The Role of PPARs in Disease - Volume III

Dear Colleagues,

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors. They function as ligand-activated transcription factors. They exist in three isoforms, i.e., PPARα, PPARβ/δ, and PPARγ. For all PPARs, lipids are endogenous ligands, linking them directly to metabolism. PPARs form heterodimers with retinoic X receptors and, upon ligand binding, modulate the gene expression of downstream target genes, depending on the presence of co-repressors or co-activators. This results in a complex, cell-type-specific regulation of proliferation, differentiation, and cell survival. Specific synthetic agonists for all PPARs are available. PPARα and PPARγ agonists are already in clinical use for the treatment of hyperlipidemia and type 2 diabetes, respectively. More recently, PPARβ/δ activation came into focus as an interesting novel approach for the treatment of metabolic syndrome and associated cardiovascular diseases.

In summary, PPARs are linked to metabolic disorders and are interesting pharmaceutical targets. PPARs play important roles in a variety of disorders, e.g., cardiovascular, hepatic, neurological, psychiatric, and immunological diseases and cancer. We guest-edited the first Special Issue on “The Role of PPARs in Disease” of Cells in 2019–2020. Despite the global health crisis, 11 papers were published in this Special Issue, which have received until now more than 60,000 views and more than 450 citations. In 2021–2022, we guest-edited the second Special Issue on the topic “The Role of PPARs in Disease II”. This Special Issue attracted even higher attention. Overall, 20 papers were finally published in this Special Issue, which have already received nearly 52,000 views and 130 citations.

We hope that this new Special Issue of Cells, with the continuous efforts of the scientific community, will be equally or even more successful. This Special Issue will bring together the most recent and exciting advances in understanding the various aspects of the action of PPARs, from basic science to applied therapeutic approaches.

Sincerely,

Dr. Kay-Dietrich Wagner
Dr. Nicole Wagner
Guest Editors

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• PPAR
• immune function
• liver
• adipose tissue
• cardiovascular system
• muscle
• neurological and psychiatric diseases
• cancer
• transcriptional regulation
• ligands
• agonists/antagonists

• The Role of PPARs in Disease in Cells (11 articles)
• The Role of PPARs in Disease II in Cells (20 articles)

Title: Tumor Suppressor Par-4 Regulates Adipogenesis via Transcriptional Repression of PPARγ
Authors: Vivek M. Rangnekar
Affiliation: na
Abstract: n/a

Title: Anticancer properties of peroxisome proliferator-activated receptor gamma (PPARγ) potential agonists 4-thiazolidinone-pyrazoline hybrids Les-4368 and Les-4370 in colorectal adenocarcinoma cells in vitro
Authors: Konrad Szychowski
Affiliation: Department of Biotechnology and Cell Biology, University of Information Technology and Management in Rzeszow, St. Sucharskiego 2, 35-225 Rzeszow, POLAND
Abstract: Presently, a major challenge is the search for new compounds, which may exhibit an inhibitory effect on tumor progression. Recently, the 4-thiazolidinone (4-TZD) group has gained attention in this research field. The aim of the present study was to evaluate the anticancer effect of two new 4-TZD-based derivatives (Z)-5-[5-(2-hydroxyphenyl)- (Les- 4368) and (Z)-5-[5-(4-dimethylaminophenyl)-3-phenyl-4,5-dihydropyrazol-1-ylmethylene]-3-(3-acetoxyphenyl)-2-thioxothiazolidin-4-ones (Les-4370) on peroxisome proliferator-activated receptor gamma (PPARγ)-dependent cytotoxicity in human colorectal adenocarcinoma cells (CACO-2) and in normal human fibroblasts (BJ) in vitro. Les-4368 and Les-4370 exerted a toxic effect on both tested cell lines in high (micromolar) concentrations (10-100 µM). In addition, Les-4368 and Les-4370 applied in the BJ and CACO-2 cells in the concentration range of 10 µM to 100 µM increased the activity of caspase-3 and the production of reactive oxygen species (ROS). The mRNA expression of PPARγ-related genes (PPARγ, AhR, PXR, and NF-κB) showed certain changes in these parameters, proving the engagement of this receptor in the induction of the biological effects of both tested 4-TZD derivatives. Moreover, the treatment of the BJ and CACO-2 cells with Les-4368, Les-4370, an antagonist (GW9662), or an agonist (rosiglitazone) of the PPARγ receptor also resulted in changes in the above-mentioned parameters. Unfortunately, the tested substances studied cell line work in a non-selective way in relatively high concentration, which reduces their potential of clinical application. Our research is the preliminary study - with the use of these compounds and requires further studies to elucidate the mechanism of action of their anticancer potential.

Title: The role of Endothelial dysfunction in MASLD
Authors: Ana P Madariaga T, Varenka J Barbero Becerra
Affiliation: Medica Sur Clinic & Foundation
Abstract: n/a