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Biology
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Antitumor and Metabolic Effects Mediated by PPARs
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Antitumor and Metabolic Effects Mediated by PPARs

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Medical Biology".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 17180

Special Issue Editor

Dr. Alessandra Ammazzalorso

E-Mail Website
Guest Editor
Department of Pharmacy, G. d’Annunzio University, 66100 Chieti, Italy
Interests: medicinal chemistry; drug discovery; aromatase inhibitors; PPAR ligands; anticancer agents
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Peroxisome Proliferator-Activated Receptors (PPARs) have been extensively studied as drug targets based on their metabolic regulatory activities in various tissues. Their roles in lipid and carbohydrate metabolism, energy homeostasis, inflammation, and cell differentiation make them interesting targets by which to restore altered metabolic functions in liver, muscle, adipose tissue, kidney, and brain. Intensive efforts by researchers have produced a wide panel of drugs targeting PPARs and able to modulate metabolic functions. The antitumor effects displayed by PPAR modulators reflect the ability to alter metabolic pathways in cancerous cells, which require different energetic needs to survive and proliferate.

In this context, this Special Issue will cover the latest developments in the physiological and pathological functions of PPARs in different organs, including their responses to nutrition and physical exercise. It will explore processes regulated by PPARs, either by natural or synthetic agonists or antagonists, affecting cellular and whole-organism metabolism.

Moreover, this Special Issue welcomes the submission of original research papers and reviews that cover multiple aspects of PPAR-mediated actions, including the modulation of signaling pathways in healthy and diseased organisms, the development of novel receptor ligands for of all three PPAR isotypes, and the structural biology of these nuclear receptors.

Dr. Alessandra Ammazzalorso
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biology is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • PPAR agonists, antagonists, and modulators 
  • Metabolic disorders 
  • Antitumor effects 
  • Lipid metabolism 
  • Cell differentiation 
  • Cancer metabolism 
  • Natural compounds 
  • Bioactive compounds

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Published Papers (4 papers)

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Research

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15 pages, 4548 KiB  
Article
Lipid Messenger Phosphatidylinositol-4,5-Bisphosphate Is Increased by Both PPARα Activators and Inhibitors: Relevance for Intestinal Cell Differentiation
by Katerina Cizkova, Katerina Koubova and Zdenek Tauber
Biology 2022, 11(7), 997; https://doi.org/10.3390/biology11070997 - 30 Jun 2022
Cited by 2 | Viewed by 1636
Abstract
We investigated the effects of PPARα activators fenofibrate and WY-14643 as well as the PPARα inhibitor GW6471 on the PI3K/Akt/PTEN pathway of intestinal cell differentiation. Our previous study showed that all these compounds increased the expression of villin, a specific marker of intestinal [...] Read more.
We investigated the effects of PPARα activators fenofibrate and WY-14643 as well as the PPARα inhibitor GW6471 on the PI3K/Akt/PTEN pathway of intestinal cell differentiation. Our previous study showed that all these compounds increased the expression of villin, a specific marker of intestinal cell differentiation in HT-29 and Caco2 cells. Our current results confirmed the central role of lipid messenger phosphatidylinositol-4,5-bisphosphate (PIP2), a known player in brush border formation, in mediating the effects of tested PPARα ligands. Although all tested compounds increased its levels, surprisingly, each of them affected different PIP2-metabolizing enzymes, especially the levels of PIP5K1C and PTEN. Moreover, we found a positive relationship between the expression of PPARα itself and PIP2 as well as PIP5K1C. By contrast, PPARα was negatively correlated with PTEN. However, the expression of antigens of interest was independent of PPARα subcellular localization, suggesting that it is not directly involved in their regulation. In colorectal carcinoma tissues we found a decrease in PTEN expression, which was accompanied by a change in its subcellular localization. This change was also observed for the regulatory subunit of PI3K. Taken together, our data revealed that fenofibrate, WY-14643, and GW6471 affected different members of the PI3K/Akt/PTEN pathway. However, these effects were PPARα-independent. Full article
(This article belongs to the Special Issue Antitumor and Metabolic Effects Mediated by PPARs)
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13 pages, 3906 KiB  
Article
Enhanced 3T3-L1 Differentiation into Adipocytes by Pioglitazone Pharmacological Activation of Peroxisome Proliferator Activated Receptor-Gamma (PPAR-γ)
by Catarina Teixeira, André P. Sousa, Inês Santos, Ana Catarina Rocha, Inês Alencastre, Ana Cláudia Pereira, Daniela Martins-Mendes, Pedro Barata, Pilar Baylina and Rúben Fernandes
Biology 2022, 11(6), 806; https://doi.org/10.3390/biology11060806 - 24 May 2022
Cited by 9 | Viewed by 3693
Abstract
Despite the primary function of pioglitazone in antidiabetic treatment, this drug is a potent inducer of PPAR-γ, a crucial receptor that is involved in adipocyte differentiation. In this work, we propose an optimized methodology to enhance the differentiation of 3T3-L1 fibroblasts into adipocytes. [...] Read more.
Despite the primary function of pioglitazone in antidiabetic treatment, this drug is a potent inducer of PPAR-γ, a crucial receptor that is involved in adipocyte differentiation. In this work, we propose an optimized methodology to enhance the differentiation of 3T3-L1 fibroblasts into adipocytes. This process is crucial for adipocyte secretome release, which is fundamental for understanding the molecular mechanisms that are involved in obesity for in vitro studies. To achieve this, a pioglitazone dose-response assay was determined over a range varying from 0 to 10 µM. Lipid accumulation was evaluated using Oil-Red-O. The results showed that 10 µM pioglitazone enhanced differentiation and increased secretome production. This secretome was then added into two cell lines: PC3 and RAW264.7. In the PC3 cells, an increase of aggressiveness was observed in terms of viability and proliferation, with the increase of anti-inflammatory cytokines. Conversely, in RAW264.7 cells, a reduction of viability and proliferation was observed, with a decrease in the overexpression of pro-inflammatory cytokines. Overall, the present work constitutes an improved method for adipocyte secretome production that is suitable for experimental biology studies and that could help with our understanding of the molecular mechanisms underlying adiposity influence in other cells. Full article
(This article belongs to the Special Issue Antitumor and Metabolic Effects Mediated by PPARs)
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Review

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17 pages, 1433 KiB  
Review
PPAR Alpha as a Metabolic Modulator of the Liver: Role in the Pathogenesis of Nonalcoholic Steatohepatitis (NASH)
by Simona Todisco, Anna Santarsiero, Paolo Convertini, Giulio De Stefano, Michele Gilio, Vito Iacobazzi and Vittoria Infantino
Biology 2022, 11(5), 792; https://doi.org/10.3390/biology11050792 - 23 May 2022
Cited by 49 | Viewed by 7759
Abstract
The strong relationship between metabolic alterations and non-alcoholic steatohepatitis (NASH) suggests a pathogenic interplay. However, many aspects have not yet been fully clarified. Nowadays, NASH is becoming the main cause of liver-associated morbidity and mortality. Therefore, an effort to understand the mechanisms underlying [...] Read more.
The strong relationship between metabolic alterations and non-alcoholic steatohepatitis (NASH) suggests a pathogenic interplay. However, many aspects have not yet been fully clarified. Nowadays, NASH is becoming the main cause of liver-associated morbidity and mortality. Therefore, an effort to understand the mechanisms underlying the pathogenesis of NASH is critical. Among the nuclear receptor transcription factors, peroxisome-proliferator-activated receptor alpha (PPARα) is highly expressed in the liver, where it works as a pivotal transcriptional regulator of the intermediary metabolism. In this context, PPARα’s function in regulating the lipid metabolism is essential for proper liver functioning. Here, we review metabolic liver genes under the control of PPARα and discuss how this aspect can impact the inflammatory condition and pathogenesis of NASH. Full article
(This article belongs to the Special Issue Antitumor and Metabolic Effects Mediated by PPARs)
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16 pages, 2775 KiB  
Review
PPAR Ligands Induce Antiviral Effects Targeting Perturbed Lipid Metabolism during SARS-CoV-2, HCV, and HCMV Infection
by Marialuigia Fantacuzzi, Rosa Amoroso and Alessandra Ammazzalorso
Biology 2022, 11(1), 114; https://doi.org/10.3390/biology11010114 - 11 Jan 2022
Cited by 16 | Viewed by 3096
Abstract
The manipulation of host metabolisms by viral infections has been demonstrated by several studies, with a marked influence on the synthesis and utilization of glucose, nucleotides, fatty acids, and amino acids. The ability of virus to perturb the metabolic status of the infected [...] Read more.
The manipulation of host metabolisms by viral infections has been demonstrated by several studies, with a marked influence on the synthesis and utilization of glucose, nucleotides, fatty acids, and amino acids. The ability of virus to perturb the metabolic status of the infected organism is directly linked to the outcome of the viral infection. A great deal of research in recent years has been focusing on these metabolic aspects, pointing at modifications induced by virus, and suggesting novel strategies to counteract the perturbed host metabolism. In this review, our attention is turned on PPARs, nuclear receptors controlling multiple metabolic actions, and on the effects played by PPAR ligands during viral infections. The role of PPAR agonists and antagonists during SARS-CoV-2, HCV, and HCMV infections will be analyzed. Full article
(This article belongs to the Special Issue Antitumor and Metabolic Effects Mediated by PPARs)
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