Hepatocarcinogenesis Prevention by Pirfenidone Is PPARγ Mediated and Involves Modification of Nuclear NF-kB p65/p50 Ratio

Abstract

Targeted therapies for regulating processes such as inflammation, apoptosis, and fibrogenesis might modulate human HCC development. Pirfenidone (PFD) has shown anti-fibrotic and anti-inflammatory functions in both clinical and experimental studies. The aim of this study was to evaluate PPARγ expression and localization in samples of primary human tumors and assess PFD-effect in early phases of hepatocarcinogenic process. Human HCC tissue samples were obtained by surgical resection. Experimental hepatocarcinogenesis was induced in male Fischer-344 rats. TGF-β1 and α-SMA expression was evaluated as fibrosis markers. NF-kB cascade, TNFα, IL-6, and COX-2 expression and localization were evaluated as inflammation indicators. Caspase-3, p53, and PARP-1 were used as apoptosis markers, PCNA for proliferation. Finally, PPARα and PPARγ expression were evaluated to understand the effect of PFD on the activation of such pathways. PPARγ expression was predominantly localized in cytoplasm in human HCC tissue. PFD was effective to prevent histopathological damage and TGF-β1 and α-SMA overexpression in the experimental model. Anti-inflammatory effects of PFD correlate with diminished IKK and decrease in both IkB-phosphorylation/NF-kB p65 expression and p65-translocation into the nucleus. Pro-apoptotic PFD-induced effects are related with p53 expression, Caspase-3 p17 activation, and PARP-1-cleavage. In conclusion, PFD acts as a tumor suppressor by preventing fibrosis, reducing inflammation, and promoting apoptosis in MRHM.

PAX6/CXCL14 regulatory axis promotes the repair of corneal injury by enhancing corneal epithelial cell proliferation

“…Notably, there was a significant upsurge in the activity of the NF-κB signaling pathway linked to elevated CXCL14 expression, as seen in Fig. 4 A, B. P65 and p50 are the most common subunits of NF-κB [ 51 ]. Western blot analysis further confirmed that the expression of NF-κB p50 and particularly NF-κB p65 markedly increased following stimulation, as seen in Fig.…”

Echinococcus granulosus Protoscoleces-Derived Exosome-like Vesicles and Egr-miR-277a-3p Promote Dendritic Cell Maturation and Differentiation

“…In its canonical signaling pathway, NF-κB is a heterodimer consisting of p65 and p50 subunits. The p65 protein functions as the activator of the p65-p50 heterodimer, and an increase in the NF-κB p65/p50 ratio is beneficial to the secretion of inflammatory factors TNF-α and IL-6 [ 24 , 25 ]. Western blotting showed that the NF-κB P65 protein levels were significantly increased after the transfection of the egr-miR-277a-3p mimic into BMDCs, while the NF-κB1 levels were significantly decreased ( Figure 7 b).…”

“…Meanwhile, in the current study, it was found that egr-miR-277a-3p could significantly upregulate the expression of NF-κB p65 in BMDCs. NF-κB can mediate inflammatory responses, and an increase in p65/p50 expression promotes the secretion of IL-6 and TNF-α [ 24 , 32 ]. Therefore, it was speculated that egr-miR-277a-3p could directly target Nfkb1 and might induce the production of these proinflammatory cytokines by modification of the NF-kB p65/p50 ratio in BMDCs.…”

Comparative Study of Docosahexaenoic Acid with Different Molecular Forms for Promoting Apoptosis of the 95D Non-Small-Cell Lung Cancer Cells in a PPARγ-Dependent Manner

“…Notably, biochemical interaction studies showed that PPARγ bound with NF-κB prevents its translocation to the nucleus. The overexpression of PPARγ could promote the ubiquitination degradation of NF-κB, resulting in anticancer effects [ 33 , 34 ]. Lee et al reported that ligand-activated PPARγ induced cell apoptosis by blocking the anti-apoptotic signaling of NF-κB [ 35 ].…”