An abnormality in the Lin28/let-7a axis is relevant to the progression of
hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), which could be
a novel therapeutic target for this malignant tumor. The present study aimed to
investigate the antiproliferative and anti-invasive effects of urolithin A in a
stable full-length HBV gene integrated cell line HepG2.2.15 using CCK-8 and
transwell assays. The RNA and protein expressions of targets were assessed by
quantitative PCR and western blot, respectively. Results revealed that urolithin
A induced cytotoxicity in HepG2.2.15 cells, which was accompanied by the
cleavage of caspase-3 protein and down-regulation of Bcl-2/Bax ratio. Moreover,
urolithin A suppressed the protein expressions of Sp-1, Lin28a, and Zcchc11, and
elevated the expression of microRNA let-7a. Importantly, urolithin A also
regulated the Lin28a/let-7a axis in transient HBx-transfected HCC HepG2 cells.
Furthermore, urolithin A decelerated the HepG2.2.15 cell invasion, which was
involved in suppressing the let-7a downstream factors HMGA2 and K-ras. These
findings indicated that urolithin A exerted the antiproliferative effect by
regulating the Lin28a/let-7a axis and may be a potential supplement for
HBV-infected HCC therapy.
Previous studies have demonstrated that the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib shows efficacy against multiple cancers, including hepatocellular carcinoma. However, whether celecoxib is effective in alleviating steatosis during hepatocarcinogenesis is unknown. In a rapid hepatocellular carcinoma (HCC) mouse model established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes, we investigated the antisteatotic and anticarcinogenic efficacy of celecoxib in vivo. Multiple HCC cell lines were employed for in vitro evaluation. Additionally, immunoblotting, immunohistochemistry, hematoxylin and eosin staining and Oil Red O staining were applied for mechanistic investigation. The results revealed that if celecoxib was administered in the early stage of AKT/c-Met-induced HCC, it resulted in disease stabilization. Moreover, celecoxib could alleviate lipid accumulation in the HCC mice and in an oleic acid-induced in vitro hepatic steatosis model. Further evidence at the molecular level indicated that celecoxib down-regulated the expression of phospho-ERK (Thr202/Tyr204) and proliferating cell nuclear antigen (PCNA) in the HCC mice. In addition, celecoxib efficiently repressed the phosphor-Akt (Thr308)/fatty acid synthase (FASN) axis both in vivo and in vitro. Altogether, this study suggests that celecoxib exerts its antilipogenic efficacy by targeting a COX-2/AKT/FASN cascade, which contributes to its ability to delay hepatocarcinogenesis.
Ellagitannins in Phyllanthus emblica L. (emblic leafflower fruits) have been thought of as the beneficial constituents for ameliorating endocrinal and metabolic diseases including diabetes. However, the effect of emblic leafflower fruits on diabetic vascular complications involved in ellagitannin-derived urolithin metabolites is still rare. In this study, acetylcholine-induced endothelium-independent relaxation in aortas was facilitated upon emblic leafflower fruit consumption in the single dose streptozotocin-induced hyperglycemic rats. Emblic leafflower fruit consumption also suppressed the phosphorylation of Akt (Thr308) in the hyperglycemic aortas. More importantly, urolithin A (UroA) and its derived phase II metabolites were identified as the metabolites upon emblic leafflower fruit consumption by HPLC-ESI-Q-TOF-MS. Moreover, UroA reduced the protein expressions of phosphor-Akt (Thr308) and β-catenin in a high glucose-induced A7r5 vascular smooth muscle cell proliferation model. Furthermore, accumulation of β-catenin protein and activation of Wnt signaling in LiCl-triggered A7r5 cells were also ameliorated by UroA treatment. In conclusion, our data demonstrate that emblic leafflower fruit consumption facilitates the vascular function in hyperglycemic rats by regulating Akt/β-catenin signaling, and the effects are potentially mediated by the ellagitannin metabolite urolithin A.
Although the suppressing effects of celastrol on hepatocellular carcinoma (HCC) have been demonstrated, evidence for the targeting of fatty acid synthetase (FASN) in the development of HCC by celastrol is still rare.In this study, the effect of celastrol on a rapid HCC model featuring co-activation of AKT/c-Met oncogenes in mice was studied. The effect of celastrol on the alpha-fetoprotein level in the liver and serum was also
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