The combination of coffee compounds attenuates early fibrosis-associated hepatocarcinogenesis in mice: involvement of miRNA profile modulation

Abstract

Aberrant microRNA expression implicates on Hepatocellular carcinoma (HCC) development/progression. Conversely, daily coffee consumption reduces by ~40% the risk for fibrosis/cirrhosis and HCC, while decaffeinated coffee does not. Are these beneficial effects related to caffeine (CAF), or to its combination with other common/highly bioavailable coffee compounds, as trigonelline (TRI) and chlorogenic acid (CGA)? We evaluated whether CAF individually or combined with TRI and/or CGA alleviates fibrosis-associated hepatocarcinogenesis, examining the involvement of miRNA profile modulation. Male C3H/HeJ mice were submitted to a diethylnitrosamine/carbon tetrachloride-induced model. Animals received CAF (50 mg/kg body weight, 5x/week, intragastrically), CAF+TRI (50 and 25 mg/kg), CAF+CGA (50 and 25 mg/kg) or CAF+TRI+CGA (50, 25 and 25 mg/kg) for 10 weeks. Only CAF+TRI+CGA treatment reduced hepatocellular preneoplastic foci development. Moreover, only the combination of all compounds reduced proliferation (Ki-67) in preneoplastic lesions and enhanced apoptosis (cleaved caspase-3) in adjacent tissue. CAF+TRI+CGA also decreased hepatic oxidative stress by enhancing antioxidant Nrf2 axis. CAF+TRI+CGA had the most pronounced effects on decreasing hepatic pro-inflammatory IL-17/NFκB signaling, contributing to reduce CD68-positive macrophage number, stellate cell activation and collagen deposition. The miRNAomic profile revealed that CAF+TRI+CGA upregulated tumor suppressors miR-144-3p and antifibrotic miR-15b-5p, frequently altered in HCC. CAF+TRI+CGA reduced protein levels of proproliferative EGFR (miR-144-3p target) and antiapoptotic Bcl-2 family members (Bcl-2, Mcl-1 and Bcl2l2, miR-15b-5p targets). The results suggest that the combination of coffee compounds, rather than CAF individually, attenuates fibrosisassociated hepatocarcinogenesis by modulating miRNA expression profile. Findings provide translational insights on therapeutic approaches based on miRNA profile modulation by coffee compounds.

Gold nanoparticles enhance microRNA 31 detection in colon cancer cells after inhibition with chlorogenic acid

“…The oncomiR-31 inhibits the translation of RAS P21 protein activator 1, an inhibitor of KRAS protooncogene, thus stimulating the transcription of the KRAS oncogene, which promotes cell cycle progression in colon cancer cells (32). According to previous research, miR-31, and other miRNAs such as miR155 ( 33) and miR144-3p (34), are modulated by CGA (Fig. 5).…”

Investigating the Opposing Effect of Two Different Green Tea Supplements on Oxidative Stress, Mitochondrial Function and Cell Viability in HepG2 Cells

“…Likewise, we demonstrate that the alkaloid caffeine is present in higher levels in dGTE2 than dGTE1. Previous studies indicate that caffeine ($8 mgÁml À1 ) can induce cytotoxicity in human hepatocarcinoma cells (Romualdo et al 2020) whilst in vivo studies suggest that caffeine consumption can reduce oxidative stress and fibrosis in settings of liver disease such as cirrhosis (Amer et al 2017;Arauz et al 2017). Given this controversy regarding hepatic response to caffeine exposure, and that dGTE1 and dGTE2 are labeled as decaffeinated, it is unlikely that caffeine is responsible for the biological effects of GTE observed however further investigation is needed to establish the levels of caffeine in each extract.…”

Environmental Impact on the Epigenetic Mechanisms Underlying Parkinson’s Disease Pathogenesis: A Narrative Review

“…Variants of manganese-dependent superoxide dismutase ( SOD2 ), a mitochondrial antioxidant enzyme, have also been associated with an increased risk of PD in some but not all studies [ 125 , 126 ]. Sirtuin 3 (SIRT3), a HDAC, has been shown to deacetylate SOD2, resulting in protection against MPTP-induced ROS accumulation and dopaminergic neurodegeneration in vivo [ 63 ].…”