Search Results (141)

Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of lipid metabolism, making its agonists valuable therapeutic targets for various diseases, including chronic peripheral neuropathy. Existing PPARα agonists face limitations such as poor selectivity, sub-optimal bioavailability, and safety concerns. We previously demonstrated that A190, a novel, potent, and selective PPARα agonist, effectively alleviates chemotherapy-induced peripheral neuropathy and CFA-induced inflammatory pain as a non-opioid therapeutic agent. However, A190 alone has solubility and permeability issues that limits its oral delivery. To overcome this challenge, in this study, four new-generation ester prodrugs of A190; A190-PD-9 (methyl ester), A190-PD-14 (ethyl ester), A190-PD-154 (isopropyl ester), and A190-PD-60 (cyclic carbonate) were synthesized and evaluated for their enzymatic bioconversion and chemical stability. The lead candidate, A190-PD-60, was further formulated as a microemulsion (A190-PD-60-ME) and optimized via Box–Behnken design. A190-PD-60-ME featured nano-sized droplets (~120 nm), low polydispersity (PDI < 0.3), and high drug loading (>90%) with significant improvement in artificial membrane permeability. Crucially, pharmacokinetic evaluation in rats demonstrated that A190-PD-60-ME reached a 16.6-fold higher Cmax (439 ng/mL) and a 5.9-fold increase in relative oral bioavailability compared with an A190-PD-60 dispersion. These findings support the combined prodrug-microemulsion approach as a promising strategy to overcome oral bioavailability challenges and advance PPARα-targeted therapies. Full article

This review highlights recent findings on the potent anti-angiogenic serpin protein, pigment epithelium-derived factor (PEDF) as it relates to metabolic disease, diabetes, angiogenesis and cardiovascular disease (CVD), listing a majority of all the publicly available studies reported to date. PEDF is involved in various physiological roles in the body, and when awry, it triggers various disease states clinically. Biomarkers such as insulin, AMP-activated protein kinase alpha (AMPK-α), and peroxisome proliferator-activated receptor gamma (PPAR-γ) are involved in PEDF effects on metabolism. Wnt, insulin receptor substate (IRS), Akt, extracellular signal-regulated kinase (ERK), and mitogen-activated protein kinase (MAPK) are implicated in diabetes effects displayed by PEDF. For CVD, oxidised LDL, Wnt/β-catenin, and reactive oxygen species (ROS) are players intertwined with PEDF activity. The review also presents an outlook on where efforts could be devoted to bring this serpin closer to clinical trials for these diseases and others in general. Full article

The focus on selecting broilers for rapid growth rates and enhanced breast muscle yield has resulted in a decline in meat quality. The differences in carcass characteristics and meat quality between Hubbard white broilers (HWs, a commercial breed) and Xueshan chickens (XSs, an indigenous breed) at market age were analyzed to determine the potential mechanisms responsible for these differences. The results show that HWs exhibited significantly better carcass performance than XSs, including the larger weight of the carcass, the breast muscle, and the thigh muscle (p < 0.01). In addition, based on HE staining analysis, HWs’ breast muscles had a considerably larger average myofiber area and diameter than those of XSs (p < 0.01). Furthermore, the physical characteristics of the meat revealed that XSs had higher redness and yellowness and also higher lightness. HW meat had a higher pH and thermal loss, but a lower shear force and drip loss than XS meat (p < 0.01). The content of saturated fatty acids (SFAs) and polyunsaturated fatty acids (PUFAs) was, remarkably, lower in the breast muscles of HWs than of XSs (p < 0.01). In contrast, HWs had a larger concentration of monounsaturated fatty acids (MUFAs) than XSs (p < 0.01). Finally, the breast muscles of XSs had lower levels of mRNA expression for genes linked to lipid metabolism, such as fatty acid binding protein 4 (Fabp4) and peroxisome proliferator-activated receptor alpha (Pparα), and had higher levels of the phosphofructokinase muscle type (Pfkm) compared to HWs (p < 0.01). These results indicate that a lower carcass yield was observed in XSs compared with HWs, but that XSs showed better performance in terms of meat quality than HW. Full article

Palmitoylethanolamide (PEA) is an endogenous lipid mediator belonging to the N-acyl-ethanolamine family, widely recognized for its multifaceted effects on neuroprotection, chronic pain management, and immune modulation. As a naturally occurring compound, PEA plays a crucial role in maintaining homeostasis under conditions of cellular stress and inflammation. Its pharmacological effects are primarily mediated through peroxisome proliferator-activated receptor-alpha (PPAR-α) activation, alongside indirect modulation of cannabinoid receptors CB1 and CB2, as well as interactions with novel targets such as GPR55 and TRPV1. These molecular mechanisms underpin its broad therapeutic potential, particularly in the management of neuroinflammatory and neurodegenerative disorders, pain syndromes, and immune dysregulation. A major advancement in PEA research has been the development of ultramicronized palmitoylethanolamide (umPEA), which significantly enhances its bioavailability and therapeutic efficacy by facilitating better tissue absorption and interaction with key molecular pathways. Preclinical and clinical studies have demonstrated that umPEA is particularly effective in reducing neuroinflammation, stabilizing mast cells, and enhancing endocannabinoid system activity, making it a promising candidate for integrative approaches in neuropsychiatric and chronic inflammatory diseases. Given its well-established safety profile, umPEA represents an attractive alternative or adjunct to conventional anti-inflammatory and analgesic therapies. This communication provides a comprehensive overview of the mechanisms of action and therapeutic applications of both PEA and umPEA, emphasizing their emerging role in clinical practice and personalized medicine. Full article

To study the pathological contribution of fatty acid (FA) metabolism regulators including fatty acid binding protein 4 (FABP4), FABP5, peroxisome proliferator-activated receptor alpha (PPARα), and PPARγ in ovarian carcinoma, non-cancerous human ovarian surface epithelium (HOSE) cells and two epithelial ovarian carcinoma (EOC) cell lines, AMOC-2 and ES2 established from ovarian serous adenocarcinoma and ovarian clear cell carcinoma, respectively, were subjected to (1) an analysis of the physical properties of spheroids, (2) qPCR analysis, (3) cellular metabolic analysis, and (4) multiomic pan-cancer analysis using the Cancer Genome Atlas (TCGA). In contrast to globe-shaped spheroids of HOSE cells, AMOC-2 and ES2 cells formed non-globe-shaped spheroids and ES2 spheroids were much more fragile than AMOC-2 spheroids. Gene expression levels of FABP4 and FABP5 in AMOC-2 cells and those of PPARγ in AMOC-2 cells were significantly higher than those in HOSE cells. Metabolic phenotypes and the effectiveness against antagonists for regulators were significantly different in the two types of cancerous cells. Those regulators were identified by a multiomic pan-cancer analysis as novel factors for the prediction of the prognosis of ovarian serous adenocarcinoma. The results show that dysregulated FA metabolism in AMOC-2 and ES2 suggests that the regulation of FA metabolism may be a critical factor in the pathogenesis of EOC. Full article

Ischemic stroke is a leading cause of death and disability worldwide. Currently, there is an unmet clinical need for pharmacological treatments that can improve ischemic stroke outcomes. In this study, we investigated the role of brain peroxisome proliferator-activated receptor alpha (PPARα) in ischemic stroke pathophysiology. We used a well-established model of cerebral ischemia in PPARα transgenic mice and conducted the RNA sequencing (RNA-seq) of mouse stroke brains harvested 48 h post-middle cerebral artery occlusion (MCAO). PPARα knockout (KO) increased brain infarct size following stroke, indicating a protective role of PPARα in brain ischemia. Our RNA-seq analysis showed that PPARα KO altered the expression of genes in mouse brains with known roles in ischemic stroke pathophysiology. We also identified many other differentially expressed genes (DEGs) upon the loss of PPARα that correlated with increased infarct size in our stroke model. Gene set enrichment analysis (GSEA) and Gene Ontology (GO) analysis revealed the upregulation of gene signatures for the positive regulation of leukocyte proliferation, apoptotic processes, acute-phase response, and cellular component disassembly in mouse stroke brains with PPARα KO. In addition, pathway analysis of our RNA-seq data revealed that TNFα signaling, IL6/STAT3 signaling, and epithelial–mesenchymal transition (EMT) gene signatures were increased in PPARα KO stroke brains. Our study highlights PPARα as an attractive drug target for ischemic stroke due to its transcriptional regulation of inflammation-, apoptosis-, and EMT-related genes in brain tissue following ischemia. Full article

Background/Objectives: The interplay between genetics and athletic performance has garnered significant attention, particularly regarding performance-enhancing polymorphisms (PEPs) and their role in determining key traits that are critical for athletic success. Therefore, this study investigates the genetic predispositions related to peroxisome proliferator-activated receptor alpha (PPARα), angiotensin converting enzyme (ACE), and creatine kinase muscle-type (CKM) gene variants and their potential influence on elite point-fighting (PF) athletes. Methods: A total of 24 elite PF athletes (12 women and 12 men; age = 22.1 ± 5.8 years; body mass = 66.1 ± 15.4 kg; and height = 173.0 ± 9.5 cm, BMI = 21.8 ± 3.2 kg·m⁻²) participated in the study. Saliva samples were collected for DNA extraction and genotyping, analyzing the prevalence of key genetic markers, including the D allele and ID genotype for the ACE variant, the G allele and GG genotype for PPARα, and the A allele and AA genotype for CKM. Results: Genotyping revealed a high prevalence of key genetic markers among participants, with the D allele (58.33%) and ID genotype (66.67%) for the ACE variant, the G allele (77.08%) and GG genotype (54.17%) for PPARα, and the A allele (77.08%) with an AA genotype (62.50%) for CKM. The Total Genetic Score (TGS) analysis indicated a mixed-oriented genetic predisposition across the sample. Conclusions: Although PF athletes showed mixed aerobic/anaerobic genetic profiles, their training routines were primarily strength-oriented, suggesting a possible misalignment between genetic predispositions and their current training approach. These findings offer preliminary insights into the genetic characteristics of elite PF athletes and may inform future investigations into the potential role of genetic information in guiding training strategies. Full article

Background: Athletic performance is a complex phenotype affected by individual traits, environmental conditions, training, and genetics. The peroxisome proliferator-activated receptor-alpha (PPARα) and alpha-actinin-3 (ACTN3) are two genes with the potential to influence human performance. The objective of the present study was to assess the genotype frequencies of ACTN3 (R/X) and PPARα (G/C) and to conduct a comparison of these frequencies among Egyptian adolescent athletes. Methods: This case–control study involved 228 individuals (118 elite-level athletes and 110 sedentary controls). Results: This study identified a statistically significant increase in the frequencies of the ACTN3 ‘R’ allele (77.5% compared to 55.9%; p < 0.001) and the PPARα ‘C’ allele (86.4% compared to 14.1%; p < 0.001) among athletes relative to the control groups. A similar pattern was noted for adolescent athletes in comparison to the control group in terms of both the R/R genotype (61.9% compared to 27.3%; p < 0.001) and the C/C genotype (80.5% compared to 2.7%; p < 0.001). In conclusion, these results imply that polymorphisms in ACTN3 and PPARα could be significant predictors for assessing the performance of adolescent Egyptian athletes. Full article

Atherosclerosis, a leading contributor to cardiovascular diseases (CVDs), is characterized by foam cell formation driven by excessive lipid accumulation in macrophages and vascular smooth muscle cells. This study elucidates the anti-atherosclerotic potential of AWLNH (P3) and PHDL (P4) peptides by assessing their effects on foam cell formation, lipid metabolism, and oxidative stress regulation. P3 and P4 effectively suppressed intracellular lipid accumulation in RAW264.7 macrophages and human aortic smooth muscle cells (hASMCs), thereby mitigating foam cell formation. Mechanistically, both peptides modulated cholesterol homeostasis by downregulating cholesterol influx mediators, cluster of differentiation 36 (CD36), and class A1 scavenger receptor (SR-A1), while upregulating cholesterol efflux transporters ATP-binding cassette subfamily A member 1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1). The activation of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α) further substantiated their role in promoting cholesterol efflux and restoring lipid homeostasis. Additionally, P3 and P4 peptides exhibited potent antioxidative properties by attenuating reactive oxygen species (ROS) generation through activation of the HO-1/Nrf2 signaling axis. HO-1 silencing via siRNA transfection abolished these effects, confirming HO-1-dependent regulation of oxidative stress and lipid metabolism. Collectively, these findings highlight P3 and P4 peptides as promising therapeutic agents for atherosclerosis by concurrently targeting foam cell formation, cholesterol dysregulation, and oxidative stress, warranting further exploration for potential clinical applications. Full article

PEG400 is widely used as a pharmaceutical excipient in the biomedical field. Increasing evidence suggests that PEG400 is not an inert drug carrier; it can influence the activity of various drug-metabolizing enzymes and transporters, thereby affecting the in vivo process of drugs. It can also alleviate obesity and adipose tissue inflammation induced by a high-fat diet. In this study, we employed proteomics to investigate the impact of PEG400 on hepatic protein expression in rats. We found that over 40 metabolic enzymes were altered, with UDP-glucuronosyltransferase 1a9 (Ugt1a9) showing the most significant upregulation. This observation is consistent with our previous findings. KEGG pathway enrichment analysis revealed that PEG400 influences retinol metabolism, steroid hormone biosynthesis, drug metabolism, bile secretion, fatty acid degradation, peroxisome proliferator-activated receptor (PPAR) signaling pathway, and pentose and glucuronate interconversions. Western blot and molecular docking were used to quantitatively analyze related proteins. The results demonstrated that PEG400 promotes the metabolism of retinol to produce retinoic acid; enhances bile secretion by upregulating bile acid synthesis and transporter proteins; and activates the PPARα signaling pathway to regulate the expression of fat metabolism-related proteins, thereby reducing lipid accumulation. Furthermore, as natural ligands for nuclear receptors, retinoic acid and bile acids may activate nuclear receptors and initiate the regulation of target gene expression. We found upregulation of the nuclear receptors PPARα, retinoid X receptor alpha (RXRα), and pregnane X receptor (PXR). RXRα can form a dimer with PPARα or PXR to regulate the expression of target genes, which may explain the changes in the expression of numerous metabolic enzymes. This study provides a comprehensive understanding of the effects of PEG400 on liver metabolism in rats, reveals its potential biological functions, and offers new insights into the application and development of PEG400. Full article

Peroxisome proliferator-activated receptors (PPARs) are considered good drug targets for breast cancer because of their involvement in fatty acid metabolism that induces cell proliferation. In this study, we used the KAIMRC1 breast cancer cell line. We showed that the PPARE-Luciferase reporter gets highly activated without adding any exogenous ligand when PPAR alpha is co-transfected, and the antagonist GW6471 can inhibit the activity. Using this reporter system, we screened 240 compounds representing kinase inhibitors, epigenetic modulators, and stem cell differentiators and identified compounds that inhibit the PPARα-activated PPARE-Luciferase reporter in the KAIMRC1 cell. We selected 11 compounds (five epigenetic modulators, two stem cell differentiators, and four kinase inhibitors) that inhibited the reporter by at least 40% compared to the controls (DMSO-treated cells). We tested them in a dose-dependent manner and measured the KAIMRC1 cell viability after 48 h. All 11 compounds induced the cell killing at different IC50 values. We selected two compounds, PHA665752 and NSC3852, to dissect how they kill KAIMRC1 cells compared to the antagonist GW6741. First, molecular docking and a TR-FRET PPARα binding assay showed that compared to GW6471, these two compounds could not bind to PPARα. This means they inhibit the PPARα pathway independently rather than binding to the receptor. We further confirmed that PHA665752 and NSC3852 induce cell killing depending on the level of PPARα expression, and as such, their potency for killing the SW620 colon cancer cell line that expresses the lowest level of PPARα was less potent than for the KAIMRC1 and MDA-MB-231 cell lines. Further, using an apoptosis array and fatty acid gene expression panel, we found that both compounds regulate the PPARα pathway by controlling the genes involved in the fatty acid oxidation process. Our findings suggest that these two compounds have opposite effects involving fatty acid oxidation in the KAIMRC1 breast cancer cell line. Although we do not fully understand their mechanism of action, our data provide new insights into the potential role of these compounds in targeting breast cancer cells. Full article

Menopause leads to a decline in estrogen levels, resulting in significant metabolic alterations that increase the risk of developing metabolic syndrome—a cluster of conditions including central obesity, insulin resistance, dyslipidemia, and hypertension. Traditional interventions such as hormone replacement therapy carry potential adverse effects, and lifestyle modifications alone may not suffice for all women. This review explores the potential role of palmitoylethanolamide (PEA), an endogenous fatty acid amide, in managing metabolic syndrome during the postmenopausal period. PEA primarily acts by activating peroxisome proliferator-activated receptor-alpha (PPAR-α), influencing lipid metabolism, energy homeostasis, and inflammation. Evidence indicates that PEA may promote the browning of white adipocytes, enhancing energy expenditure and reducing adiposity. It also improves lipid profiles by boosting fatty acid oxidation and decreasing lipid synthesis, potentially lowering low-density lipoprotein cholesterol and triglyceride levels while increasing high-density lipoprotein cholesterol. Additionally, the anti-inflammatory properties of PEA enhance insulin sensitivity by reducing pro-inflammatory cytokines that interfere with insulin signaling. PEA may aid in weight management by influencing appetite regulation and improving leptin sensitivity. Furthermore, its neuroprotective effects may address the mood disturbances and cognitive decline associated with menopause. Given these multifaceted biological activities and a favorable safety profile, PEA may represent a promising non-pharmacological supplement for managing metabolic syndrome in postmenopausal women. However, further large-scale clinical studies are necessary to establish its efficacy, optimal dosing, and long-term safety. If validated, PEA could become an integral part of strategies to improve metabolic and neuropsychological health outcomes in this population. Full article

Golden tomato (GT), harvested at the veraison stage, has gained attention due to its rich content of bioactive compounds and potential health benefits. Previous studies have highlighted GT’s antioxidant properties and its positive effects on metabolic syndrome (MetS), a condition characterized by obesity, dyslipidemia, and oxidative stress. This study investigates for the first time a derivative from GT, i.e., the juice (GTJ), which could be a potential candidate for development as a functional food. We first characterized GT juice, identifying 9-oxo-10(E),12(E)-octadecadienoic (9-oxo-10(E),12(E)-ODA) fatty acid, a known peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, using High-Performance Liquid Chromatography (HPLC)–mass spectrometry. Then, using a high-fat-diet (HFD) rat model, we assessed the impact of daily GT juice supplementation in addressing MetS. We outlined that GTJ improved body weight and leptin-mediated food intake. Moreover, it ameliorated glucose tolerance, lipid profile, systemic redox homeostasis, hepatic oxidative stress, and steatosis in HFD rats. Furthermore, GT juice enhances the hepatic transcription of PPAR-α, thus putatively promoting fatty acid oxidation and lipid metabolism. These findings suggest that GT juice mitigates lipidic accumulation and putatively halters oxidative species at the hepatic level through PPAR-α activation. Our study underscores the protective effects of GT juice against MetS, highlighting its future potential as a nutraceutical for improving dysmetabolism and associated alterations. Full article

Background: (E)-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (HMC), a homoisoflavonoid isolated from Portulaca oleracea, has significant anti-adipogenesis potential; it regulates adipogenic transcription factors. However, whether HMC improves hepatic steatosis in hepatocytes remains vague. This study investigated whether HMC ameliorates hepatic steatosis in free fatty acid-treated human hepatocellular carcinoma (HepG2) cells, and if so, its mechanism of action was analyzed. Methods: Hepatic steatosis was induced by a free fatty acid mixture in HepG2 cells. Thereafter, different HMC concentrations (10, 30, and 50 µM) or fenofibrate (10 µM, a PPARα agonist, positive control) was treated in HepG2 cells.Results: HMC markedly decreased lipid accumulation and triglyceride content in free fatty acid-treated HepG2 cell; it (10 and 50 μM) markedly upregulated protein expressions of pAMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. HMC (10 and 50 μM) markedly inhibited the expression of sterol regulatory element-binding protein-1c, fatty acid synthase, and stearoyl-coA desaturase 1, which are the enzymes involved in lipid synthesis. Furthermore, HMC (10 and 50 μM) markedly upregulated the protein expression of peroxisome proliferator-activated receptor alpha (PPARα) and enhanced the protein expressions of carnitine palmitoyl transferase 1 and acyl-CoA oxidase 1. Conclusion: HMC inhibits lipid accumulation and promotes fatty acid oxidation by AMPK and PPARα pathways in free fatty acid-treated HepG2 cells, thereby attenuating hepatic steatosis. Full article

Atherosclerosis is a key etiological event in the development of cardiovascular diseases (CVDs), strongly linked to the formation of foam cells. This study explored the effects of two blue mussel-derived bioactive peptides (BAPs), PIISVYWK (P1) and FSVVPSPK (P2), on inhibiting foam cell formation and mitigating inflammation in oxLDL-treated RAW264.7 macrophages. Both peptides significantly suppressed intracellular lipid accumulation and cholesterol levels while promoting cholesterol efflux by downregulating cluster of differentiation 36 (CD36) and class A1 scavenger receptors (SR-A1) and upregulating ATP binding cassette subfamily A member 1 (ABCA-1) and ATP binding cassette subfamily G member 1 (ABCG-1) expressions. The increased expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α) further validated their role in enhancing cholesterol efflux. Additionally, P1 and P2 inhibited foam cell formation in oxLDL-treated human aortic smooth muscle cells and exerted anti-inflammatory effects by reducing pro-inflammatory cytokines, nitric oxide (NO), prostaglandin E₂ (PGE₂), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), primarily through inhibiting NF-κB activation. Furthermore, P1 and P2 alleviated oxidative stress by activating the Nrf2/HO-1 pathway. Our findings demonstrate that P1 and P2 have significant potential in reducing foam cell formation and inflammation, both critical factors in atherosclerosis development. These peptides may serve as promising therapeutic agents for the prevention and treatment of CVDs associated with oxidative stress and inflammation. Full article