RESUMO
Metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma (MASH-HCC) is a global clinical challenge for which there is a limited understanding of disease pathogenesis and a subsequent lack of therapeutic interventions. We previously identified that tumor necrosis factor-alpha (TNF-α) upregulated apoptosis antagonizing transcription factor (AATF) in MASH. Here, we investigated the effect of TNF-α converting enzyme (TACE) inhibition as a promising targeted therapy against AATF-mediated steatohepatitis to hepatocarcinogenesis. A preclinical murine model that recapitulates human MASH-HCC was used in the study. C57Bl/6 mice were fed with chow diet normal water (CD) or western diet sugar water (WD) along with a low dose of carbon tetrachloride (CCl4; 0.2 µL·g-1, weekly) for 24 weeks. TACE activity, TNF-α levels, and AATF expression were measured. The mice were treated with the TACE inhibitor Marimastat for 12 weeks, followed by analyses of liver injury, fibrosis, inflammation, and oncogenic signaling. In vitro experiments using stable clones of AATF control and AATF knockdown were also conducted. We found that AATF expression was upregulated in WD/CCl4 mice, which developed severe MASH at 12 weeks and advanced fibrosis with HCC at 24 weeks. WD/CCl4 mice showed increased TACE activity with reduced hepatic expression of sirtuin 1 (Sirt1) and tissue inhibitor of metalloproteinase 3 (Timp3). The involvement of the SIRT1/TIMP3/TACE axis was confirmed by the release of TNF-α, which upregulated AATF, a key molecular driver of MASH-HCC. Interestingly, TACE inhibition by Marimastat reduced liver injury, dyslipidemia, AATF expression, and oncogenic signaling, effectively preventing hepatocarcinogenesis. Furthermore, Marimastat inhibited the activation of JNK, ERK1/2, and AKT, which are key regulators of tumorigenesis in WD/CCl4 mice and in AATF control cells, but had no effect on AATF knockdown cells. This study shows that TACE inhibition prevents AATF-mediated inflammation, fibrosis, and oncogenesis in MASH-HCC, offering a potential target for therapeutic intervention.
RESUMO
There is a great demand to replace non-renewable materials with eco-friendly renewable materials for many applications in recent times. In the present study, such an attempt was made to substitute synthetic polymer-based films used for food packaging applications with films prepared out of renewable materials derived from waste. The pectin/polyvinyl alcohol (PP) and pectin-MgO/polyvinyl alcohol (PMP) films were prepared and characterized to ascertain their suitability for packaging applications. To improve the mechanical strength and thermal stability of films, MgO nanoparticles were incorporated in situ into the polymer matrix. The pectin used in the study was extracted from citrus fruit peel. The prepared nanocomposite films were evaluated for physico-mechanical properties, water contact angle, thermal stability, crystallinity, morphology, compositional purity and biodegradability. The elongation at break for PP film was 42.24% and for PMP film it was 39.18%. Also, the ultimate modulus in terms of MPa for PP film was 6.8 and for PMP it was 7.9. So, it was found that PMP films have better ductility and modulus than PP films due to the presence of MgO nanoparticles. The spectral studies confirmed the compositional purity of the prepared films. The biodegradation studies revealed that both films could be degraded at ambient conditions at appreciable time span, suggesting them to be a better choice as an environmentally friendly food packaging material.
