Hesperidin suppressed hepatic precancerous lesions via modulation of exophagy in rats

Abstract

The enormous cost of modern medicines warrants alternative strategies for the better management of hepatocellular carcinoma. Recently, exosomes have been shown to relay the oncogenic information through the horizontal transfer of RNAs between the cells. In this study, we modulated exosomal production and autophagy (exophagy) by the administration of hesperidin and evaluated its effect on the development of hepatic precancerous lesion (HPC) in rats. Diethylnitrosamine and 2‐acetylaminofluorene were used in vivo to induce HPC in rats. Rats were allocated into five groups: naïve, HPC, and three hesperidin treated (50, 100, and 200 mg/kg/d; orally) for 4 consecutive days per week for 16 weeks. Liver tissues and blood samples were collected for histopathological, immunohistochemical, and transmission electron microscope examinations, liver function, alfa‐fetoprotein level, and isolation of exosomal and autophagy RNAs. Hesperidin administration showed hepato‐protective effects and improved the microscopic hepatic features with a decrease in glutathione S‐transferase placental precancerous foci and the abundance of exosomes in liver tissues. Hesperidin improved liver function with a significant decrease in alfa‐fetoprotein levels. Hesperidin dose‐dependently decreased exosomal RAB11A messsenger RNA and long noncoding RNA‐RP11‐583F2.2 along with the increase in exosomal miR‐1298, involved in the exophagy process. In conclusion, hesperidin likely suppresses liver carcinogenesis in rat model via the modulation of exosomal secretion and autophagy.

Sesame Extract Promotes Chemopreventive Effect of Hesperidin on Early Phase of Diethylnitrosamine-Initiated Hepatocarcinogenesis in Rats

“…These results are in accordance with the findings of certain other reports which found that hesperidin could suppress cell proliferation and stimulate cell death in rat hepatocarcinogenesis. Hesperidin modulated exosome production and autophagy, resulting in the suppression of preneoplastic cell proliferation in DEN-initiated rats [36]. It also disrupted the induction of both canonical and noncanonical Wnt pathways in thioacetamide-induced hepatocarcinogenesis in rats [37].…”

Hesperidin Alleviates Hepatic Injury Caused by Deoxynivalenol Exposure through Activation of mTOR and AKT/GSK3β/TFEB Pathways

“…In the meantime, it has been suggested that treatment of neuronal cells with HDN inhibits amyloid β (Aβ)-induced autophagy . HDN inhibited rat hepatocellular carcinoma by regulating exosome secretion and autophagy . However, the mechanism by which HDN, a flavonoid with hepatoprotective bioactivity, treats DON exposure-induced liver injury is not clear.…”

Advances of multi-omics applications in hepatic precancerous lesions and hepatocellular carcinoma: The role of extracellular vesicles

“…Another study evaluating a largely unexplored EVs-associated unannotated small RNA clusters (smRCs) demonstrated that the 3-smRC signature was significantly overexpressed in plasma EVs from HCC patients, which exhibited high sensitivity and specificity for the detection of early HCC in an independent validation cohort evidenced by the AUC of 0.87 ( von Felden et al, 2021 ). Through a series of studies, Abd El Gwad A et al demonstrated the role of three EV RNA-based biomarkers (lncRNA-RP11-513I15.6, miR-1262 and RAB11A) in inducing the formation of precancerous lesions in rats, and their excellent ability to differentiate HCC patients from chronic hepatitis and healthy volunteers ( Abd El Gwad et al, 2018 ; Matboli et al, 2019 ; Hasanin et al, 2020 ). Comprehensive analysis of other extracellular RNAs also revealed the diagnostic value of different RNA detection panels in HCC, such as the combination of circRNA (SNORD3B-1, circ-0080695) with miR-122 ( Zhu et al, 2021 ; Cabiati et al, 2022 ).…”