DH9, a novel PPARγ agonist suppresses the proliferation of ADPKD epithelial cells: An association with an inhibition of β-catenin signaling

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease that exclusively progresses to renal failure. An important target for the treatment of ADPKD is to reduce cystic cell proliferation. PPARγ agonists such as TZDs are insulin sensitizing agents that have also been reported to decrease tumor growth. Here we tested DH9, a newly synthesized PPARγ agonist on the proliferation of an ADPKD cell line, WT9-12. DH9 showed a potent anti-proliferative activity against ADPKD cells. At high concentration, DH9 also induced apoptotic cell death. The effect of DH9 on cell proliferation was mediated by a PPARγ independent mechanism. Since DH9 decreased the levels of β-catenin in cells via a GSK3β mediated degradation pathway, this acts as a mechanism for growth inhibition by DH9.

Biology-oriented development of novel lipophilic antioxidants with neuroprotective activity

“…In fact, GSK-3b is signicantly involved in key pathological events, namely Tau hyperphosphorylation, amyloidogenesis, inammatory response and ACh decit. 55 As the modulation of GSK-3b activity was also mediated by a diversity of polyphenolic systems [56][57][58] it was decided to screen HCAs and derivatives (compounds 1, 2 and 7-14) towards GSK-3b, at a xed concentration of 10 mM, using a previously described luminescent technique. Recent studies report the ability of compound 1 and its natural phenethyl ester derivative (CAPE) to modulate the Akt/GSK-3b signalling pathway and GSK-3b activity.…”

“…53,54 Moreover, a synthetic hydrocinnamic derivative (DH9) has also been reported to modulate GSK-3b activity by inducing its phosphorylation. 55 As the modulation of GSK-3b activity was also mediated by a diversity of polyphenolic systems [56][57][58] it was decided to screen HCAs and derivatives (compounds 1, 2 and 7-14) towards GSK-3b, at a xed concentration of 10 mM, using a previously described luminescent technique. 59 From the data one can concluded that none of the tested compound displayed noteworthy activity at the established concentration (Table 1).…”

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

“…The TZDs, rosiglitazone and pioglitazone, are currently in clinical use for the treatment of type-II diabetes, while troglitazone was withdrawn from clinical use because it was linked to idiosyncratic liver toxicity [24] . Other non-TZD synthetic ligands include certain non-steroidal anti-inflammatory drugs such as isoxzolidinedione JTT-501 [25] , tyrosine-based GW7845 [26] and DH9, a newly synthesized PPARγ agonist [27] . Naturally occurring compounds that activate PPARγ include long chain polyunsaturated fatty acids which are found in fish oil (e.g.…”

Cinnamic acid decreases periodontal inflammation and alveolar bone loss in experimental periodontitis

“…13 PPAR-γ activation can also inhibit osteoblastic activity by modulating β-catenin pathway. 14 Prevention of inflammatory state prevents the destructive process and improves periodontal health. 4,7 In this regard, unsaturated carboxylic acids have been shown to exhibit significant inhibitory effects on the pro-inflammatory pathways such as NF-κB and MAPK.…”