Comprehensive Analysis of Copy Number Variation, Nucleotide Mutation, and Transcription Level of PPAR Pathway-Related Genes in Endometrial Cancer

Endometrial cancer is a common malignant tumor in gynecology, and the prognosis of advanced patients is dismal. Recently, many studies on the peroxisome proliferator-activated receptor pathway have elucidated its crucial involvement in endometrial cancer. Copy number variation (CNA) and nucleotide mutations often occur in tumor tissues, leading to abnormal protein expression and changes in protein structure. We analyzed the exon sequencing data of endometrial cancer patients in the TCGA database and found that somatic changes in PPAR pathway-related genes (PPAR-related-gene) often occur in UCEC patients. Patients with CNA or mutation changes in the exon region of the PPAR-related-gene usually have different prognostic outcomes. Furthermore, we found that the mRNA transcription and protein translation levels of PPAR-related-gene in UCEC are significantly different from that of adjacent tissues/normal uterus. The transcription level of some PPAR-related-gene (DBI, CPT1A, CYP27A1, and ME1) is significantly linked to the prognosis of UCEC patients. We further constructed a prognostic predicting tool called PPAR Risk score, a prognostic prediction tool that is a strong independent risk factor for the overall survival rate of UCEC patients. Comparing to the typical TNM classification system, this tool has higher prediction accuracy. We created a nomogram by combining PPAR Risk score with clinical characteristics of patients in order to increase prediction accuracy and promote clinical use. In summary, our study demonstrated that PPAR-related-gene in UCEC had significant alterations in CNA, nucleotide mutations, and mRNA transcription levels. These findings can provide a fresh perspective for postoperative survival prediction and individualized therapy of UCEC patients.

In Vivo and Ex Vivo Evaluation of 1,3-Thiazolidine-2,4-Dione Derivatives as Euglycemic Agents

Thiazolidinediones (TZDs), used to treat type 2 diabetes mellitus, act as full agonists of the peroxisome proliferator-activated receptor gamma. Unfortunately, they produce adverse effects, including weight gain, hepatic toxicity, and heart failure. Our group previously reported the design, synthesis, in silico evaluation, and acute oral toxicity test of two TZD derivatives, compounds 40 (C40) and 81 (C81), characterized as category 5 and 4, respectively, under the Globally Harmonized System. The aim of this study was to determine whether C40, C81, and a new compound, C4, act as euglycemic and antioxidant agents in male Wistar rats with streptozotocin-induced diabetes. The animals were randomly divided into six groups ( n = 7 ): the control, those with diabetes and untreated, and those with diabetes and treated with pioglitazone, C40, C81, or C4 (daily for 21 days). At the end of the experiment, tissue samples were collected to quantify the level of glucose, insulin, triglycerides, total cholesterol, and liver enzymes, as well as enzymatic and nonenzymatic antioxidant activity. C4, without a hypoglycemic effect, displayed the best antioxidant activity. Whereas C81 could only attenuate the elevated level of blood glucose, C40 generated euglycemia by the end of the treatment. All compounds produced a significant decrease in triglycerides.

Identification of a Novel PPAR Signature for Predicting Prognosis, Immune Microenvironment, and Chemotherapy Response in Bladder Cancer

Background. Mounting evidence has confirmed that peroxisome proliferator-activated receptors (PPARs) played a crucial role in the development and progression of bladder cancer (BLCA). The purpose of this study is to comprehensively investigate the function and prognostic value of PPAR-targeted genes in BLCA. Methods. The RNA sequencing data and clinical information of BLCA patients were acquired from The Cancer Genome Atlas (TCGA). The differentially expressed PPAR-targeted genes were investigated. Cox analysis and least absolute shrinkage and selection operator (LASSO) analysis were performed for screening prognostic PPAR-targeted genes and constructing the prognostic PPAR signature and then validated by GSE13507 cohort and GSE32894 cohort. A nomogram was constructed to predict the outcomes of BLCA patients in combination with PPAR signature and clinical factors. Gene set enrichment analysis (GSEA) and immune cell infiltration were implemented to explore the molecular characteristics of the signature. The Genomics of Drug Sensitivity in Cancer (GDSC) database was used to predict the chemotherapy responses of the prognostic signature. The candidate small molecule drugs targeting PPAR-targeted genes were screened by the CMAP database. Results. We constructed and validated the prognostic signature comprising of 4 PPAR-targeted genes (CPT1B, CALR, AHNAK, and FADS2), which was an independent prognostic biomarker in BLCA patients. A nomogram based on the signature and clinical factors was established in the TCGA set, and the calibration plots displayed the excellent predictive capacity. GSEA analysis indicated that PPAR signature was implicated in multiple oncogenic signaling pathways and correlated with tumor immune cell infiltration. Patients in the high-risk groups showed greater sensitivity to chemotherapy than those in the low-risk groups. Moreover, 11 candidate small molecule drugs were identified for the treatment of BLCA. Conclusion. We constructed and validated a novel PPAR signature, which showed the excellent performance in predicting prognosis and chemotherapy sensitivity of BLCA patients.

Contribution of Nanotechnologies to Vaccine Development and Drug Delivery against Respiratory Viruses

According to the Center for Disease Control and Prevention (CDC), the coronavirus disease 2019, a respiratory viral illness linked to significant morbidity, mortality, production loss, and severe economic depression, was the third-largest cause of death in 2020. Respiratory viruses such as influenza, respiratory syncytial virus, SARS-CoV-2, and adenovirus, are among the most common causes of respiratory illness in humans, spreading as pandemics or epidemics throughout all continents. Nanotechnologies are particles in the nanometer range made from various compositions. They can be lipid-based, polymer-based, protein-based, or inorganic in nature, but they are all bioinspired and virus-like. In this review, we aimed to present a short review of the different nanoparticles currently studied, in particular those which led to publications in the field of respiratory viruses. We evaluated those which could be beneficial for respiratory disease-based viruses; those which already have contributed, such as lipid nanoparticles in the context of COVID-19; and those which will contribute in the future either as vaccines or antiviral drug delivery systems. We present a short assessment based on a critical selection of evidence indicating nanotechnology’s promise in the prevention and treatment of respiratory infections.

Antioxidant Potential of Adiponectin and Full PPAR-γ Agonist in Correcting Streptozotocin-Induced Vascular Abnormality in Spontaneously Hypertensive Rats

Oxidative stress, which is associated with metabolic and anthropometric perturbations, leads to reactive oxygen species production and decrease in plasma adiponectin concentration. We investigated pharmacodynamically the pathophysiological role and potential implication of exogenously administered adiponectin with full and partial peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists on modulation of oxidative stress, metabolic dysregulation, and antioxidant potential in streptozotocin-induced spontaneously hypertensive rats (SHR). Group I (WKY) serves as the normotensive control, whereas 42 male SHRs were randomized equally into 7 groups ( n = 6 ); group II serves as the SHR control, group III serves as the SHR diabetic control, and groups IV, V, and VI are treated with irbesartan (30 mg/kg), pioglitazone (10 mg/kg), and adiponectin (2.5 μg/kg), whereas groups VII and VIII received cotreatments as irbesartan+adiponectin and pioglitazone+adiponectin, respectively. Diabetes was induced using an intraperitoneal injection of streptozotocin (40 mg/kg). Plasma adiponectin, lipid contents, and arterial stiffness with oxidative stress biomarkers were measured using an in vitro and in vivo analysis. Diabetic SHRs exhibited hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and increased arterial stiffness with reduced plasma adiponectin and antioxidant enzymatic levels ( P < 0.05 ). Diabetic SHRs pretreated with pioglitazone and adiponectin separately exerted improvements in antioxidant enzyme activities, abrogated arterial stiffness, and offset the increased production of reactive oxygen species and dyslipidemic effects of STZ, whereas the blood pressure values were significantly reduced in the irbesartan-treated groups (all P < 0.05 ). The combined treatment of exogenously administered adiponectin with full PPAR-γ agonist augmented the improvement in lipid contents and adiponectin concentration and restored arterial stiffness with antioxidant potential effects, indicating the degree of synergism between adiponectin and full PPAR-γ agonists (pioglitazone).

Rosiglitazone Alleviates Mechanical Allodynia of Rats with Bone Cancer Pain through the Activation of PPAR-γ to Inhibit the NF-κB/NLRP3 Inflammatory Axis in Spinal Cord Neurons

Bone cancer pain (BCP) is a serious clinical problem that affects the quality of life of cancer patients. However, the current treatment methods for this condition are still unsatisfactory. This study investigated whether intrathecal injection of rosiglitazone modulates the noxious behaviors associated with BCP, and the possible mechanisms related to this effect were explored. We found that rosiglitazone treatment relieved bone cancer-induced mechanical hyperalgesia in a dose-dependent manner, promoted the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) in spinal cord neurons, and inhibited the activation of the nuclear factor-kappa B (NF-κB)/nod-like receptor protein 3 (NLRP3) inflammatory axis induced by BCP. However, concurrent administration of the PPAR-γ antagonist GW9662 reversed these effects. The results show that rosiglitazone inhibits the NF-κB/NLRP3 inflammation axis by activating PPAR-γ in spinal neurons, thereby alleviating BCP. Therefore, the PPAR-γ/NF-κB/NLRP3 signaling pathway may be a potential target for the treatment of BCP in the future.

PPARα Gene Is Involved in Body Composition Variation in Response to an Aerobic Training Program in Overweight/Obese

The objective of this study was to investigate the relationship of the polymorphism in Intron 7 G/C (rs 4253778) of the peroxisome proliferator-activated receptor alpha (PPARα) gene with the magnitude of changes in the body composition of an overweight and obese population that underwent an aerobic training program. Fifty-eight previously inactive men and women, body mass index (BMI) 31.5 ± 2.8 kg / m 2 , 46.5% ( n = 27 ) genotyped as CC genotype and 53.5% ( n = 31 ) as CA+AA, underwent a 12-week aerobic training (walking/running). Aerobic capacity (ergospirometry), body composition (DXA), and nutritional assessment were made before and 48 h after the experimental protocol. Two-way ANOVA, chi-square test, and logistic regression were used ( p < 0.05 ). Twenty-seven volunteers (46.5%) were identified as CC genotype and 31 (53.5%) as CA+AA genotype. Time-group interaction showed that there was no difference in these between two allele groups. However, differences in distribution of respondents or nonresponders according to allele A were identified for fat mass ( p ≤ 0.003 ), percentage fat mass ( p ≤ 0.002 ), the waist ( p ≤ 0.009 ), abdomen ( p ≤ 0.000 ), and hip ( p ≤ 0.001 ), this difference being independent for the fat mass. Meanwhile, sex, age, and nutritional management have also been found to be influential factors. It is concluded that the PPARα gene is involved in varying body composition in response to an aerobic training program.

Nobiletin Attenuates Pathological Cardiac Remodeling after Myocardial Infarction via Activating PPARγ and PGC1α

Rationale. Pathological cardiac remodeling serves as a vital mechanism during the progression from myocardial infarction (MI) to chronic heart failure (CHF). Nobiletin (NOB), an active monomer extracted from the peel of citrus fruit, has been reported to have beneficial effects in cardiovascular diseases. Our study was aimed at describing the specific mechanisms through which NOB protects against pathological cardiac remodeling after MI. Materials and Methods. C57BL/6 mice were treated with coronary artery ligation to generate an MI model, followed by treatment for 3 weeks with NOB (50 mg/kg/d) or vehicle (50 mg/kg/d), with or without the peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor T0070907 (1 mg/kg/d). Cardiac function (echocardiography, survival rate, Evans blue, and triphenyl tetrazolium chloride staining), fibrosis (Masson’s trichrome staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot (WB)), hypertrophy (haematoxylin-eosin staining, wheat germ agglutinin staining, and qRT-PCR), and apoptosis (WB and terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining) were evaluated. Hypoxia-induced apoptosis (TUNEL, WB) and phenylephrine- (PE-) induced pathological hypertrophy (immunofluorescence staining, qRT-PCR) models were established in primary neonatal rat ventricular myocytes (NRVMs). The effects of NOB with or without T0070907 were examined for the expression of PPARγ and PPARγ coactivator 1α (PGC1α) by WB in mice and NRVMs. The potential downstream effectors of PPARγ were further analyzed by WB in mice. Results. Following MI in mice, NOB intervention enhanced cardiac function across three predominant dimensions of pathological cardiac remodeling, which reflected in decreasing cardiac fibrosis, apoptosis, and hypertrophy decompensation. NOB intervention also alleviated apoptosis and hypertrophy in NRVMs. NOB intervention upregulated PPARγ and PGC1α in vivo and in vitro. Furthermore, the PPARγ inhibitor abolished the protective effects of NOB against pathological cardiac remodeling during the progression from MI to CHF. The potential downstream effectors of PPARγ were nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1). Conclusions. Our findings suggested that NOB alleviates pathological cardiac remodeling after MI via PPARγ and PGC1α upregulation.

Computational Analysis of Gly482Ser Single-Nucleotide Polymorphism in PPARGC1A Gene Associated with CAD, NAFLD, T2DM, Obesity, Hypertension, and Metabolic Diseases

Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PPARGC1A) regulates the expression of energy metabolism’s genes and mitochondrial biogenesis. The essential roles of PPARGC1A encouraged the researchers to assess the relation between metabolism-related diseases and its variants. To study Gly482Ser (+1564G/A) single-nucleotide polymorphism (SNP) after PPARGC1A modeling, we substitute Gly482 for Ser482. Stability prediction tools showed that this substitution decreases the stability of PPARGC1A or has a destabilizing effect on this protein. We then utilized molecular dynamics simulation of both the Gly482Ser variant and wild type of the PPARGC1A protein to analyze the structural changes and to reveal the conformational flexibility of the PPARGC1A protein. We observed loss flexibility in the RMSD plot of the Gly482Ser variant, which was further supported by a decrease in the SASA value in the Gly482Ser variant structure of PPARGC1A and an increase of H-bond with the increase of β-sheet and coil and decrease of turn in the DSSP plot of the Gly482Ser variant. Such alterations may significantly impact the structural conformation of the PPARGC1A protein, and it might also affect its function. It showed that the Gly482Ser variant affects the PPARGC1A structure and makes the backbone less flexible to move. In general, molecular dynamics simulation (MDS) showed more flexibility in the native PPARGC1A structure. Essential dynamics (ED) also revealed that the range of eigenvectors in the conformational space has lower extension of motion in the Gly482Ser variant compared with WT. The Gly482Ser variant also disrupts PPARGC1A interaction. Due to this single-nucleotide polymorphism in PPARGC1A, it became more rigid and might disarray the structural conformation and catalytic function of the protein and might also induce type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), and nonalcoholic fatty liver disease (NAFLD). The results obtained from this study will assist wet lab research in expanding potent treatment on T2DM.

Targeting the EZH2-PPAR Axis Is a Potential Therapeutic Pathway for Pancreatic Cancer

Enhancer of zeste homolog 2 (EZH2) is abnormally highly expressed in pancreatic cancer (PC). However, it is not ideal to treat PC by inhibiting EZH2. This study reported that the combined use of pan-peroxisome proliferator-activated receptor (PPAR) agonist could significantly improve the anti-PC effect of EZH2 inhibitor. In vitro, PC cell lines PANC-1 and AsPC-1 were cultured, and MTT and flow cytometry were performed to observe the effects of pan-PPAR agonist bezafibrate and EZH2 selective inhibitor GSK126 on cell viability and apoptosis. In vivo, CDXs of PANC-1 and AsPC-1 were established to observe the effects of bezafibrate and GSK126 on bearing tumors. Western blotting was performed to detect the protein expressions of H3K27me3, β-catenin, p-β-catenin, cyclin D1, c-Myc, and cleaved caspase 3 in vitro and in vivo. The results showed that bezafibrate significantly improved the effects of GSK126 on proliferation inhibition and apoptosis promotion in vitro and the growth suppression of CDX tumors in vivo. It also significantly enhanced the effects of GSK126 on upregulating the expression level of p-β-catenin and that of cleaved caspase 3 in vitro and in vivo. In parallel, downregulation of the expression levels of H3K27me3, β-catenin, cyclin D1, and c-Myc was also observed in vitro or in vivo. These results suggest that the combination of bezafibrate and GSK126 has synergistic effects on PC, and the molecular mechanism may be related to the enhanced inhibition of the Wnt/β-catenin signaling pathway. We believe that targeting the EZH2-PPAR axis is a potential therapeutic pathway for PC.