Variation of PPARG Expression in Chemotherapy-Sensitive Patients of Hypopharyngeal Squamous Cell CarcinomaRead the full article
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PPARD May Play a Protective Role for Major Depressive Disorder
Activation of PPARD has been shown to inhibit depressive behaviors and enhances neurogenesis. However, whether PPARD is involved in the pathological development of major depressive disorder (MDD) is largely unknown. To explore the potential connection between PPARD and MDD, we first conducted a literature-based data mining to construct a PPARD-driven MDD regulating network. Then, we tested the PPARD expression changes in MDD patients from 18 independent MDD RNA expression datasets, followed by coexpression analysis, multiple linear regression analysis, and a heterogeneity analysis to study the influential factors for PPARD expression levels. Our results showed that overexpression of PPARD could inhibit inflammatory cytokine signaling pathways and the ROS and glutamate pathways that have been shown to play important roles in the pathological development of MDD. However, PPARD could also activate nitric oxide formation and ceramide synthesis, which was implicated as promoters in the pathogenesis of MDD, indicating the complexity of the relationship between PPARD and MDD. PPARG presented significant within- and between-study variations in the 18 MDD datasets ( value = 0.97), which were significantly associated with the population region (country) and sample source (). Our results suggested that PPARD could be a potential regulator rather than a biomarker in the pathological development of MDD. This study may add new insights into the understanding of the PPARD-MDD relationship.
PPAR-Alpha Agonist Fenofibrate Combined with Octreotide Acetate in the Treatment of Acute Hyperlipidemia Pancreatitis
At present, there are more and more patients with acute hypertriglyceridemia pancreatitis in clinical practice. Common treatment measures include fasting and water withdrawal, fluid resuscitation, and somatostatin. In recent years, studies have pointed out that the PPARa agonist fenofibrate may help improve the condition of such patients. Therefore, through clinical research and analysis, we reported for the first time that fenofibrate combined with octreotide acetate has a more excellent effect in the treatment of patients with acute hypertriglyceridemia pancreatitis, and from the perspective of signal pathways, we revealed that the combination of the two drugs has an effect on NF-κB P65. The synergistic inhibitory effect proves that the combined treatment is beneficial to control inflammation, protect liver function, and improve the prognosis of patients. It is worthy of clinical promotion.
Inhibition of miR-128-3p Attenuated Doxorubicin-Triggered Acute Cardiac Injury in Mice by the Regulation of PPAR-γ
Background. The clinical usefulness of doxorubicin (DOX), an anthracycline with antitumor activity, is limited by its cardiotoxicity. Oxidative stress and myocardial apoptosis were closely associated with DOX-induced cardiac dysfunction. It has been reported that microRNA-128-3p (miR-128-3p) was involved into the regulation of redox balance. However, the role of miR-128-3p in DOX-related cardiac injury remains not yet understood. The aim of this study was to investigate the biological effect of miR-128-3p in DOX-induced cardiotoxicity. Methods. To induce DOX-related acute cardiac injury, mice were subjected to a single injection of DOX. Inhibition of myocardial miR-128-3p was achieved by an adeno-associated virus (AAV9) system carrying a miR-128-3p sponge. Results. The data in our study indicated that miR-128-3p was upregulated in DOX-treated hearts and cardiomyocytes. Inhibition of miR-128-3p attenuated DOX-related cardiac injury and improved cardiac function in mice. Moreover, miR-128-3p inhibition could suppress myocardial inflammatory response, oxidative damage, and cell apoptotic death in DOX-treated mice. Further analysis showed that miR-128-3p could directly target peroxisome proliferator-activated receptor γ (PPAR-γ) and decrease PPAR-γ expression. Moreover, the protective effects provided by miR-128-3p inhibition were abolished by a PPAR-γ antagonist in vivo and in vitro. Conclusions. miR-128-3p inhibition attenuated DOX-related acute cardiac injury via the regulation of PPAR-γ in mice.
Hydroxychloroquine Potentiates Apoptosis Induced by PPARα Antagonist in 786-O Clear Cell Renal Cell Carcinoma Cells Associated with Inhibiting Autophagy
Clear cell renal cell carcinoma (ccRCC) is the major pathological pattern of renal cell carcinoma. The ccRCC cells exhibit a certain degree of inherent drug resistance due to some genetic mutations. In recent years, peroxisome proliferator-activated receptor-α (PPARα) antagonists have been reported as a targeted therapeutic drug capable of inducing apoptosis and cell cycle arrest in the ccRCC cell line. Autophagy, which can be induced by stress in eukaryotic cells, plays a complex role in the proliferation, survival, and death of tumor cells. In our study, we found that the expression of PPARα was low in highly differentiated ccRCC tissues and 786-O cell line but high in poorly differentiated ccRCC tissues. The level of PPARα expression in ccRCC tissues is correlated to the grade of differentiation, but not to the sex or age of ccRCC patients. The findings also revealed that the PPARα antagonist GW6471 can lower cell viability and induce autophagy in the 786-O ccRCC cell line. This autophagy can be inhibited by hydroxychloroquine. When treated with a combination of hydroxychloroquine and GW6471, the viability of the 786-O cells was decreased further when compared to the treatment with GW6471 or hydroxychloroquine alone, and apoptosis was promoted. Meanwhile, when human kidney 2 cells were cotreated with hydroxychloroquine and GW6471, cell viability was only slightly influenced. Hence, our finding indicates that the combination of GW6471 and hydroxychloroquine may constitute a novel and potentially effective treatment for ccRCC. Furthermore, this approach is likely to be safe owing to its minimal effects on normal renal tissues.
Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A
Peroxisome proliferator-activated receptor alpha (PPARA) is the molecular target of fibrates commonly used to treat dyslipidemia and diabetes. Recently, the potential role of PPARA in other pathological conditions, such as cancers, has been recognized. Here, using bioinformatics analysis, we found that PPARA was expressed at relatively low levels in pancancers, and Kaplan-Meier analyses revealed that high PPARA protein expression was correlated with better survival of patients with colon cancer. In vitro experiments showed that fenofibrate regulated cell cycle distribution, promoted apoptosis, and suppressed cell proliferation and epithelial mesenchymal transition by activating PPARA. PPARA activation inhibited DNMT1 activity and abolished methylation-mediated CDKN2A repression. Downregulation of cyclin-CDK complexes led to the restoration of CDKN2A, which caused cell cycle arrest in the G1 phase via regulation of the CDKN2A/RB/E2F pathway. Finally, we demonstrated that fenofibrate administration inhibited tumor growth and DNMT1 activity in vivo. The PPARA agonist, fenofibrate, might serve as an applicable agent for epigenetic therapy of colon cancer patients.
Investigation of PPARβ/δ within Human Dental Pulp Cells: A Preliminary In Vitro Study
Controlling the inflammatory response to restore tissue homeostasis is a crucial step to maintain tooth vitality after pathogen removal from caries-affected dental tissues. The nuclear peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) is a ligand-activated transcription factor with emerging anti-inflammatory roles in many cells and tissues. However, its expression and functions are poorly understood in human dental pulp cells (hDPCs). Thus, this study evaluated PPARβ/δ expression and assessed the anti-inflammatory effects evoked by activation of PPARβ/δ in lipopolysaccharide- (LPS-) induced hDPCs. Our results showed that hDPCs constitutively expressed PPARβ/δ mRNA/protein, and treatment with LPS increased PPARβ/δ mRNA expression. The selective PPARβ/δ agonist GW0742 significantly decreased inflammation-related mRNA expression in hDPCs (IL6, IL1β, TNFα, MMP1, and MMP2) and RAW264.7 cells (Il6 and Tnfα). Further, PPARβ/δ agonist attenuated MMP2/9 gelatinolytic activity in hDPCs. Previously LPS-conditioned hDPCs increased the migration of RAW264.7 cells through the membrane of a Transwell coculture system. Conversely, pretreatment with GW0742 markedly decreased macrophage recruitment. These findings provide among the first evidence that hDPCs express PPARβ/δ. In addition, they suggest that activation of PPARβ/δ by GW0742 can attenuate some cellular and molecular in vitro aspects related to the inflammatory process, pointing out to investigate its potential target role in dental pulp inflammation.