Bisphenol A diglycidyl ether induces apoptosis in tumour cells independently of peroxisome proliferator-activated receptor-gamma, in caspase-dependent and -independent manners.
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ABSTRACT:
SUBMITTER: Fehlberg S
PROVIDER: S-EPMC1222420 | biostudies-other | 2002 Mar
REPOSITORIES: biostudies-other
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Project description:BackgroundBisphenol A (BPA) and bisphenol A diglycidyl ether (BADGE), used in manufacturing coatings and resins, leach from packaging materials into food. Numerous studies suggested that BPA and BADGE may have adverse effects on human health, including the possibility that exposure to such chemicals can be superimposed on traditional risk factors to initiate or exacerbate the development of obesity. BPA is a suspected obesogen, whereas BADGE, described as a peroxisome proliferator-activated receptor gamma (PPAR?) antagonist, could reduce weight gain.ObjectivesWe sought to test the adipogenic effects of BADGE in a biologically relevant cell culture model.MethodsWe used multipotent mesenchymal stromal stem cells (MSCs) to study the adipogenic capacity of BADGE and BPA and evaluated their effects on adipogenesis, osteogenesis, gene expression, and nuclear receptor activation.DiscussionBADGE induced adipogenesis in human and mouse MSCs, as well as in mouse 3T3-L1 preadipocytes. In contrast, BPA failed to promote adipogenesis in MSCs, but induced adipogenesis in 3T3-L1 cells. BADGE exposure elicited an adipogenic gene expression profile, and its ability to induce adipogenesis and the expression of adipogenic genes was not blocked by known PPAR? antagonists. Neither BADGE nor BPA activated or antagonized retinoid "X" receptor (RXR) or PPAR? in transient transfection assays.ConclusionsBADGE can induce adipogenic differentiation in both MSCs and in preadipocytes at low nanomolar concentrations comparable to those that have been observed in limited human biomonitoring. BADGE probably acts through a mechanism that is downstream of, or parallel to, PPAR?.
| S-EPMC3404682 | biostudies-literature
Project description:Peroxisome proliferator-activated receptor gamma agonists have been proposed as breast cancer preventives. Individuals who carry a mutated copy of BRCA1, DNA repair-associated gene, are at increased risk for development of breast cancer. Published data in the field suggest there could be interactions between peroxisome proliferator-activated receptor gamma and BRCA1 that could influence the activity of peroxisome proliferator-activated receptor gamma agonists for prevention. This review explores these possible interactions between peroxisome proliferator-activated receptor gamma, peroxisome proliferator-activated receptor gamma agonists and BRCA1 and discusses feasible experimental directions to provide more definitive information on the potential connections.
| S-EPMC6494719 | biostudies-literature
Project description:Abscisic acid (ABA) has shown efficacy in the treatment of diabetes and inflammation; however, its molecular targets and the mechanisms of action underlying its immunomodulatory effects remain unclear. This study investigates the role of peroxisome proliferator-activated receptor ? (PPAR ?) and lanthionine synthetase C-like 2 (LANCL2) as molecular targets for ABA. We demonstrate that ABA increases PPAR ? reporter activity in RAW 264.7 macrophages and increases ppar ? expression in vivo, although it does not bind to the ligand-binding domain of PPAR ?. LANCL2 knockdown studies provide evidence that ABA-mediated activation of macrophage PPAR ? is dependent on lancl2 expression. Consistent with the association of LANCL2 with G proteins, we provide evidence that ABA increases cAMP accumulation in immune cells. ABA suppresses LPS-induced prostaglandin E(2) and MCP-1 production via a PPAR ?-dependent mechanism possibly involving activation of PPAR ? and suppression of NF-?B and nuclear factor of activated T cells. LPS challenge studies in PPAR ?-expressing and immune cell-specific PPAR ? null mice demonstrate that ABA down-regulates toll-like receptor 4 expression in macrophages and T cells in vivo through a PPAR ?-dependent mechanism. Global transcriptomic profiling and confirmatory quantitative RT-PCR suggest novel candidate targets and demonstrate that ABA treatment mitigates the effect of LPS on the expression of genes involved in inflammation, metabolism, and cell signaling, in part, through PPAR ?. In conclusion, ABA decreases LPS-mediated inflammation and regulates innate immune responses through a bifurcating pathway involving LANCL2 and an alternative, ligand-binding domain-independent mechanism of PPAR ? activation.
| S-EPMC3024745 | biostudies-literature
Project description:The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis. The PPARgamma subtype plays a central role in the regulation of adipogenesis and is the molecular target for the 2, 4-thiazolidinedione class of antidiabetic drugs. Structural studies have revealed that agonist ligands activate the PPARs through direct interactions with the C-terminal region of the ligand-binding domain, which includes the activation function 2 helix. GW0072 was identified as a high-affinity PPARgamma ligand that was a weak partial agonist of PPARgamma transactivation. X-ray crystallography revealed that GW0072 occupied the ligand-binding pocket by using different epitopes than the known PPAR agonists and did not interact with the activation function 2 helix. In cell culture, GW0072 was a potent antagonist of adipocyte differentiation. These results establish an approach to the design of PPAR ligands with modified biological activities.
| S-EPMC26842 | biostudies-literature
Project description:Oleuropein, the major phenolic compound found in olive leaves and oil, exerts antioxidant, anti-inflammatory and anti-atherogenic effects and suppresses the adipocyte differentiation in vitro. Herein, we characterized molecular mechanisms underlying the anti-adipogenic effects of oleuropein on 3T3-L1 cells and adipocytes derived from stromal-vascular fraction of dorsolumbar and gonadal fat dissected from mice. We found that oleuropein (>100 ?M) decreased viability of preadipocytes proliferating in vitro and did not exerted any cytotoxic effects in post-confluent cells after induction of differentiation. Oleuropein (>100 ?M) inhibited adipocyte differentiation, suppressed gene expression of peroxisome proliferator-activated receptor ? (PPAR?), CCAAT-/enhancer-binding protein ?, sterol regulatory element-binding transcription factor 1c and fatty acid synthase. Furthermore, we tested ability of oleuropein to regulate of PPAR?-, PPAR?- or PPAR?-/PPAR?-mediated ?-lactamase expression in appropriate reporter gene assays. Oleuropein between 10 and 400 ?M concentrations did not affect activity of PPAR? or PPAR?/?. Contrary, PPAR? activity, either basal or rosiglitazone activated, was inhibited by oleuropein. Our data suggest that oleuropein exerts anti-adipogenic effect through direct inhibition of PPAR? transcriptional activity.
| S-EPMC3896615 | biostudies-literature
Project description:Single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor gamma (PPARG) gene have been associated with cardiovascular risk factors, particularly obesity and diabetes. We assessed the relationship between 4 PPARG SNPs (C-681G, C-689T, Pro12Ala, and C1431T) and coronary heart disease (CHD) in the PRIME (249 cases/494 controls, only men) and ADVANCE (1,076 cases/805 controls, men or women) studies. In PRIME, homozygote individuals for the minor allele of the PPARG C-689T, Pro12Ala, and C1431T SNPs tended to have a higher risk of CHD than homozygote individuals for the frequent allele (adjusted OR [95% CI] = 3.43 [0.96-12.27], P = .058, 3.41 [0.95-12.22], P = .060 and 5.10 [0.99-26.37], P = .050, resp.). No such association could be detected in ADVANCE. Haplotype distributions were similar in cases and control in both studies. A meta-analysis on the Pro12Ala SNP, based on our data and 11 other published association studies (6,898 CHD cases/11,287 controls), revealed that there was no evidence for a significant association under the dominant model (OR = 0.99 [0.92-1.07], P = .82). However, there was a borderline association under the recessive model (OR = 1.29 [0.99-1.67], P = .06) that became significant when considering men only (OR = 1.73 [1.20-2.48], P = .003). In conclusion, the PPARG Ala12Ala genotype might be associated with a higher CHD risk in men but further confirmation studies are needed.
| S-EPMC2792957 | biostudies-literature
Project description:Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor drugable by agonists approved for treatment of type 2 diabetes, but also inhibits carcinogenesis and cell proliferation in vivo. Activating mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene mitigate these beneficial effects by promoting a negative feedback-loop comprising extracellular signal-regulated kinase 1/2 (ERK1/2) and mitogen-activated kinase kinase 1/2 (MEK1/2)-dependent inactivation of PPARγ. To overcome this inhibitory mechanism, we searched for novel post-translational regulators of PPARγ. Phosphoinositide phosphatase Myotubularin-Related-Protein-7 (MTMR7) was identified as cytosolic interaction partner of PPARγ. Synthetic peptides were designed resembling the regulatory coiled-coil (CC) domain of MTMR7, and their activities studied in human cancer cell lines and C57BL6/J mice. MTMR7 formed a complex with PPARγ and increased its transcriptional activity by inhibiting ERK1/2-dependent phosphorylation of PPARγ. MTMR7-CC peptides mimicked PPARγ-activation in vitro and in vivo due to LXXLL motifs in the CC domain. Molecular dynamics simulations and docking predicted that peptides interact with the steroid receptor coactivator 1 (SRC1)-binding site of PPARγ. Thus, MTMR7 is a positive regulator of PPARγ, and its mimicry by synthetic peptides overcomes inhibitory mechanisms active in cancer cells possibly contributing to the failure of clinical studies targeting PPARγ.
| S-EPMC7286916 | biostudies-literature
Project description:CONTEXT: Obesity is a multifactorial disorder, that is, a disease determined by the combined effect of genes and environment. In this context, polygenic approaches are needed. OBJECTIVE: To investigate the possibility of the existence of a crosstalk between the CALPAIN 10 homologue CALPAIN 5 and nuclear receptors of the peroxisome proliferator-activated receptors family. DESIGN: Cross-sectional, genetic association study and gene-gene interaction analysis. SUBJECTS: The study sample comprise 1953 individuals, 725 obese (defined as body mass index > or = 30) and 1228 non obese subjects. RESULTS: In the monogenic analysis, only the peroxisome proliferator-activated receptor delta (PPARD) gene was associated with obesity (OR = 1.43 [1.04-1.97], p = 0.027). In addition, we have found a significant interaction between CAPN5 and PPARD genes (p = 0.038) that reduces the risk for obesity in a 55%. CONCLUSION: Our results suggest that CAPN5 and PPARD gene products may also interact in vivo.
| S-EPMC2527300 | biostudies-literature
Project description:BACKGROUND: The occurrence of halogenated analogs of the xenoestrogen bisphenol A (BPA) has been recently demonstrated both in environmental and human samples. These analogs include brominated [e.g., tetrabromobisphenol A (TBBPA)] and chlorinated [e.g., tetrachlorobisphenol A (TCBPA)] bisphenols, which are both flame retardants. Because of their structural homology with BPA, such chemicals are candidate endocrine disruptors. However, their possible target(s) within the nuclear hormone receptor superfamily has remained unknown. OBJECTIVES: We investigated whether BPA and its halogenated analogs could be ligands of estrogen receptors (ERs) and peroxisome proliferator-activated receptors (PPARs) and act as endocrine-disrupting chemicals. METHODS: We studied the activity of compounds using reporter cell lines expressing ERs and PPARs. We measured the binding affinities to PPAR? by competitive binding assays with [3H]-rosiglitazone and investigated the impact of TBBPA and TCBPA on adipocyte differentiation using NIH3T3-L1 cells. Finally, we determined the binding mode of halogenated BPAs to PPAR? by X-ray crystallography. RESULTS: We observed that TBBPA and TCBPA are human, zebrafish, and Xenopus PPAR? ligands and determined the mechanism by which these chemicals bind to and activate PPAR?. We also found evidence that activation of ER?, ER?, and PPAR? depends on the degree of halogenation in BPA analogs. We observed that the bulkier brominated BPA analogs, the greater their capability to activate PPAR? and the weaker their estrogenic potential. CONCLUSIONS: Our results strongly suggest that polyhalogenated bisphenols could function as obesogens by acting as agonists to disrupt physiological functions regulated by human or animal PPAR?.
| S-EPMC3230400 | biostudies-literature
Project description:Studies have demonstrated cross talk between beta-catenin and peroxisome proliferator-activated receptor gamma (PPARgamma) signaling pathways. Specifically, activation of PPARgamma induces the proteasomal degradation of beta-catenin in cells that express an adenomatous polyposis coli-containing destruction complex. In contrast, oncogenic beta-catenin is resistant to such degradation and inhibits the expression of PPARgamma target genes. In the present studies, we demonstrate a functional interaction between beta-catenin and PPARgamma that involves the T-cell factor (TCF)/lymphocyte enhancer factor (LEF) binding domain of beta-catenin and a catenin binding domain (CBD) within PPARgamma. Mutation of K312 and K435 in the TCF/LEF binding domain of an oncogenic beta-catenin (S37A) significantly reduces its ability to interact with and inhibit the activity of PPARgamma. Furthermore, these mutations render S37A beta-catenin susceptible to proteasomal degradation in response to activation of PPARgamma. Mutation of F372 within the CBD (helices 7 and 8) of PPARgamma disrupts its binding to beta-catenin and significantly reduces the ability of PPARgamma to induce the proteasomal degradation of beta-catenin. We suggest that in normal cells, PPARgamma can function to suppress tumorigenesis and/or Wnt signaling by targeting phosphorylated beta-catenin to the proteasome through a process involving its CBD. In contrast, oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain.
| S-EPMC1592783 | biostudies-literature