Abstract:Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natu… Show more
“…PPAR-γ is frequently expressed in various cancer cells, including breast, lung, colon, lips, kidney, pancreatic and thyroid [ 32 ]. Several studies have revealed that PPAR-γ activation by its agonists imposes cell cycle arrest [ 33 ], apoptosis [ 34 ], angiogenesis [ 35 ], inhibition [ 36 ], and redifferentiation [ 37 ], which are the key molecular processes associated with the prevention of tumor growth and progression. The expression of angiogenesis-related proteins such as vascular endothelial growth factor (VEGF) and cyclooxygenase-2 as well as inflammatory mediators in the tumor microenvironment are all inhibited by PPAR-γ activation [ 38 ].…”
Section: Functional Diversity Of Ppar-γmentioning
confidence: 99%
“…They are considered as weak activators of PPAR-γ compared with full agonists, which shows lower transactivation potential and imparts desirable effect [ 69 ]. Agonist-mediated activation of PPAR-γ has been reported to exhibit anti-inflammatory properties, growth inhibitory effects and prevent proliferation of many human cancer cell lines [ 34 , 64 ]. Likewise, the antagonist activity has also been observed to destabilize H12 and stabilize H3 and β-sheet.…”
Section: Ppar-γ Activation By Various Ligandsmentioning
Peroxisome proliferator-activated receptor-γ (PPAR-γ) has emerged as one of the most extensively studied transcription factors since its discovery in 1990, highlighting its importance in the etiology and treatment of numerous diseases involving various types of cancer, type 2 diabetes mellitus, autoimmune, dermatological and cardiovascular disorders. Ligands are regarded as the key determinant for the tissue-specific activation of PPAR-γ. However, the mechanism governing this process is merely a contradictory debate which is yet to be systematically researched. Either these receptors get weakly activated by endogenous or natural ligands or leads to a direct over-activation process by synthetic ligands, serving as complete full agonists. Therefore, fine-tuning on the action of PPAR-γ and more subtle modulation can be a rewarding approach which might open new avenues for the treatment of several diseases. In the recent era, researchers have sought to develop safer partial PPAR-γ agonists in order to dodge the toxicity induced by full agonists, akin to a balanced activation. With a particular reference to cancer, this review concentrates on the therapeutic role of partial agonists, especially in cancer treatment. Additionally, a timely examination of their efficacy on various other disease-fate decisions has been also discussed.
“…PPAR-γ is frequently expressed in various cancer cells, including breast, lung, colon, lips, kidney, pancreatic and thyroid [ 32 ]. Several studies have revealed that PPAR-γ activation by its agonists imposes cell cycle arrest [ 33 ], apoptosis [ 34 ], angiogenesis [ 35 ], inhibition [ 36 ], and redifferentiation [ 37 ], which are the key molecular processes associated with the prevention of tumor growth and progression. The expression of angiogenesis-related proteins such as vascular endothelial growth factor (VEGF) and cyclooxygenase-2 as well as inflammatory mediators in the tumor microenvironment are all inhibited by PPAR-γ activation [ 38 ].…”
Section: Functional Diversity Of Ppar-γmentioning
confidence: 99%
“…They are considered as weak activators of PPAR-γ compared with full agonists, which shows lower transactivation potential and imparts desirable effect [ 69 ]. Agonist-mediated activation of PPAR-γ has been reported to exhibit anti-inflammatory properties, growth inhibitory effects and prevent proliferation of many human cancer cell lines [ 34 , 64 ]. Likewise, the antagonist activity has also been observed to destabilize H12 and stabilize H3 and β-sheet.…”
Section: Ppar-γ Activation By Various Ligandsmentioning
Peroxisome proliferator-activated receptor-γ (PPAR-γ) has emerged as one of the most extensively studied transcription factors since its discovery in 1990, highlighting its importance in the etiology and treatment of numerous diseases involving various types of cancer, type 2 diabetes mellitus, autoimmune, dermatological and cardiovascular disorders. Ligands are regarded as the key determinant for the tissue-specific activation of PPAR-γ. However, the mechanism governing this process is merely a contradictory debate which is yet to be systematically researched. Either these receptors get weakly activated by endogenous or natural ligands or leads to a direct over-activation process by synthetic ligands, serving as complete full agonists. Therefore, fine-tuning on the action of PPAR-γ and more subtle modulation can be a rewarding approach which might open new avenues for the treatment of several diseases. In the recent era, researchers have sought to develop safer partial PPAR-γ agonists in order to dodge the toxicity induced by full agonists, akin to a balanced activation. With a particular reference to cancer, this review concentrates on the therapeutic role of partial agonists, especially in cancer treatment. Additionally, a timely examination of their efficacy on various other disease-fate decisions has been also discussed.
“…The close interplay between lipid oxidation, chronic inflammation, and cancer [ 16 ] oriented the researchers to also explore the antitumor activity of PPAR ligands, leading to a significant amount of literature data, sometimes reporting contrasting results. In fact, PPAR isoforms can function as tumor suppressors or inducers, depending on the biological context and the cancer type [ 17 , 18 ]. A remarkable attention has been paid to PPARα antagonists, whose activity on fatty acid metabolism could be responsible for a metabolic alteration of cancer cells, by promoting a switching from glycolysis to fatty acid oxidation [ 19 ].…”
The NF-E2-related factor 2 transcription factor (Nrf2) orchestrates the basal and stress-inducible activation of a vast array of antioxidant genes. A high amount of reactive oxygen species (ROS) promotes carcinogenesis in cells with defective redox-sensitive signaling factors such as Nrf2. In breast cancer (BC), emerging evidence indicates that increased Nrf2 activity enhances cell metastatic potential. An interconnection between peroxisome proliferator-activated receptors (PPARs) and Nrf2 pathways in cancer has been shown. In this light, newly synthesized PPARα antagonists, namely IB42, IB44, and IB66, were tested in the BC cell line MCF7 in parallel with GW6471 as the reference compound. Our results show that the most promising compound of this phenylsulfonimide series (IB66) is able to decrease MCF7 proliferation by blocking cells at the G2/M checkpoint. The underlying mechanism has been investigated, disclosing a caspase 3/Akt-dependent apoptotic/pyroptotic pathway induced by the increased generation of oxidative stress. Moreover, the involvement of Nrf2 and COX2 in IB66-treated MCF7 cell response has been highlighted. The reported data lay the groundwork for the development of alternative targeted therapy involving the Nrf2/PPARα molecular axis, able to overcome BC cell chemoresistance and cause better clinical outcomes, promoting other forms of programmed cell death, such as pyroptosis.
“…PPARs belong to the group of nuclear receptors that activate or repress target genes as heterodimers with retinoic X receptors (RxR). PPARs family included: PPAR alpha (PPARα), PPAR beta/delta (PPARβ/δ), and PPAR gamma (PPARγ) [ 32 ]. Different types of cells exhibited various expressions of PPARs; thus, the outcome of its activation might be different in various tissues [ 33 ].…”
Huntington’s disease (HD) is a rare neurodegenerative disease that is accompanied by skeletal muscle atrophy and cardiomyopathy. Tissues affected by HD (central nervous system [CNS], skeletal muscle, and heart) are known to suffer from deteriorated cellular energy metabolism that manifests already at presymptomatic stages. This work aimed to test the effects of peroxisome proliferator-activated receptor (PPAR)-γ agonist—rosiglitazone on grip strength and heart function in an experimental HD model—on R6/1 mice and to address the mechanisms. We noted that rosiglitazone treatment lead to improvement of R6/1 mice grip strength and cardiac mechanical function. It was accompanied by an enhancement of the total adenine nucleotides pool, increased glucose oxidation, changes in mitochondrial number (indicated as increased citric synthase activity), and reduction in mitochondrial complex I activity. These metabolic changes were supported by increased total antioxidant status in HD mice injected with rosiglitazone. Correction of energy deficits with rosiglitazone was further indicated by decreased accumulation of nucleotide catabolites in HD mice serum. Thus, rosiglitazone treatment may not only delay neurodegeneration but also may ameliorate cardio- and myopathy linked to HD by improvement of cellular energetics.
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