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Respiratory System
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Tom P. McKevitt, David J. Lewis
With some orally delivered drugs, multifocal foamy macrophage aggregates appear scattered throughout the parenchyma. This effect, which often becomes more evident in the 2-year oncogenicity studies, has been seen in rats with peroxisome proliferator-activated receptor alpha (PPARα) agonists such as clofibrate and nafenopin, a PPARδ agonist, a p38 kinase inhibitor, and an iNOS inhibitor (Fringes et al. 1988a,b,c). These compounds do not have a cationic amphiphilic drug (CAD)-like structure; hence, the lesions were not consistent with PLO (discussed later). Similar changes were not seen in the corresponding mouse studies or the 9-month dog or nonhuman primate studies. The macrophages were not associated with any other inflammatory cell infiltration.
Treatment of Vulnerable Plaques: Current and Future Strategies
Published in Levon Michael Khachigian, High-Risk Atherosclerotic Plaques, 2004
Leonard Kritharides, David Brieger, S. Benedict Freedman, Harry C. Lowe
PPAR-α is highly expressed in tissues that readily catabolize free fatty acids, such as fat, liver, and heart, and contributes to the regulation of genes responsible for fatty acid esterification and oxidation. The fibrate class of lipid lowering drugs such as gemfibrozil and fenofibrate are low-affinity agonists of PPAR-α. While their PPAR agonist activity contributes to their lipid lowering and antiatherogenic properties, newer selective agents with greater PPAR affinities may exert very profound antiinflammatory lipid lowering effects.139 Gemfibrozil, one of the major currently available fibrates, has been shown to reduce cardiovascular events in patients with impaired insulin sensitivity and elevated triglycerides, and the extent of benefit correlates with the degree of elevation of HDL.130 There appear to be differences between fibrates in their regulation of key lipoprotein genes in different tissues140 and these may be due to differential PPAR cofactor recruitment or differential affinity of binding to PPAR-α.
Mitochondria in Huntington’s Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Mitochondrial biogenesis is a promising therapeutic target in HD. Overexpression of PGC-1α enhanced the mitochondrial membrane potential and reduced mitochondrial toxicity in in-vitro models of HD (Weydt et al., 2006). Lentiviral delivery of PGC-1α to the striatum of R6/2 HD mice prevented striatal atrophy at the site of PGC-1α injections (Cui et al., 2006). Administration of a PPARγ agonist, thiazolidinedione, was shown to produce beneficial effects on weight loss, mutant huntingtin aggregates, and global ubiquitination profiles in R6/2 mice (Chiang et al., 2010). Bezafibrate, which is a pan-PPAR agonist, stimulated PPAR-PGC-1α-axis; improved expression of PGC-1α and downstream target genes; restored mitochondrial numbers and function; improved behavioral deficits, survival, and striatal atrophy; and reduced oxidative damage in a truncated and full-length mutant huntingtin model of HD, the R6/2 and the BACHD mice (Johri et al., 2012; Chandra et al., 2016). Both pioglitazone and rosiglitazone, which are PPAR-γ agonists, were shown to exert beneficial effects in in-vitro and in-vivo models of HD. Pioglitazone attenuated quinolinic acid-induced neurotoxicity in animals (Kalonia et al., 2010). The protective effect of pioglitazone was also demonstrated in a 3-NP model of HD (Napolitano et al., 2011). In striatal HdhQ111/Q111 cells, PPARγ activation by rosiglitazone prevents mitochondrial dysfunction and oxidative stress that occurs when mutant striatal cells are challenged with pathological increases in calcium (Quintanilla et al., 2008). Rosiglitazone significantly attenuated mutant huntingtin-induced toxicity in striatal cells, and chronic administration of rosiglitazone significantly improved motor function, attenuated hyperglycemia, rescued BDNF deficiency, and protected against neuronal loss in N171-82Q HD mice (Jin et al., 2013). Moreover, it prevented PGC-1α reduction and increased Sirt6 protein levels in the HD mouse brain (Jin et al., 2013). Rosiglitazone mediates neuroprotection in the mutant huntingtin expressing neuroblastoma cell line (N2A), where it upregulates the endogenous expression of PPARγ, its downstream target genes (including PGC1α, NRF-1, and Tfam), and mitochondrial function (Chiang et al., 2015).
Peroxisome proliferator-activated receptor agonists and antagonists: a patent review (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Ichiro Takada, Makoto Makishima
Cadila Healthcare Ltd. claimed the use of PPAR agonists for diabetic retinopathy [89] and nephropathy [90]. Diabetic retinopathy and nephropathy are common complications of diabetes, leading to blindness and chronic renal failure, respectively. PPARγ and PPARα are promising drug targets in the treatment of diabetic retinopathy. PPARγ agonist suppresses retinal neurodegeneration and microangiopathy, and PPARα agonist regulates lipid transport and shows antioxidant and antiangiogenic activities [91]. PPARα agonist and PPARγ agonist also have a therapeutic potential against diabetic nephropathy [92,93]. The inventors showed the preventative effect of the PPARα/γ dual agonist saroglitazar (31) (Figure 5(a)) in experimental models of diabetic retinopathy and nephropathy [89,90]. The adverse effects of PPARγ agonist, specifically fluid retention and congestive heart failure, should be carefully monitored in the treatment of diabetic patients.
Current status of GPR40/FFAR1 modulators in medicinal chemistry (2016–2019): a patent review
Published in Expert Opinion on Therapeutic Patents, 2020
Zheng Li, Zongtao Zhou, Luyong Zhang
The peroxisome proliferator-activated receptors (PPARs) have three subtypes: PPARα, PPARγ, and PPARδ. The PPARα or PPARγ agonist exhibited therapeutic benefits for glucose and lipid metabolism [77,78]. PPARδ is involved in lipid metabolism and inflammation, and considered as potent target of obesity and atherosclerosis [79]. It is worth mentioning that the endogenous ligands of FFAR1 and PPARs are free fatty acids, which provided the possibility to obtain multiple target agonists [80]. Indeed, several groups have reported some lead compounds (such as 53–56) with multiple potencies for FFAR1 and PPARs, though the activities are limited to micromolar levels [81–84]. CN102040517 has filed a series of resveratrol derivatives as quadruple PPARα/γ/δ and FFAR1 agonists, including compounds 53 and 54 [85]. Compound 53 could reduce oxidative stress, inflammation, lipid levels, and alleviate insulin resistance. In nonalcoholic steatohepatitis model, compound 53 significantly improved steatosis, inflammation and fibrosis of liver [86]. Based on hybrid strategy, the highly potent FFAR1/PPARδ agonists (such as 57 and 58) have been identified [87,88]. The dual agonist 57 significantly improved the glucose tolerance of ob/ob mice in a dose-dependent manner [87].
β-catenin and PPAR-γ levels in bone marrow of myeloproliferative neoplasm: an immunohistochemical and ultrastructural study
Published in Ultrastructural Pathology, 2018
Tijana Subotički, Olivera Mitrović Ajtić, Mileva Mićić, Tamara Kravić Stevović, Dragoslava Đikić, Miloš Diklić, Danijela Leković, Mirjana Gotić, Vladan P. Čokić
Although the role of PPARγ was investigated in different hematological malignancies,20 so far its role in MPNs has received no attention. Our data show that in contrast to β-catenin expression, PPARγ has opposite pattern. The highest number of PPARγ immunopositive cells was detected in PMF patients, while the lowest number in ET patients. Also, immunoreactivity for PPARγ was localized mostly in megakaryocytes of MPNs. Previous study showed that PPARγ is not restricted to the nucleus, but is also expressed in the cytoplasm.21 Transcriptional activity of PPARγ is controlled primarily by ligand binding and its ligands include both synthetic and natural molecules.22 Synthetic PPARγ ligands, including drugs of the thiazolidinedione (TZD) family, have potent insulin sensing properties, and are commonly used for the treatment of type 2 diabetes.22,23 There are also many synthetic compounds that can function as PPARγ agonist. One of them, triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), binds to PPARγ with nanomolar affinity and displays anti-proliferative and differentiating activities, making it useful as a chemotherapeutic agent.24 PPARγ ligands have anti-proliferative, pro-differentiated, anti-metastatic and pro-apopototic effects on several hematological malignancies, making PPARγ a promising target in therapeutic regimens designed to combat these types of cancer.11