PPAR Research最新文献

[This corrects the article DOI: 10.1155/2021/6632137.].

The receptor known as peroxisome proliferator-activated receptor gamma (PPARγ) is crucial for effective wound healing, and recent progress has given a deeper understanding of its complex functions. As a biological switch, PPARγ regulates the immune response by shifting macrophages from promoting inflammation to supporting tissue regeneration, while suppressing pro-inflammatory signals to create an ideal healing environment. At the cellular level, PPARγ enhances the migration of keratinocytes and promotes re-epithelialization, thereby accelerating the wound closure process. It also promotes the differentiation of preadipocytes and the formation of new blood vessels, making a significant contribution to tissue regeneration. At the molecular level, PPARγ plays a dual role in guiding epithelial-mesenchymal transformation to aid healing while preventing excessive scarring. It improves mitochondrial efficiency to provide the energy needed for tissue repair. Despite these promising mechanisms, the clinical use of current PPARγ agonists faces hurdles due to side effects and regulatory hurdles. Moving forward, research should aim to develop targeted delivery methods, tailor therapies to individual needs, and investigate how PPARγ interacts synergistically with other signaling pathways, all of which are essential steps toward translating these findings into clinical practice.

Objective: The objective was to investigate the effects and potential molecular mechanisms of emodin on colorectal cancer via network pharmacology combined with experimental validation.

Methods: The active components and targets of emodin were retrieved from TCMSP and BATMAN-TCM databases, while colorectal cancer (CRC)-related genes were screened via GeneCards, OMIM, and DisGeNET. The intersection targets were used to construct a compound-disease network and a protein-protein interaction (PPI) network. GO and KEGG enrichment analyses were conducted to reveal key biological functions and pathways. Molecular docking was used to assess binding affinities between core targets and active components. In vitro experiments (CCK-8, colony formation, and apoptosis assays) and in vivo xenograft models were performed to validate the antitumor effect of emodin. Quantitative real-time PCR and Western blot were used to evaluate the regulation of hub genes and signaling pathways.

Results: A total of 37 active components and 235 targets of emodin were identified, of which 82 overlapped with CRC-related genes. Core targets (CASP3, MMP9, BCL2, PTGS2, and IL1B) were highlighted through network analysis. These targets were enriched in oxidative stress, apoptosis, inflammation, and metabolic pathways. Molecular docking showed strong interactions between emodin and hub targets. Emodin significantly suppressed proliferation, colony formation, and induced apoptosis in CRC cell lines in a dose-dependent manner. In vivo, emodin inhibited tumor growth and activated the PPARγ-TP53 signaling axis.

Conclusion: Emodin exerts anti-CRC effects via a multitarget, multipathway mechanism, particularly through modulation of the PPARγ-TP53 axis. These findings support emodin's potential as a natural compound for CRC treatment.

Background and aims: The selective peroxisome proliferator-activated receptor delta (PPARD) agonist seladelpar reduces liver injury and modulates bile acid metabolism in preclinical models. Seladelpar was recently approved for the secondary treatment of primary biliary cholangitis (PBC). Despite its beneficial effects for liver diseases, the target cells of seladelpar on a single-cell level remain unknown. This study is aimed at investigating the effect of seladelpar on single liver cells.

Methods and results: CD-1 mice were gavaged with vehicle or seladelpar (10 mg/kg body weight), and the liver was harvested 6 h later. Single-nuclei RNA sequencing (snRNA-seq) analysis showed the engagement of PPARD target genes primarily in hepatocytes and cholangiocytes by seladelpar. The top two upregulated genes, Ehhadh and Cyp4a14, are related to fatty acid metabolism and were increased in hepatocytes, cholangiocytes, and Kupffer cells. Abcb4, an important canalicular transporter with hepatoprotective effects, was significantly upregulated in hepatocytes. We confirmed upregulated Abcb4 gene expression in seladelpar-treated primary mouse hepatocytes isolated from C57BL/6 mice. We further incubated nonparenchymal liver cells with seladelpar. Although there was a significant increase in the PPARD-responsive genes Pdk4 and Angptl4 in cholangiocytes, Kupffer cells, and hepatic stellate cells, seladelpar did not exert specific liver-protective effects in these cell types.

Conclusion: The selective PPARD agonist seladelpar induced PPARD-responsive genes primarily in hepatocytes and cholangiocytes. Seladelpar upregulated Abcb4 in hepatocytes, which might contribute to its beneficial effects in cholestatic liver disorders.

Perivascular adipose tissue (PVAT) plays a crucial role in vascular homeostasis. Recent studies in adipose tissue demonstrated that endoplasmic reticulum (ER) stress and autophagy are activated in Type 2 diabetes mellitus (T2DM), while the precise role of ER stress and autophagy in PVAT is unclear. We aimed to investigate the possible influence of pioglitazone on ER stress and autophagy response in PVAT of T2DM rats. T2DM was induced by high-fat diet/low-dose streptozotocin (HFD/STZ) in male Wistar rats (8-10 weeks), and pioglitazone (20 mg/kg/p.o.) was administered for 6 weeks. Changes in biochemical parameters (nonfasting glucose, total cholesterol, and triglyceride) were verified in blood samples. ER stress-related (ATF4, CHOP, and GRP78) and autophagy-related (MAP1LC3B/LC3-II, BECN-1/Beclin, and SQSTM1/p62) gene expression levels in thoracic PVAT were measured by RT-PCR. Pioglitazone treatment reversed the increased nonfasting glucose and triglyceride levels in T2DM. ER stress and autophagy responses were significantly increased in PVAT of T2DM rats. Pioglitazone increased ER stress-related GRP78 gene expression while decreasing autophagy-related MAP1LC3B and BECN-1 gene expression levels in T2DM. Interestingly, SQSTM1 gene expression levels were increased by pioglitazone in the control and T2DM groups. The current study provides original findings regarding the effects of pioglitazone on ER stress and autophagy response in PVAT of HFD/STZ-induced T2DM rats. Pioglitazone treatment in T2DM increased GRP78 and SQSTM1 gene expressions, which both play a crucial role in adipocyte differentiation and adipogenesis, besides ER stress and autophagy. Further studies clarifying the adipogenic effect of pioglitazone on PVAT are needed for a better understanding of its effect on the vascular system.

Peroxisome proliferator-activated receptors (PPARs) modulate bile metabolism and are important therapeutic options in cholestatic diseases. This study was aimed at understanding the effects of single and multiple doses of seladelpar, a PPARδ (peroxisome proliferator-activated receptor delta) agonist, on plasma C4 (a freely diffusible metabolite accepted as a proxy for de novo bile acid biosynthesis), Fibroblast Growth Factor 21 (Fgf21), and gene expression changes in the liver of male and female mice. C57BL/6 mice were treated with seladelpar 10 mg/kg/day or vehicle through oral gavage before lights out on Day 1 (single dose) or from Day 1 to Day 7 (multiple doses). Liver samples were obtained at 0, 1, 2, 4, 8, 12, 16, and 24 h postdosing, and plasma C4 and Fgf21 levels were measured. In vehicle-treated mice, C4 levels were higher in the dark cycle compared to the light cycle, with higher levels in females than in males. Plasma Fgf21 did not vary substantially over the dark-light cycle or show a sex-specific expression pattern. Seladelpar treatment significantly reduced plasma C4 and increased Fgf21 levels in both sexes, which coincided with a decrease in cholesterol 7α-hydroxylase mRNA and an increase in Fgf21 mRNA in the livers. Untargeted RNA sequencing revealed a strong correlation between the genes differentially expressed after single- and multiple-dose seladelpar treatment. PPAR-responsive genes, including pyruvate dehydrogenase kinase 4, acyl-CoA thioesterase 2, and angiopoietin-like 4, were upregulated. No changes in nuclear receptors, clock genes, and sex-specific genes were observed. Overall, these results are consistent with a model where seladelpar treatment reduces bile acid synthesis by upregulating Fgf21 and modulating other PPAR-responsive genes.

Triple-negative breast cancer (TNBC) is highly heterogeneous and poses a significant medical challenge due to limited treatment options and poor outcomes. Peroxisome proliferator-activated receptors (PPARs) play a crucial role in regulating metabolism and cell fate. While the association between PPAR signal and human cancers has been a topic of concern, its specific relationship with TNBC remains unclear. Integrated analysis of large published datasets from clinical cohorts and cell lines through databases has proven to be a powerful and essential approach for understanding cancer and uncovering new molecular targets. Here, we conducted a comprehensive study investigating the clinical relevance and drug modulation of the PPAR signaling pathway in TNBC, using data from The Cancer Genome Atlas (TCGA) for TNBC patients and Genomics of Drug Sensitivity in Cancer (GDSC) for TNBC cell lines, along with drug perturbation information from Connectivity Map (CMap). In the TCGA-TNBC cohort, higher PPAR signaling activity was not associated with clinical stage, prognosis, tumor mutational burden, microsatellite instability, homologous recombination deficiency, stemness, or proliferation status. However, it was linked to older age; an elevated rate of piccolo presynaptic cytomatrix protein (PCLO) mutations; and oncogenic signal transduction involving MAPK, Ras, and PI3K-Akt pathways. Additionally, it influenced biological pathways including fatty acid metabolism, AMPK signaling, and ferroptosis. Strikingly, higher PPAR activity appeared to promote the formation of an antitumor immune and microbial microenvironment. In the GDSC-TNBC cells, nevertheless, it seemed to incur chemoresistance. Furthermore, we identified a batch of potential compounds that can regulate the PPAR signaling pathway. Lastly, our experimental validation demonstrated the ability of the histone deacetylase (HDAC) inhibitor chidamide to activate the PPAR signal in TNBC cells. In conclusion, the PPAR signaling pathway likely has pleiotropic biological effects in TNBC. These preliminary but interesting findings enhance our understanding of the role played by PPAR signal and provide new insights into the heterogeneity driven by it in TNBC.

Background: Hyperlipidemia is a critical risk factor for obesity, diabetes, cardiovascular diseases, and other chronic diseases. Our study was to determine the effects and mechanism of mangiferin (MF) and epigallocatechin gallate (EGCG) compounds on improving hyperlipidemia in HepG2 cells. Methods: HepG2 cells were treated with 0.25 mM palmitic acid (PA) and then incubated with MF (12.5, 25, and 50 μM) or EGCG (25, 50, and 100 μM) or MF:EGCG (0:0, 6.25:12.5, 25:50, and 50:100 μM:μM) for 24 h. The improvement of hyperlipidemia was verified by Oil Red O staining, changes in triglyceride (TG) and free fatty acid (FFA) levels, and the expression of lipid metabolizing proteins in western blotting. Results: MF (12.5, 25, and 50 μM) or EGCG (25, 50, and 100 μM) markedly lowered lipid accumulations by lipid index levels. Furthermore, we found that the optimum concentration of MF and EGCG compounds was 25:50 (μM:μM), which significantly reduced the FFA level, TG, and total cholesterol (TC) accumulations and increased FFA uptake in HepG2 cells, and the effect was better than that of single phytochemicals. The adenosine 5⁣'-monophosphate (AMP)-activated protein kinase (AMPK) protein and its downstream proteins sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor α (PPARα), and those involved in fatty acid translocase (CD36) and carnitine palmitoyltransferase 1 (CPT1) were also markedly increased in HepG2 cells. The upregulation of protein expression was reversed when AMPK-specific inhibitor Compound C was added. Conclusions: MF and EGCG (25:50 μM) compounds protect against hyperlipidemia by promoting the FFA oxidation, alleviating TG and TC accumulations via the AMPK/PPARα pathway in PA-treated HepG2 cells.

Paraquat (PQ) is an herbicide toxin that induces injury in different organs. The anti-inflammatory and antioxidant effects of carvacrol were reported previously. The effects of carvacrol and pioglitazone (Pio) alone and their combination on inhaled PQ-induced systemic and lung oxidative stress and inflammation as well as behavioral changes were examined in rats. In this study, animals were exposed to saline (control [Ctrl]) or PQ (PQ groups) aerosols. PQ-exposed animals were treated with 0.03 mg/kg/day dexamethasone (Dexa), 20 and 80 mg/kg/day carvacrol (C-L and C-H), 5 mg/kg/day Pio, and Pio+C-L for 16 days. Inhaled PQ markedly enhanced total and differential white blood cell (WBC) counts, nitric oxide (NO), and malondialdehyde (MDA) levels but decreased catalase (CAT) and superoxide dismutase (SOD) activities and thiol levels both in the bronchoalveolar lavage fluid (BALF) and blood and increased interferon-gamma (INF-γ) and interleukin-10 (IL-10) levels in the BALF (p < 0.001 for all cases) except lymphocyte count in blood which was not significantly changed. The escape latency and traveled distance were increased in the PQ group. However, the time spent in the target quadrant in the Morris water maze (MWM) test and the duration of time latency in the dark room in the shuttle box test were reduced after receiving an electrical shock (p < 0.05-p < 0.001). Inhaled PQ-induced changes were significantly improved in carvacrol, Pio, Dexa, and especially in the combination of the Pio+C-L treated groups (p < 0.05-p < 0.001). Carvacrol and Pio improved PQ-induced changes similar to Dexa, but ameliorative effects produced by combination treatments of Pio+C-L were more prominent than Pio and C-L alone, suggesting a potentiating effect for the combination of the two agents.

We have previously reported the identification of a novel splicing variant of the mouse peroxisome proliferator-activated receptor-γ (Pparγ), referred to as Pparγ1sv. This variant, encoding the PPARγ1 protein, is abundantly and ubiquitously expressed, playing a crucial role in adipogenesis. Pparγ1sv possesses a unique promoter and 5' untranslated region (5'UTR), distinct from those of the canonical mouse Pparγ1 and Pparγ2 mRNAs. We observed a significant increase in DNA methylation at two CpG sites within the proximal promoter region (-733 to -76) of Pparγ1sv during adipocyte differentiation. Concurrently, chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) using antibodies against H3K4me3 and H3K27ac indicated marked elevations in both methylation and acetylation of histone H3, while the repressive histone mark H3K9me2 significantly decreased, at the transcription start sites of both Pparγ1sv and Pparγ2 following differentiation. Knocking down Pparγ1sv using specific siRNA also led to a decrease in Pparγ2 mRNA and PPARγ2 protein levels; conversely, knocking down Pparγ2 resulted in reduced Pparγ1sv mRNA and PPARγ1 protein levels, suggesting synergistic transcriptional regulation of Pparγ1sv and Pparγ2 during adipogenesis. Furthermore, our experiments utilizing the CRISPR-Cas9 system identified crucial PPARγ-binding sites within the Pparγ gene locus, underscoring their significance in adipogenesis. Based on these findings, we propose a model of positive feedback regulation for Pparγ1sv and Pparγ2 expression during the adipocyte differentiation process in 3T3-L1 cells.