users and nonusers from Taiwan’s National Health Insurance Research Database between January 1, 2000, and December 31, 2017. The Cox proportional hazards models were used for comparing the risk of morbidity and mortality associated with pneumonias.ResultsCompared with the nonuse of TZDs, the adjusted hazard ratios (95% CI) for TZD use in hospitalization for all-cause pneumonia, bacterial pneumonia, invasive mechanical ventilation, and death due to pneumonia were 0.92 (0.88–0.95), 0.95 (0.91–0.99), 0.80 (0.77–0.83), and 0.73 (0.64–0.82), respectively. The subgroup analysis revealed that pioglitazone, not rosiglitazone, was associated with a significantly lower risk of hospitalization for all-cause pneumonia [0.85 (0.82–0.89)]. Longer cumulative duration and higher cumulative dose of pioglitazone were associated with further lower adjusted hazard ratios in these outcomes compared to no-use of TZDs.DiscussionThis cohort study demonstrated that TZD use was associated with significantly lower risks of hospitalization for pneumonia, invasive mechanical ventilation, and death due to pneumonia in patients with T2D. Higher cumulative duration and dose of pioglitazone were associated with a further lower risk of outcomes.
... PPARs are a protein family of ligand-activated nuclear receptors and paracrine regulators expressed in various cells of the immune system (Christofides et al., 2021;Daynes and Jones, 2002;Glass and Ogawa, 2006). In fact, phthalate metabolites have been shown to interact in vitro with PPARɣ (Kratochvil et al., 2019) including several of their chemical substitutes (Schaffert et al., 2022) and to activate, in rat liver extracts (Lapinskas et al., 2005) and different cell lines (Hurst and Waxman, 2003), various members of the PPAR nuclear receptor family. ...
Exposure to phthalates is widespread in Europe. Phthalates are considered endocrine disrupting compounds and are classified as toxic for reproduction. However how phthalates affect the transcriptome in humans remains largely unknown. To investigate the effects of phthalate exposure on the transcriptomic profile we conducted RNA sequencing on peripheral blood samples from the Norwegian EuroMix cohort. We compared gene expression changes between participants with high, medium, and low exposure of six phthalates and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH). Comparing high and low exposure groups, DINCH was the compound that showed the highest number of differentially expressed genes (126 genes) followed by mono-n-butyl phthalate (MnBP; 89 genes) and mono-iso-nonyl phthalate (MiBP; 70 genes). Distributions between up- or down-regulated genes were similar across the different phthalates and DINCH. All phthalates including DINCH shared common differentially expressed genes ranging from 3 to 37 overlaps. Enriched Gene Ontology (GO) and biological pathway analysis revealed that most of the differentially expressed genes were associated with general cellular metabolism GO terms. MnBP and DINCH, particularly, showed a marked enrichment in various immunological function pathways including neutrophil degranulation, adaptive immune system and signaling by interleukins. Furthermore, the association between genes involved in the peroxisome proliferator activated receptor (PPAR) signaling pathway and phthalates, including DINCH, was evaluated. In total, 15 genes showed positive or negative associations across 5 phthalates and DINCH. MnBP and MiBP were the phthalate metabolites with the highest number of associations: 8 and 4 PPAR signaling pathway genes, respectively. Overall, we have performed an association study between phthalate exposure levels and modulation of transcriptomic profiles in human peripheral blood cells. DINCH, which is often mentioned as a substitute for phthalates, had comparable effects on differential gene expression in peripheral blood cells as phthalates.
... PPARs are a protein family of ligand-activated nuclear receptors and paracrine regulators expressed in various cells of the immune system (Christofides et al., 2021;Daynes and Jones, 2002;Glass and Ogawa, 2006). In fact, phthalate metabolites have been shown to interact in vitro with PPARɣ (Kratochvil et al., 2019) including several of their chemical substitutes (Schaffert et al., 2022) and to activate, in rat liver extracts (Lapinskas et al., 2005) and different cell lines (Hurst and Waxman, 2003), various members of the PPAR nuclear receptor family. ...
... Peroxisome proliferation-activated receptor gamma (PPARγ) (Hegde et al., 2015;O'Sullivan, 2016) is an important target of CBD. PPARγ is a member of the ligandactivated transcriptional factor of the nuclear hormone receptor superfamily, which is a key mediator of energy homeostasis and associated with many biological functions including inflammation (Daynes and Jones, 2002). Several studies have reported that PPARγ agonists exhibit neuroprotective effects via regulating gene transcription related to the pathogenesis of neurodegeneration . ...
Despite the significant advances in neurology, the cure for neurodegenerative conditions remains a formidable task to date. Among various factors arising from the complex etiology of neurodegenerative diseases, neuroinflammation and oxidative stress play a major role in pathogenesis. To this end, some phytocannabinoids isolated from Cannabis sativa (widely known as marijuana) have attracted significant attention as potential neurotherapeutics. The profound effect of ∆9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, has led to the discovery of the endocannabinoid system as a molecular target in the central nervous system (CNS). Cannabidiol (CBD), the major non-psychoactive component of cannabis, has recently emerged as a potential prototype for neuroprotective drug development due to its antioxidant and anti-inflammatory properties and its well-tolerated pharmacological behavior. This review briefly discusses the role of inflammation and oxidative stress in neurodegeneration and demonstrates the neuroprotective effect of cannabidiol, highlighting its general mechanism of action and disease-specific pathways in Parkinson’s disease (PD) and Alzheimer’s disease (AD). Furthermore, we have summarized the preclinical and clinical findings on the therapeutic promise of CBD in PD and AD, shed light on the importance of determining its therapeutic window, and provide insights into identifying promising new research directions.
... Troglitazone is a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist. PPARgamma, a member of the nuclear hormone receptor superfamily, is involved in the regulation of immune and inflammatory processes [117]. Troglitazone activate PPARgamma to inhibit the release of TNF-α from RSV infected A549 cells in a dose-dependent manner. ...
COVID-19 pandemic poses a severe threat to public health. However, so far, there are no effective drugs for COVID-19. Transcriptomic changes and key genes related to Th2 cells in COVID-19 have not been reported. These genes play an important role in host interactions with SARS-COV-2 and may be used as promising target. We analyzed five COVID-19-associated GEO datasets (GSE157103, GSE152641, GSE171110, GSE152418, and GSE179627) using the xCell algorithm and weighted gene co-expression network analysis (WGCNA). Results showed that 5 closely correlated modular genes to COVID-19 and Th2 cell enrichment levels, including purple, blue, pink, tan and turquoise, were intersected with differentially expressed genes (DEGs) and 648 shared genes were obtained. GO and KEGG pathway enrichment analyses revealed that they were enriched in cell proliferation, differentiation, and immune responses after virus infection. The most significantly enriched pathway involved the regulation of viral life cycle. Three key genes, namely CCNB1, BUB1, and UBE2C, may clarify the pathogenesis of COVID-19 associated with Th2 cells. 11 drug candidates were identified that could down-regulate three key genes using the cMAP database and demonstrated strong drugs binding energies aganist the three keygenes using molecular docking methods. BUB1, CCNB1 and UBE2C were identified key genes for COVID-19 and could be promising therapeutic targets.
... VA activates peroxisome proliferator-activated receptors (PPARs) in the intestines and mediates anti-inflammatory effects by antagonizing the actions of a pro-inflammatory transcription factor: nuclear factor- -κB). This action leads to downregulation of expression of pro-inflammatory markers, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-12 (Daynes and Jones 2002;Loscher et al., 2005). Moreover, expression of IL-1β and TNF-α is upregulated via NF-κB signaling , which occurs during the early stage of CIM and induces mucosal injury not only by direct damage to tissue but also by providing a positive-feedback loop to amplify the primary damage (Davis 2000;Angel et al., 2001;Bamba et al., 2003). ...
Chemotherapy-induced intestinal mucositis (CIM) is a major dose-limiting side effect of chemotherapy, especially in regimens containing irinotecan (CPT-11). Several studies on the pathologic mechanisms of CIM focused on both the genomics and molecular pathways triggered by chemotherapy. However, systematic evaluation of metabolomic analysis in irinotecan-induced intestinal mucositis (IIM) has not been investigated. This study aimed to comprehensively analyze metabolite changes in main tissues of IIM mouse models. Male ICR mice were assigned to two groups: the model group (n = 11) treated with CPT-11 (20 mg/kg daily; i.p.) and the control group (n= 11) with solvent for 9 days. Gas chromatography-mass spectrometry (GC-MS) was used to investigate the metabolic alterations in the serum, intestinal, colonic, hepatic, and splenic samples of mice between two groups by multivariate statistical analyses, including GC–MS data processing, pattern recognition analysis, and pathway analysis. Forty-six metabolites, including hydrocarbons, amino acids, lipids, benzenoids, hydroxy acids, and amines, had significant changes in levels in tissues and sera of IIM mouse models. The most important pathways related to the identified metabolites were the glycerolipid metabolism in the colon and aminoacyl-tRNA biosynthesis; glycine, serine, and threonine metabolism; and glyoxylate and dicarboxylate metabolism in the liver. Our study firstly provided a comprehensive and systematic view of metabolic alterations of IIM using GC-MS analysis. The characterizations of metabolic changes could offer profound and theoretical insight into exploring new biomarkers for diagnosis and treatment of IIM.
... The feeding of PPARα agonists to aged mice restored the cellular redox balance, evidenced by a lowering of tissue lipid peroxidation, an elimination of constitutively active NF-κB, and a loss of spontaneous inflammatory cytokine production [446]. PPARα further directly represses pro-inflammatory genes such as STAT, activator protein-1 (AP-1), NF-κB, and nuclear factor of activated T cells (NFAT) and activates anti-inflammatory components such as interleukin-1 receptor antagonist (IL1-Ra), Vanin-1, and mannose-binding lectin (MBL), as reviewed in [447,448]. PPARα further functions as a natural suppressor of the enzyme 11-β hydroxysteroid dehydrogenase 1 (HSD11B1), a widely expressed enzyme that converts biologically inactive cortisone to the functional glucocorticoid cortisol, known to exert multiple immunomodulatory effects [449]. In contrast to the suggested anti-inflammatory role of PPARα, Hill and colleagues observed, in a mouse model of endotoxemia, higher TNFα levels in animals treated with PPARα agonists [450]. ...
Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with ret-inoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natural ligands, PPARs are mainly focused on as targets for the treatment of metabolic syndrome and its associated complications. Nevertheless, many publications are available that implicate PPARs in malignancies. In several instances, they are controversial for very similar models. Thus, to better predict the potential use of PPAR modulators for personalized medicine in therapies against malignancies, it seems necessary and timely to review the three PPARs in relation to the didactic concept of cancer hallmark capabilities. We previously described the functions of PPAR beta/delta with respect to the cancer hallmarks and reviewed the implications of all PPARs in angiogenesis. Thus, the current review updates our knowledge on PPAR beta and the hallmarks of cancer and extends the concept to PPAR alpha and PPAR gamma.
... For example, we found two genes from the peroxisome proliferatoractivated receptors (PPARG and PPARA) in this subnetwork. PPARs function in inflammation and immunity [74], coordinate glucose and energy metabolism [75,76], and are known to positively influence AD pathology. In addition to this, PPARA regulates genes involved in fatty acid metabolism and activates hepatic autophagy [77]. ...
Dysregulation of gene expression in Alzheimer’s disease (AD) remains elusive, especially at the cell type level. Gene regulatory network, a key molecular mechanism linking transcription factors (TFs) and regulatory elements to govern gene expression, can change across cell types in the human brain and thus serve as a model for studying gene dysregulation in AD. However, AD-induced regulatory changes across brain cell types remains uncharted. To address this, we integrated single-cell multi-omics datasets to predict the gene regulatory networks of four major cell types, excitatory and inhibitory neurons, microglia and oligodendrocytes, in control and AD brains. Importantly, we analyzed and compared the structural and topological features of networks across cell types and examined changes in AD. Our analysis shows that hub TFs are largely common across cell types and AD-related changes are relatively more prominent in some cell types (e.g., microglia). The regulatory logics of enriched network motifs (e.g., feed-forward loops) further uncover cell type-specific TF-TF cooperativities in gene regulation. The cell type networks are also highly modular and several network modules with cell-type-specific expression changes in AD pathology are enriched with AD-risk genes. The further disease-module-drug association analysis suggests cell-type candidate drugs and their potential target genes. Finally, our network-based machine learning analysis systematically prioritized cell type risk genes likely involved in AD. Our strategy is validated using an independent dataset which showed that top ranked genes can predict clinical phenotypes (e.g., cognitive impairment) of AD with reasonable accuracy. Overall, this single-cell network biology analysis provides a comprehensive map linking genes, regulatory networks, cell types and drug targets and reveals cell-type gene dysregulation in AD.
Macrophages play diverse roles in development, homeostasis, and immunity. Accordingly, the dysfunction of macrophages is involved in the occurrence and progression of various diseases, such as coronavirus disease 2019 and atherosclerosis. The protective or pathogenic effect that macrophages exert in different conditions largely depends on their functional plasticity, which is regulated via signal transduction such as Janus kinase–signal transducer and activator of transcription, Wnt and Notch pathways, stimulated by environmental cues. Over the past few decades, the molecular mechanisms of signaling pathways in macrophages have been gradually elucidated, providing more alternative therapeutic targets for diseases treatment. Here, we provide an overview of the basic physiology of macrophages and expound the regulatory pathways within them. We also address the crucial role macrophages play in the pathogenesis of diseases, including autoimmune, neurodegenerative, metabolic, infectious diseases, and cancer, with a focus on advances in macrophage‐targeted strategies exploring modulation of components and regulators of signaling pathways. Last, we discuss the challenges and possible solutions of macrophage‐targeted therapy in clinical applications. We hope that this comprehensive review will provide directions for further research on therapeutic strategies targeting macrophage signaling pathways, which are promising to improve the efficacy of disease treatment.
Mounting evidence suggests safety and tolerability of cannabis-derived and psychedelic drugs as potential novel therapeutics for psychiatric, as well as sleep and pain disorders. Evidence concerning the therapeutic efficacy of these compounds remains controversial, although some promising preliminary results are available for them in specific disorders. For example, CBD is approved as medication for treatment-refractory epilepsy, while MDMA and psilocybin are being tested in phase 3 clinical trials respectively for treatment-refractory PTSD and MDD. Despite encouraging preliminary results, further preclinical and clinical trials are required to validate these findings. Most importantly, more systematic research is required to assess the potential long-term side effects that might arise following the use of cannabinoids and psychedelic compounds in psychiatric settings.
Kanserde kinürenin yolağının ilgili enzimlerinin aşırı aktivasyonu ve kimyasal dönüşüm metabolitlerinin kan serum seviyelerindeki artışı, mutant hücrelerin hayatta kalması ve çevre dokuları istila etmesi için immünolojik olarak duyarlı bir mikro ortam sağlar. Özellikle indoleamin 2,3-dioksijenaz 1 aşırı aktivasyonunun gastrointestinal kanserler, jinekolojik kanserler, hematolojik maligniteler, meme kanseri, akciğer kanseri, glioma, melanom, prostat ve pankreas kanseri gibi çeşitli kanserlerde hastalığın patogenezinin ve kötü prognozunun bir belirleyicisi olarak rol oynadığı düşünülmektedir. Ek olarak, kinürenik asitin, beyin omurilik sıvısındaki kinolinik asit konsantrasyonlarını artırarak inflamasyona yol açtığı ve depresif semptomlara yol açtığı gösterilmiştir. Bu bağlamda tümör oluşumu, prognozu, kanserin kendisine veya tedavilerine bağlı oluşan yan etkilerin açıklanmasında kinürenin yolağı metabolitleri ile ilgili araştırmalar hız kazanmıştır. Önceki çalışmalarda hem akut hem de kronik egzersizin, çeşitli hastalıklarda (diyabet, depresyon, multiple skleroz gibi) kinürenin yolağı enzimleri ve metabolitleri üzerine up/down regülasyona neden olabileceği gösterilmiştir. Kinürenin yolağının mediatörü olarak egzersizin etkinliğini kanser alanında araştıran çalışma sayısı oldukça kısıtlıdır. Bu geleneksel derlemede, kinürenin yolağının egzersize bağlı modülasyonları ile ilgili mevcut bilgiler, altta yatan mekanizmalar ayrıca egzersizle indüklenen kinürenin yolağı ve egzersiz/kanser ilişkisi incelenecektir.
Mounting evidence demonstrates that hydrogen sulfide (H 2S) promotes anti-inflammatory molecules and inhibits pro-inflammatory cytokines in endothelial cells (ECs). This study aims to investigate the favorable action of H 2S on endothelial function in senescence by inhibiting the production of inflammatory molecules. Senescent ECs exhibit a reduction in H 2S, endothelial nitric oxide synthase (eNOS) and peroxisome proliferator-activated receptor δ (PPARδ), coupled with increased inflammatory molecules, sodium glucose transporter type 2 (SGLT2) and phosphorylation of STAT3, which could be reversed by the administration of a slow but sustained release agent of H 2S, GYY4137. Decreased production of eNOS and upregulated p-STAT3 and SGLT2 levels in senescent ECs are reversed by replenishment of the SGLT2 inhibitor EMPA and the PPARδ agonist GW501516. The PPARδ antagonist GSK0660 attenuates eNOS expression and increases the production of p-STAT3 and SGLT2. However, supplementation with GYY4137 has no beneficial effect on GSK0660-treated ECs. GYY4137, GW501516 and EMPA preserve endothelial-dependent relaxation (EDR) in D-gal-treated aortae, while GSK0660 destroys aortic relaxation even with GYY4137 supplementation. In summary, senescent ECs manifest aggravated the expressions of the inflammatory molecules SGLT2 and p-STAT3 and decreased the productions of PPARδ, eNOS and CSE. H 2S ameliorates endothelial dysfunction through the anti-inflammatory effect of the PPARδ/SGLT2/p-STAT3 signaling pathway in senescent ECs and may be a potential therapeutic target for anti-ageing treatment.
Cardiovascular disease (CVD) is closely associated with obesity through risk factors such as dyslipidemia and chronic low-grade inflammation, which may be affected by diet. Dietary fats have been extensively studied in relation to CVD risk, however these studies have not always yielded consistent results, most likely due to lack in control of experimental conditions and confounding factors. Here we studied the effects of different plant and animal fats on dyslipidemia, inflammation, and atherosclerosis. Ldlr-/-.Leiden mice were fed isocaloric energy-dense diets with translational macronutrient composition for 28 weeks. The diets were identical apart from the type of fat they contained: either (1) a mixture of olive and rapeseed oil, (2) sunflower oil, (3) pork fat, (4) beef fat, or (5) milk fat. The fatty acid composition of the diets was determined and effects on circulating lipid and inflammatory risk factors and atherosclerosis were examined, complemented by adipose tissue histology and liver transcriptomics. While visceral fat mass, adipocyte size, and adipose tissue inflammation were not differentially affected by the diets, atherosclerotic lesion load and severity was more pronounced with increasing dietary saturated fatty acid content and decreasing monounsaturated and polyunsaturated fatty acid content, and hence most pronounced with beef and milk fat. These differential effects were accompanied by increases in pro-atherogenic plasma lipids/lipoproteins (e.g., triglycerides, apolipoprotein B), activation of pro-atherogenic cytokine/chemokine signaling pathways in liver, and with circulating pro-atherogenic mediators of inflammation altogether providing a rationale for the differential effects of plant and animal fats.
Mammalian lipid droplets (LDs) are specialized cytosolic organelles consisting of a neutral lipid core surrounded by a membrane made up of a phospholipid monolayer and a specific population of proteins that varies according to the location and function of each LD. Over the past decade, there have been significant advances in the understanding of LD biogenesis and functions. LDs are now recognized as dynamic organelles that participate in many aspects of cellular homeostasis plus other vital functions. LD biogenesis is a complex, highly-regulated process with assembly occurring on the endoplasmic reticulum although aspects of the underpinning molecular mechanisms remain elusive. For example, it is unclear how many enzymes participate in the biosynthesis of the neutral lipid components of LDs and how this process is coordinated in response to different metabolic cues to promote or suppress LD formation and turnover. In addition to enzymes involved in the biosynthesis of neutral lipids, various scaffolding proteins play roles in coordinating LD formation. Despite their lack of ultrastructural diversity, LDs in different mammalian cell types are involved in a wide range of biological functions. These include roles in membrane homeostasis, regulation of hypoxia, neoplastic inflammatory responses, cellular oxidative status, lipid peroxidation, and protection against potentially toxic intracellular fatty acids and lipophilic xenobiotics. Herein, the roles of mammalian LDs and their associated proteins are reviewed with a particular focus on their roles in pathological, immunological and anti-toxicological processes.
Peroxisome proliferator-activated receptors (PPARs) are associated with the regulation of metabolic homeostasis. Based on a previous report that 1'-homologated 4'-thionucleoside acts as a dual PPARγ/δ modulator, carbocyclic nucleosides 2-5 with various sugar conformations were synthesized to determine whether sugar puckering affects binding to PPARs. (S)-conformer 2 was synthesized using Charette asymmetric cyclopropanation, whereas (N)-conformer 3 was synthesized using stereoselective Simmons-Smith cyclopropanation. All synthesized nucleosides did not exhibit binding affinity to PPARα but exhibited significant binding affinities to PPARγ/δ. The binding affinity of final nucleosides to PPARγ did not differ significantly based on their conformation, but their affinity to PPARδ depended greatly on their conformation, correlated with adiponectin production. (N)-conformer 3h was discovered to be the most potent PPARδ antagonist with good adiponectin production, which exhibited the most effective activity in inhibiting the mRNA levels of LPS-induced IL-1β expression in RAW 264.7 macrophages, implicating its anti-inflammatory activity.
Coronavirus disease 2019 (COVID-19) is a severe respiratory disease caused by
infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
that affects the lower and upper respiratory tract in humans. SARS-CoV-2
infection is associated with the induction of a cascade of uncontrolled
inflammatory responses in the host, ultimately leading to hyperinflammation or
cytokine storm. Indeed, cytokine storm is a hallmark of SARS-CoV-2
immunopathogenesis, directly related to the severity of the disease and
mortality in COVID-19 patients. Considering the lack of any definitive
treatment for COVID-19, targeting key inflammatory factors to regulate the
inflammatory response in COVID-19 patients could be a fundamental step to
developing effective therapeutic strategies against SARS-CoV-2 infection.
Currently, in addition to well-defined metabolic actions, especially lipid
metabolism and glucose utilization, there is growing evidence of a central role
of the ligand-dependent nuclear receptors and peroxisome proliferator activated
receptors (PPARs) including PPARa, PPARb/d, and PPARg in the
control of inflammatory signals in various human inflammatory diseases. This
makes them attractive targets for developing therapeutic approaches to control/
suppress the hyperinflammatory response in patients with severe COVID-19. Inthis review, we (1) investigate the anti-inflammatory mechanisms mediated by
PPARs and their ligands during SARS-CoV-2 infection, and (2) on the basis of the
recent literature, highlight the importance of PPAR subtypes for the development
of promising therapeutic approaches against the cytokine storm in severe
COVID-19 patients.
Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimer’s disease (AD). Across the CNS, astrocytes are the predominant expressor of APOE while also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional inflammation and metabolic processes, yet insights into the molecular constituents driving these responses remain unclear. Utilizing complementary approaches across humanized APOE mice and isogenic human iPSC astrocytes, we demonstrate that ApoE4 alters the astrocyte immunometabolic response to pro-inflammatory stimuli. Our findings show that ApoE4-expressing astrocytes acquire distinct transcriptional repertoires at single-cell and spatially-resolved domains, which are driven in-part by preferential utilization of the cRel transcription factor. Further, inhibiting cRel translocation in ApoE4 astrocytes abrogates inflammatory-induced glycolytic shifts and in tandem mitigates production of multiple pro-inflammatory cytokines. Altogether, our findings elucidate novel cellular underpinnings by which ApoE4 drives maladaptive immunometabolic responses of astrocytes.
Cryptococcosis is an opportunistic mycosis that mainly affects immunosuppressed patients. The treatment is a combination of three antifungal agents: amphotericin B, 5-flucytosine and fluconazole. However, these drugs have many disadvantages, such as high nephrotoxicity, marketing bans in some countries and fungal resistance. One of the solutions to find possible new drugs is pharmacological repositioning. This work presents repositioned drugs as an alternative for new antifungal therapies for cryptococcosis. All the studies here were performed in vitro or in animal models, except for sertraline, which reached phase 3 in humans. There is still no pharmacological repositioning approval for cryptococcosis in humans, though this review shows the potential of repurposing as a rapid approach to finding new agents to treat cryptococcosis.
Background
Anaphylaxis is an acute life-threatening allergic reaction and a concern at a global level; therefore, further progress in understanding the underlying mechanisms and more effective strategies for diagnosis, prevention and management are needed.
Objective
We sought to identify the global architecture of blood transcriptomic features of anaphylaxis by integrating expression data from human patients and mouse model of anaphylaxis.
Methods
Bulk RNA-sequencings of peripheral whole blood were performed in: i) 14 emergency department (ED) patients with acute anaphylaxis, predominantly to Hymenoptera venom, ii) 11 patients with peanut allergy undergoing double-blind, placebo-controlled food challenge (DBPCFC) to peanut, iii) murine model of IgE-mediated anaphylaxis. Integrative characterisation of differential gene expression, immune cell-type-specific gene expression profiles, and functional and pathway analysis was undertaken.
Results
1023 genes were commonly and significantly dysregulated during anaphylaxis in ED and DBPCFC patients; of those genes, 29 were also dysregulated in the mouse model. Cell-type-specific gene expression profiles showed a rapid downregulation of blood basophil and upregulation of neutrophil signature in ED and DBPCFC patients and the mouse model, but no consistent and/or significant differences were found for other blood cells. Functional and pathway analysis demonstrated that human and mouse blood transcriptomic signatures of anaphylaxis follow trajectories of upregulation of cell movement, migration and neuroinflammatory signalling, and downregulation of lipid activating nuclear receptors signalling.
Conclusion
Our study highlights the matched and extensive blood transcriptomic changes and suggests the involvement of discrete cellular components and upregulation of migration and neuroinflammatory pathways during anaphylaxis.
The immune response is in its basis a highly regulated expression of relevant gene information encoded within a heterochromatin composed of DNA and histone proteins. Protein biosynthesis is divided into mRNA-forming transcription, mRNA processing, and protein-forming translation. Relevant expression regulations include epigenetic mechanisms for active gene silencing as well as regulations by transcription factors, regulatory mechanisms of post-transcriptional alternative splicing, and pretranslational RNA interference. As relevant environmental factors, nutritional status and various food components influence these regulatory mechanisms and play a decisive role in determining the expression of immune-relevant genes.
This book provides up-to-date information on the crucial interaction of pathogenic bacteria and professional phagocytes, the host cells whose purpose is to ingest, kill, and digest bacteria in defense against infection. The introductory chapters focus on the receptors used by professional phagocytes to recognize and phagocytose bacteria, and the signal transduction events that are essential for phagocytosis of bacteria. Subsequent chapters discuss specific bacterial pathogens and the strategies they use in confronting professional phagocytes. Examples include Helicobacter pylori, Streptococcus pneumoniae, and Yersinae, each of which uses distinct mechanisms to avoid being phagocytosed and killed. Contrasting examples include Listeria monocytogenes and Mycobacterium tuberculosis, which survive and replicate intracellularly, and actually cooperate with phagocytes to promote their entry into these cells. Together, the contributions in this book provide an outstanding review of current knowledge regarding the mechanisms of phagocytosis and how specific pathogenic bacteria avoid or exploit these mechanisms.
Ocular ischemia is one of the leading causes of blindness. It is related to various ocular diseases and disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma, and corneal injury. Ocular ischemia occurs due to an abnormal supply of oxygen and nutrients to the eye, resulting in ocular metabolic dysfunction. These changes can be linked with pathologic conditions in the eye, such as inflammation, neovascularization, and cell death, ultimately leading to vision loss. The current treatment care for ocular ischemia is limited. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor protein functioning in regulating lipid metabolism, fatty acid oxidation, and glucose homeostasis. Recently, PPARα activation has been suggested as a useful therapeutic target in treating ocular ischemia. However, its applications have not been well summarized. In this review, we cover an overview of the therapeutic roles of PPARα activation in various ocular ischemic conditions with recent experimental evidence and further provide clinical implications of its therapeutic applications. Our review will enable more approaches to comprehensively understand the therapeutic roles of PPARα activation for preventing ocular ischemic diseases.
Non-alcoholic fatty liver disease (NAFLD) is a complex and heterogeneous disorder considered a liver-damaging manifestation of metabolic syndrome. Its prevalence has increased in the last decades due to modern-day lifestyle factors associated with overweight and obesity, making it a relevant public health problem worldwide. The clinical progression of NAFLD is associated with advanced forms of liver injury such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). As such, diverse pharmacological strategies have been implemented over the last few years, principally focused on metabolic pathways involved in NAFLD progression. However, a variable response rate has been observed in NAFLD patients, which is explained by the interindividual heterogeneity of susceptibility to liver damage. In this scenario, it is necessary to search for different therapeutic approaches. It is worth noting that chronic low-grade inflammation constitutes a central mechanism in the pathogenesis and progression of NAFLD, associated with abnormal composition of the intestinal microbiota, increased lymphocyte activation in the intestine and immune effector mechanisms in liver. This review aims to discuss the current knowledge about the role of the immune response in NAFLD development. We have focused mainly on the impact of altered gut-liver-microbiota axis communication on immune cell activation in the intestinal mucosa and the role of subsequent lymphocyte homing to the liver in NAFLD development. We further discuss novel clinical trials that addressed the control of the liver and intestinal immune response to complement current NAFLD therapies.
Food allergy is a serious public health problem because of its high incidence and risk. Probiotics can induce immune regulation in patients with allergic diseases, but its mechanism is not fully clear. In this paper, β-lactoglobulin (β-LG)-sensitized mice were used as models to explore the mechanism of Bifidobacterium animalis KV9 (KV9) and Lactobacillus vaginalis FN3 (FN3) on reducing allergic reactions and regulating immune cell function. The results showed that oral administration of KV9 and FN3 significantly reduced the scores of allergic symptoms, hypothermia symptoms, and serum levels of β-LG-specific immunoglobulins E (β-LG-sIgE), histamine, and mast cell protease in allergic mice. Flow cytometry analysis of intestinal dendritic cells (DCs) showed that the proportion of CD11c+major histocompatibility complex (MHC)-II+DCs, CD11c+CD80+DCs, and CD11c+ CD86+DCs increased after KV9 and FN3 intervention, indicating that the strains induced immature DCs and decreased the antigen-presenting capacity of DCs. Meanwhile, the toll-like receptor 4 (TLR4)-NF-κB signaling pathway was activated in DCs. The secretion of interleukin-12 (IL-12) was significantly increased, while interleukin-4 (IL-4) was decreased by DCs after KV9 and FN3 intervention, indicating that DCs have the potential to promote T-cell differentiation into T helper type 1 (Th1) cells. Furthermore, the proportion of CD3+CD8−IFN-γ+ T cells in the spleen increased, while CD3+CD8−IL-4+T cells decreased after oral administration of KV9 and FN3, correcting the T helper type 2 (Th2)-skewed immune responses. These results indicate that KV9 and FN3 reduce β-LG-induced allergic symptoms in mice, and suggest that the two potential probiotics might be used as an alternative therapeutic agent for mitigating food allergy.
A 53-day feeding trial was conducted to investigate the effects of dietary acetylferulic paeonol ester (APE) levels on the growth performance, body composition, serum biochemical indicators and lipid and glucose metabolism of of Nile tilapia, Oreochromis niloticus. The results showed that 100 and 200 mg kg⁻¹ APE significantly increased the weight gain (WG), while 200–3200 mg kg⁻¹ APE significantly decreased the crude lipid content of the liver. The supplementation of APE affected the serum biochemistry parameters associated with lipid and glucose metabolism. The liver transcriptome analysis revealed that the genes (such as hadhb, acads, acadl, acaa2, cpt1) related to fatty acid oxidation and degradation were significantly up-regulated, whereas the genes related to fatty acid biosynthesis (such as acaca, fasn, elovl5, acsl3a, scd, fads2) were significantly down-regulated by 200 mg kg⁻¹ APE. PPAR (peroxisome proliferator-activated receptor) and AMPK (Adenosine 5′-monophosphate (AMP)-activated protein kinase) signaling pathways were significantly enriched at 200 mg kg⁻¹ APE for differentially expressed genes (DEGs). The qPCR results showed an excellent agreement on those of RNA-seq for both up- and down-regulated genes (a total of seventeen genes selected for validation). Furthermore, 200 mg kg⁻¹ APE influenced hepatic glucose and lipid metabolism of tilapia at the enzymatic level and the mRNA level (genes included acads, acaa2, acadl, cpt1ab, ecil, fabp1b.l, hadhb, pcxb,cyp24, tktb, fads2, rgn, scd). Thus, APE reduced lipid accumulation in the liver of tilapia by modulating lipid and glucose metabolism.
The vitamin D receptor (VDR) normally functions as a ligand-dependent transcriptional activator. Here we show that, in the presence of Ets-1, VDR stimulates the prolactin promoter in a ligand-independent manner, behaving as a constitutive activator. Mutations in the AF2 domain abolish vitamin D-dependent transactiva- tion but do not affect constitutive activation by Ets-1. Therefore, in contrast with the actions of vitamin D, activation by Ets-1 is independent of the AF2 domain. Ets-1 also conferred a ligand-independent activation to the estrogen receptor and to peroxisome proliferator-activated receptor a. In addition, Ets-1 cooperated with the unliganded receptors to stimulate the activity of reporter constructs containing consensus response elements fused to the thymidine kinase promoter. There is a direct interaction of the receptors with Ets-1 which requires the DNA binding domains of both proteins. Interaction with Ets-1 induces a conformational change in VDR which can be detected by an increased resistance to proteolytic digestion. Furthermore, a retinoid X receptor-VDR heterodimer in which both receptors lack the core C-terminal AF2 domain can recruit coacti- vators in the presence, but not in the absence, of Ets-1. This suggests that Ets-1 induces a conformational change in the receptor which creates an active interaction surface with coactivators even in the AF2-defective mutants. These results demonstrate the existence of a novel mechanism, alternative to ligand binding, which can convert an unliganded receptor from an inactive state into a competent transcriptional activator.
Activation of the macrophage cell line RAW 264.7 with lipopolysaccharide (LPS) and gamma interferon (IFN-γ) induces the expression
of gene products involved in host defense, among them type 2 nitric oxide synthase. Treatment of cells with 15-deoxy-Δ12,14-prostaglandin J2(15dPGJ2) inhibited the LPS- and IFN-γ-dependent synthesis of NO, a process that was not antagonized by similar concentrations of
prostaglandin J2, prostaglandin E2, or rosiglitazone, a peroxisomal proliferator-activated receptor γ ligand. Incubation of activated macrophages with 15dPGJ2 inhibited the degradation of IκBα and IκBβ and increased their levels in the nuclei. NF-κB activity, as well as the transcription
of NF-κB-dependent genes, such as those encoding type 2 nitric oxide synthase and cyclooxygenase 2, was impaired under these
conditions. Analysis of the steps leading to IκB phosphorylation showed an inhibition of IκB kinase by 15dPGJ2 in cells treated with LPS and IFN-γ, resulting in an impaired phosphorylation of IκBα, at least in the serine 32 residue
required for targeting and degradation of this protein. Incubation of partially purified activated IκB kinase with 2 μM 15dPGJ2 reduced by 83% the phosphorylation in serine 32 of IκBα, suggesting that this prostaglandin exerts direct inhibitory effects
on the activity of the IκB kinase complex. These results show rapid actions of 15dPGJ2, independent of peroxisomal proliferator receptor γ activation, in macrophages challenged with low doses of LPS and IFN-γ.
The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that is predominantly expressed in adipose tissue, adrenal gland and spleen. PPAR-gamma has been demonstrated to regulate adipocyte differentiation and glucose homeostasis in response to several structurally distinct compounds, including thiazolidinediones and fibrates. Naturally occurring compounds such as fatty acids and the prostaglandin D2 metabolite 15-deoxy-delta prostaglandin J2 (15d-PGJ2) bind to PPAR-gamma and stimulate transcription of target genes. Prostaglandin D2 metabolites have not yet been identified in adipose tissue, but are major products of arachidonic-acid metabolism in macrophages, raising the possibility that they might serve as endogenous PPAR-gamma ligands in this cell type. Here we show that PPAR-gamma is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ2 and synthetic PPAR-gamma ligands. PPAR-gamma inhibits gene expression in part by antagonizing the activities of the transcription factors AP-1, STAT and NF-kappaB. These observations suggest that PPAR-gamma and locally produced prostaglandin D2 metabolites are involved in the regulation of inflammatory responses, and raise the possibility that synthetic PPAR-gamma ligands may be of therapeutic value in human diseases such as atherosclerosis and rheumatoid arthritis in which activated macrophages exert pathogenic effects.
An important subdivision of effector T cells can be made based on patterns of cytokine production and functional programs. Type 1 T cells produce IFN-gamma and protect against viral pathogens, whereas type 2 cells produce cytokines such as IL-4 and IL-5 and protect against large extracellular parasites. Both CD4(+) and CD8(+) T cells can be polarized into type 1 or type 2 cytokine-secreting cells, suggesting that both populations play a regulatory role in immune responses. In this study, we used high-density oligonucleotide arrays to produce a comprehensive picture of gene expression in murine CD4(+) Th1 and Th2 cells, as well as CD8(+) type 1 and type 2 T cells. Polarized type 1 and 2 cells transcribed mRNA for an unexpectedly large number of genes, most of which were expressed in a similar fashion between type 1 and type 2 cells. However, >100 differentially expressed genes were identified for both the CD4(+) and CD8(+) type 1 and 2 subsets, many of which have not been associated with T cell polarization. These genes included cytokines, transcription factors, molecules involved in cell migration, as well as genes with unknown function. The program for type 1 or type 2 polarization was similar for CD4(+) and CD8(+) cells, since gene expression patterns were roughly the same. The expression of select genes was confirmed using real-time PCR. The identification of genes associated with T cell polarization may give important insights into functional and phenotypic differences between effector T cell subsets and their role in normal responses and inflammatory disease.
Three novel members of the Xenopus nuclear hormone receptor superfamily have been cloned. They are related to each other and similar to the group of receptors that includes those for thyroid hormones, retinoids, and vitamin D3. Their transcriptional activity is regulated by agents causing peroxisome proliferation and carcinogenesis in rodent liver. All three Xenopus receptors activate the promoter of the acyl coenzyme A oxidase gene, which encodes the key enzyme of peroxisomal fatty acid beta-oxidation, via a cognate response element that has been identified. Therefore, peroxisome proliferators may exert their hypolipidemic effects through these receptors, which stimulate the peroxisomal degradation of fatty acids. Finally, the multiplicity of these receptors suggests the existence of hitherto unknown cellular signaling pathways for xenobiotics and putative endogenous ligands.
Peroxisome proliferators are a diverse group of chemicals, including several hypolipidaemic drugs, that activate a nuclear hormone receptor termed the peroxisome proliferator activated receptor (PPAR). The peroxisomal enzyme acyl CoA oxidase (ACO) is the most widely used marker of peroxisome proliferator action. We have examined the 5' flanking region of the rat ACO gene for sequences that mediate the transcriptional effect of peroxisome proliferators and have identified an element located 570 bp upstream of the ACO gene that confers responsiveness to the hypolipidaemic peroxisome proliferator Wy-14,643. This peroxisome proliferator response element (PPRE) contains a direct repeat of the sequence motifs TGACCT and TGTCCT and binds PPAR. These data therefore indicate an important role of PPAR in mediating the action of peroxisome proliferators including the induction of ACO.
Dehydroisoandrosterone, administered orally to New Zealand Black/New Zealand White F1 hybrid mice, prevented the formation of antibodies to double-stranded DNA and prolonged survival in this murine model of lupus erythematosus.
The peroxisome proliferator-activated receptor (PPAR) is a member of the steroid hormone receptor superfamily and is activated by a variety of fibrate hypolipidaemic drugs and non-genotoxic rodent hepatocarcinogens that are collectively termed peroxisome proliferators. A key marker of peroxisome proliferator action is the peroxisomal enzyme acyl CoA oxidase, which is elevated about ten fold in the livers of treated rodents. Additional peroxisome proliferator responsive genes include other peroxisomal beta-oxidation enzymes and members of the cytochrome P450 IVA family. A peroxisome proliferator response element (PPRE), consisting of an almost perfect direct repeat of the sequence TGACCT spaced by a single base pair, has been identified in the upstream regulatory sequences of each of these genes. The retinoid X receptor (RXR) forms a heterodimer with PPAR and binds to the PPRE. Furthermore, the RXR ligand, 9-cis retinoic acid, enhances PPAR action. Retinoids may therefore modulate the action of peroxisome proliferators and PPAR may interfere with retinoid action, perhaps providing one mechanism to explain the toxicity of peroxisome proliferators. Interestingly, a variety of fatty acids can activate PPAR supporting the suggestion that fatty acids, or their acyl CoA derivatives, may be the natural ligands of PPAR and that the physiological role of PPAR is to regulate fatty acid homeostasis. Taken together, the discovery of PPAR has opened up new opportunities in understanding how lipid homeostasis is regulated, how the fibrate hypolipidaemic drugs may act and should lead to improvements in the assessment of human risk from peroxisome proliferators based upon a better understanding of their mechanism of action.
Inflammation is a local immune response to 'foreign' molecules, infection and injury. Leukotriene B4, a potent chemotactic agent that initiates, coordinates, sustains and amplifies the inflammatory response, is shown to be an activating ligand for the transcription factor PPARalpha. Because PPARalpha regulates the oxidative degradation of fatty acids and their derivatives, like this lipid mediator, a feedback mechanism is proposed that controls the duration of an inflammatory response and the clearance of leukotriene B4 in the liver. Thus PPARalpha offers a new route to the development of anti- or pro-inflammatory reagents.
Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily, is expressed predominantly in adipose tissue. Forced expression of the two isoforms of this receptor, PPARgamma1 and PPARgamma2, in fibroblasts initiates a transcriptional cascade that leads to the development of adipocyte phenotype. Using the yeast two-hybrid system and GAL4-PPARgamma as bait to screen mouse liver cDNA library, we isolated a mouse steroid receptor coactivator (mSRC-1) involved in nuclear hormone receptor transcriptional activity as a mPPARgamma interactive protein. mSRC-1 cDNA we isolated contains an open reading frame of 1447 amino acids and encodes a new member of the basic helix-loop-helix-PAS domain family. We show that the binding of mSRC-1 to mPPARgamma is ligand independent and coexpression of mSRC-1 with mPPARgamma increases the transcriptional activity of mPPARgamma in the presence of mPPARgamma ligand. We have identified the presence of two putative mPPARgamma binding sites in the mSRC-1, one between residues 620 and 789, and the second between residues 1231 and 1447. These two regions exhibit different degrees of binding affinity for mPPARgamma. We also show that mSRC-1 exhibits its own constitutive transcriptional activity in the yeast as well as in mammalian cells. These results suggest that mSRC-1 interacts with PPARgamma and plays a role in the PPARgamma-mediated signaling pathway.
We have defined two principles of corepressor function that account for differences in transcriptional repression by nuclear hormone receptors (NHRs). First, we have determined that receptor stoichiometry is a crucial determinant of transcriptional repression mediated by the corepressors N-CoR and SMRT. This provides a molecular explanation for the observation that NHRs repress transcription as dimers but not monomers. Second, corepressor function is restricted by steric effects related to DNA binding in a receptor-specific manner. Thus, although N-CoR and SMRT are capable of binding to several NHRs in solution, they are highly selective about receptor binding on DNA, a context that reflects their in vivo function more accurately. These stoichiometric and steric principles govern specific interactions between corepressors and NHRs, thus providing evidence that N-CoR and SMRT do not serve redundant functions but rather contribute to receptor-specific transcriptional repression.
As the obligate member of most nuclear receptor heterodimers, retinoid X receptors (RXRs) can potentially perform two functions: cooperative binding to hormone response elements and coordinate regulation of target genes by RXR ligands. In this paper we describe allosteric interactions between RXR and two heterodimeric partners, retinoic acid receptors (RARs) and peroxisome proliferator-activated receptors (PPARs); RARs and PPARs prevent and permit activation by RXR-specific ligands, respectively. By competing for dimerization with RXR on response elements consisting of direct-repeat half-sites spaced by 1 bp (DR1 elements), the relative abundance of RAR and PPAR determines whether the RXR signaling pathway will be functional. In contrast to RAR, which prevents the binding of RXR ligands and recruits the nuclear receptor corepressor N-CoR, PPAR permits the binding of SRC-1 in response to both RXR and PPAR ligands. Overexpression of SRC-1 markedly potentiates ligand-dependent transcription by PPARgamma, suggesting that SRC-1 serves as a coactivator in vivo. Remarkably, the ability of RAR to both block the binding of ligands to RXR and interact with corepressors requires the CoR box, a structural motif residing in the N-terminal region of the RAR ligand binding domain. Mutations in the CoR box convert RAR from a nonpermissive to a permissive partner of RXR signaling on DR1 elements. We suggest that the differential recruitment of coactivators and corepressors by RAR-RXR and PPAR-RXR heterodimers provides the basis for a transcriptional switch that may be important in controlling complex programs of gene expression, such as adipocyte differentiation.
The malic enzyme (ME) gene is a target for both thyroid hormone receptors and peroxisome proliferator-activated receptors (PPAR). Within the ME promoter, two direct repeat (DR)-1-like elements, MEp and MEd, have been identified as putative PPAR response elements (PPRE). We demonstrate that only MEp and not MEd is able to bind PPAR/retinoid X receptor (RXR) heterodimers and mediate peroxisome proliferator signaling. Taking advantage of the close sequence resemblance of MEp and MEd, we have identified crucial determinants of a PPRE. Using reciprocal mutation analyses of these two elements, we show the preference for adenine as the spacing nucleotide between the two half-sites of the PPRE and demonstrate the importance of the two first bases flanking the core DR1 in 5'. This latter feature of the PPRE lead us to consider the polarity of the PPAR/RXR heterodimer bound to its cognate element. We demonstrate that, in contrast to the polarity of RXR/TR and RXR/RAR bound to DR4 and DR5 elements respectively, PPAR binds to the 5' extended half-site of the response element, while RXR occupies the 3' half-site. Consistent with this polarity is our finding that formation and binding of the PPAR/RXR heterodimer requires an intact hinge T region in RXR while its integrity is not required for binding of the RXR/TR heterodimer to a DR4.
In an attempt to identify cofactors that could possibly influence the transcriptional activity of peroxisome proliferator-activated receptors (PPARs), we used a yeast two-hybrid system with Gal4-PPARgamma as bait to screen a mouse liver cDNA library and have identified steroid receptor coactivator-1 (SRC-1) as a PPAR transcriptional coactivator. We now report the isolation of a cDNA encoding a 165-kDa PPARgamma-binding protein, designated PBP which also serves as a coactivator. PBP also binds to PPARalpha, RARalpha, RXR, and TRbeta1, and this binding is increased in the presence of specific ligands. Deletion of the last 12 amino acids from the carboxyl terminus of PPARgamma results in the abolition of interaction between PBP and PPARgamma. PBP modestly increased the transcriptional activity of PPARgamma, and a truncated form of PBP (amino acids 487-735) acted as a dominant-negative repressor, suggesting that PBP is a genuine coactivator for PPAR. In addition, PBP contains two LXXLL signature motifs considered necessary and sufficient for the binding of several coactivators to nuclear receptors. In situ hybridization and Northern analysis showed that PBP is expressed in many tissues of adult mice, including the germinal epithelium of testis, where it appeared most abundant, and during ontogeny, suggesting a possible role for this cofactor in cellular proliferation and differentiation.
The initiation and propagation of immune responses is dependent on the ability of antigen-presenting cells (APCs) to convert proteins into peptides, to load them intracellularly onto major histocompatibility complex (MHC) products and then to deliver the peptide-MHC complexes to the plasma membrane. Perhaps the most effective or 'professional' of all APCs are dendritic cells (DCs). DCs express high levels of MHC molecules together with a variety of 'accessory molecules' that help render DCs more effective at stimulating T cells than any other cell type. However, much of the capacity of a DC for T-cell stimulation reflects a remarkable ability to regulate the organization and function of its endocytic and secretory pathways during its development. This review describes recent insights into the cell-biological specializations responsible for the 'professional' status of the DC in antigen processing and presentation.
Nuclear receptor genes represent a large family of genes encoding receptors for various hydrophobic ligands such as steroids, vitamin D, retinoic acid and thyroid hormones. This family also contains genes encoding putative receptors for unknown ligands. Nuclear receptor gene products are composed of several domains important for transcriptional activation, DNA binding (C domain), hormone binding and dimerization (E domain). It is not known whether these genes have evolved through gene duplication from a common ancestor or if their different domains came from different independent sources. To test these possibilities we have constructed and compared the phylogenetic trees derived from two different domains of 30 nuclear receptor genes. The tree built from the DNA binding C domain clearly shows a common progeny of all nuclear receptors, which can be grouped into three subfamilies: (i) thyroid hormone and retinoic acid receptors, (ii) orphan receptors and (iii) steroid hormone receptors. The tree constructed from the central part of the E domain which is implicated in transcriptional regulation and dimerization shows the same distribution in three subfamilies but two groups of receptors are in a different position from that in the C domain tree: (i) the Drosophila knirps family genes have acquired very different E domains during evolution, and (ii) the vitamin D and ecdysone receptors, as well as the FTZ‐F1 and the NGF1B genes, seem to have DNA binding and hormone binding domains belonging to different classes. These data suggest a complex evolutionary history for nuclear receptor genes in which gene duplication events and swapping between domains of different origins took place.
Peroxisomes are single membrane-bound organelles, found in all cells, that contain a variety of enzymes involved in a number of metabolic processes1. The most well characterized reactions carried out by peroxisomes are those involved in fatty acid I3-oxidation. The peroxisomal β-oxidation system metabolizes very long chain and long chain fatty acids and cannot metabolize short chain fatty acids (<6 units) whereas the mitochondrial system most efficiently oxidizes long, medium and short chain fatty acids down to two carbon units. The peroxisomal acyl-CoA oxidase enzyme generates H2O2 while the corresponding mitochondrial enzymes lead to production of NADH. Since plants lack mitochondria, peroxisomes are solely responsible for their fatty acid β-oxidation. The production of H2O2 by peroxisomal acyl-CoA oxidase has been used as a cytological marker for the organelle through staining with diaminobenzidine and historically accounts for the name “peroxisomes”1. Peroxisome proliferation can result in an excess of H2O2 that can potentially result in toxicity as discussed below. Under usual circumstances H2O2 is decomposed to molecular oxygen and water by catalase and glutathione peroxidase.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily PPARα is highly expressed in liver, skeletal muscle, kidney, heart and the vascular wall. PPARγ is predominantly detected in adipose tissue, intestine and macrophages. PPARs are activated by fatty-acid derivatives and pharmacological agents such as fibrates and glitazones which are specific for PPARα and PPARγ respectively. PPARs regulate lipid and lipoprotein metabolism, glucose homeostasis, cell proliferation and differentiation, and apoptosis. PPARα controls intra- and extracellular lipid metabolisms whereas PPARγ triggers adipocyte differentiation and promotes lipid storage. In addition. PPARs also modulate the inflammatory response. PPAR activators have been shown to exert antiinflammatory activities in various cell types by inhibiting the expression of proinflammatory genes such as cytokines, metalloproteases and acute-phase proteins. PPARs negatively regulate the transcription of inflammatory response genes by antagonizing the AP-1, nuclear factor-KB (NF-κB), signal transducer and activator of transcription and nuclear factor of activated T-cells signalling pathways and by stimulating the catabolism of proinflammatory eicosanoids. These recent findings indicate a modulatory role for PPARs in inflammation with potential therapeutical applications in chronic inflammatory diseases.
Endothelium injury is a primary event in atherogenesis, which is followed by monocyte infiltration, macrophage differentiation, and smooth muscle cell migration. Peroxisome proliferator-activated receptors (PPARs) are transcription factors now recognized as important mediators in the inflammatory response. The aim of this study was to develop a human endothelial model to evaluate anti-inflammatory properties of PPAR activators. PPAR proteins (α, δ and γ) are expressed in EAhy926 endothelial cells (ECs). Pirinixic acid (Wy-14643), fenofibrate, fenofibric acid, the Merck ligand PPARδ activator L-165041, 15-deoxy-Δ12,14-prostaglandin J2, but not rosiglitazone (BRL-49653) inhibited the induced expression of vascular cell adhesion molecule-1 (VCAM-1), as measured by enzyme linked immunosorbent assay (ELISA), and monocyte binding to activated-EAhy926 cells. The PPARδ activator L-165041 had the greatest potency to reduce cytokine-induced monocyte chemotactic protein-1 (MCP-1) secretion. All PPAR activators tested which impaired VCAM-1 expression reduced significantly nuclear p65 amount. These results show that EAhy926 endothelial cells are an adequate tool to substantiate and characterize inflammatory impacts of PPAR activators.
Prostaglandins (PGs) of the J2 series form in vivo and exert effects on a variety of biological processes. While most PGs mediate their effects through G protein-coupled receptors, the mechanism of action for the J2 series of PGs remains unclear. Here, we report that PGJ2 and its derivatives are efficacious activators of peroxisome proliferator-activated receptors α and γ (PPARγ and PPARγ, respectively), orphan nuclear receptors implicated in lipid homeostasis and adipocyte differentiation. The PGJ2 metabolite 15-deoxy-Δ12,14-PGJ2 binds directly to PPARγ and promotes efficient differentiation of C3H10T1/2 fibroblasts to adipocytes. These data provide strong evidence that a fatty acid metabolite can function as an adipogenic agent through direct interactions with PPARγ and, furthermore, suggest a novel mechanism of action for PGs of the J2 series.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily. They are divided into three subtypes (α, β or δ, and γ) and are involved in lipid and glucose homeostasis and in the control of inflammation. In this study, we analyzed the expression of PPARs in murine dendritic cells (DCs), the most potent antigen presenting cells. We find that immature as well as mature spleen-derived DCs express PPARγ, but not PPARα, mRNA and protein. We also show that the PPARγ activator rosiglitazone does not interfere with the maturation of DCs in vitro nor modifies their ability to activate naive T lymphocytes in vivo. Finally, we present evidence that PPARγ activators down-modulate the CD40-induced secretion of interleukin-12, a potent Th1-driving factor. These data suggest a possible role for PPARγ in the regulation of immune responses.
OBJECTIVES:Previous research has demonstrated that ligands for the γ subtype of peroxisome proliferator-activated receptors (PPARs) reduce inflammation in two different murine models of colitis. This study was designed to examine the potential efficacy of rosiglitazone, a ligand for the γ subtype of PPARs, as a therapy for active ulcerative colitis.METHODS:Fifteen patients with mild to moderately active ulcerative colitis despite therapy with 5-aminosalicylic acid compounds were enrolled in an open-label study of rosiglitazone (4 mg b.i.d. p.o.) for 12 wk. Thirteen of 15 patients were receiving concomitant therapy with corticosteroids and/or immunomodulator medications. Disease activity was measured with the Disease Activity Index.RESULTS:After 12 wk of therapy, four patients (27%) had achieved clinical remission, of whom three (20%) also had an endoscopic remission. Four additional patients (27%) had a clinical response without achieving remission. Two patients were hospitalized with worsened disease activity, and one patient was withdrawn for nephrotic syndrome.CONCLUSIONS:These data suggest that ligands for the γ subtype of PPARs may represent a novel therapy for ulcerative colitis. A double blind, placebo-controlled, randomized trial is warranted.
Fibrates are widely used hypolipidemic drugs that act by modulating the expression of genes involved in lipid and lipoprotein metabolism. Whereas the activation of gene transcription by fibrates occurs via the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR alpha) interacting with response elements consisting of a direct repeat of the AGGTCA motif spaced by one nucleotide (DR1), the mechanisms of negative gene regulation by fibrates and PPAR alpha are largely unknown. In the present study, we demonstrate that fibrates induce the expression of the nuclear receptor Rev-erb alpha, a negative regulator of gene transcription. Fibrates increase Rev-erb alpha mRNA levels both in primary human hepatocytes and in HepG2 hepatoblastoma cells. In HepG2 cells, fibrates furthermore induce Rev-erb alpha protein synthesis rates. Transfection studies with reporter constructs driven by the human Rev-erb alpha promoter revealed that fibrates induce Rev-erb alpha expression at the transcriptional level via PPAR alpha. Site-directed mutagenesis experiments identified a PPAR response element that coincides with the previously identified Rev-erb alpha negative autoregulatory Rev-DR2 element. Electromobility shift assay experiments indicated that PPAR alpha binds as heterodimer with 9-cis-retinoic acid receptor to a subset of DR2 elements 5' flanked by an A/T-rich sequence such as in the Rev-DR2. PPAR alpha and Rev-erb alpha bind with similar affinities to the Rev-DR2 site. In conclusion, these data demonstrate human Rev-erb alpha as a PPAR alpha target gene and identify a subset of DR2 sites as novel PPAR alpha response elements. Finally, the PPAR alpha and Rev-erb alpha signaling pathways crosstalk through competition for binding to those response elements.
The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-dependent nuclear receptor that has been implicated in the modulation of critical aspects of development and homeostasis, including adipocyte differentiation, glucose metabolism, and macrophage development and function. PPAR-gamma is activated by a range of synthetic and naturally occurring substances, including antidiabetic thiazolidinediones,, polyunsaturated fatty acids, 15-deoxy-Delta12,14prostaglandin J2 (refs 8, 9) and components of oxidized low-density lipoprotein, such as 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE). However, the identities of endogenous ligands for PPAR-gamma and their means of production in vivo have not been established. In monocytes and macrophages, 13-HODE and 15-HETE can be generated from linoleic and arachidonic acids, respectively, by a 12/15-lipoxygenase that is upregulated by the TH2-derived cytokine interleukin-4 (ref. 11). Here we show that interleukin-4 also induces the expression of PPAR-gamma and provide evidence that the coordinate induction of PPAR-gamma and 12/15-lipoxygenase mediates interleukin-4-dependent transcription of the CD36 gene in macrophages. These findings reveal a physiological role of 12/15-lipoxygenase in the generation of endogenous ligands for PPAR-gamma, and suggest a paradigm for the regulation of nuclear receptor function by cytokines.
Peroxisome proliferator-activated receptors (PPARs) have been implicated in metabolic diseases, such as obesity, diabetes,
and atherosclerosis, due to their activity in liver and adipose tissue on genes involved in lipid and glucose homeostasis.
Here, we show that the PPARα and PPARγ forms are expressed in differentiated human monocyte-derived macrophages, which participate
in inflammation control and atherosclerotic plaque formation. Whereas PPARα is already present in undifferentiated monocytes,
PPARγ expression is induced upon differentiation into macrophages. Immunocytochemistry analysis demonstrates that PPARα resides
constitutively in the cytoplasm, whereas PPARγ is predominantly nuclear localized. Transient transfection experiments indicate
that PPARα and PPARγ are transcriptionally active after ligand stimulation. Ligand activation of PPARγ, but not of PPARα,
results in apoptosis induction of unactivated differentiated macrophages as measured by the TUNEL assay and the appearance
of the active proteolytic subunits of the cell death protease caspase-3. However, both PPARα and PPARγ ligands induce apoptosis
of macrophages activated with tumor necrosis factor α/interferon γ. Finally, PPARγ inhibits the transcriptional activity of
the NFκB p65/RelA subunit, suggesting that PPAR activators induce macrophage apoptosis by negatively interfering with the
anti-apoptotic NFκB signaling pathway. These data demonstrate a novel function of PPAR in human macrophages with likely
consequences in inflammation and atherosclerosis.
Peroxisome proliferator-activated receptor-γ (PPARγ) has been shown to play an important role in the regulation of expression
of a subclass of adipocyte genes and to serve as the molecular target of the thiazolidinedione (TZD) and certain non-TZD antidiabetic
agents. Hypercorticosteroidism leads to insulin resistance, a variety of metabolic dysfunctions typically seen in diabetes,
and hypertrophy of visceral adipose tissue. In adipocytes, the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1)
converts inactive cortisone into the active glucocorticoid cortisol and thereby plays an important role in regulating the
actions of corticosteroids in adipose tissue. Here, we show that both TZD and non-TZD PPARγ agonists markedly reduced 11β-HSD-1
gene expression in 3T3-L1 adipocytes. This diminution correlated with a significant decrease in the ability of the adipocytes
to convert cortisone to cortisol. The half-maximal inhibition of 11β-HSD-1 mRNA expression by the TZD, rosiglitazone, occurred
at a concentration that was similar to its K
d for binding PPARγ and EC50 for inducing adipocyte differentiation thereby indicating that this action was PPARγ-dependent. The time required for the
inhibitory action of the TZD was markedly greater for 11β-HSD-1 gene expression than for leptin, suggesting that these genes
may be down-regulated by different molecular mechanisms. Furthermore, whereas regulation of PPARγ-inducible genes such as
phosphoenolpyruvate carboxykinase was maintained when cellular protein synthesis was abrogated, PPARγ agonist inhibition of
11β-HSD-1 and leptin gene expression was ablated, thereby supporting the conclusion that PPARγ affects the down-regulation
of 11β-HSD-1 indirectly. Finally, treatment of diabetic db/db mice with rosiglitazone inhibited expression of 11β-HSD-1 in
adipose tissue. This decrease in enzyme expression correlated with a significant decline in plasma corticosterone levels.
In sum, these data indicate that some of the beneficial effects of PPARγ antidiabetic agents may result, at least in part,
from the down-regulation of 11β-HSD-1 expression in adipose tissue.
