Tanshinone IIA promotes the proliferation of WB-F344 hepatic oval cells via Wnt/β-catenin signaling

Abstract

Tanshinone IIA (TSA) is a widely used traditional Chinese medicine, which has been demonstrated to protect damaged liver cells and is currently administered in the treatment of liver fibrosis. Liver precursor cells, also termed oval cells, are key in the repair of liver tissues following injury. However, whether TSA improves the function of liver cells and protects the liver from injury by enhancing the growth and proliferation of hepatic oval cells remains to be elucidated. In the present study, low to moderate concentrations of TSA were observed to stimulate proliferation, did not induce apoptosis in WB-F344 rat hepatic oval cells and the increased expression levels of β-catenin. WB-F344 cells were treated with various concentrations of TSA (0–80 µg/ml) for 24, 48, 72 and 96 h. Cell proliferation was measured using a Cell Counting kit-8 (CCK-8) assay, a 5-ethynyl-2′-deoxyuridine assay and a carboxyfluorescein diacetate succinimidyl ester (CFSE) assay. The CCK-8 assay demonstrated that treatment of WB-F344 cells with 20–40 µg/ml TSA for up to 72 h significantly increased proliferation. Similar results were observed in the subsequent EdU and CFSE assays. Furthermore, a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay demonstrated that 20–40 µg/ml TSA treatment for up to 96 h did not induce apoptosis of the WB-F344 cells. Notably, the results of western blot, immunofluorescence and reverse transcription-quantitative polymerase chain reaction analyses demonstrated that treatment of the WB-F344 cells with 20–40 µg/ml TSA for up to 72 h significantly increased the expression levels of β-catenin. These data indicated that TSA at concentrations between 20 and 40 µg/ml may induce WB-F344 cell proliferation by activating the canonical Wnt signaling pathway. The results of the present study suggest that TSA may be a useful natural agent to enhance repair and regeneration of the injured liver, and improve liver regeneration following orthotopic liver transplantation.

Yiqi Huoxue Recipe Improves Liver Regeneration in Rats after Partial Hepatectomy via JNK Pathway

“…e prescription consists of several traditional Chinese herbal medicines, such as Astragalus membranaceus, Salvia miltiorrhiza, red peony root, Poria, radix curcumae, and Amomum cardamomum. Tanshinone IIA is an extract from the sage plant, Salvia miltiorrhiza, which has been reported to increase the proliferation of WB-F344 hepatic oval cells by activating canonical Wnt signaling pathway [8]. Astragaloside IV, extracted from the traditional Chinese medicine Astragalus membranaceus, has been extensively tested and proved to be effective for antifibrosis [9] and metastasis suppression in hepatoma cells [10].…”

Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury

“…Rationale for examining Wnt/β-catenin signaling pathway in our heteroprotection model of hepatotoxicity is that, (1) pro-regenerative cyclin D1 is a target gene for β-catenin signaling pathway 55 and (2) activation of β-catenin signaling through endogenous and pharmacological interventions caused compensatory liver regeneration. 17 - 19 Moreover, Wnt/β-catenin was recently shown to exert antioxidant and mitochondrial protective effects during ischemia reperfusion liver injury. 21 In our studies, we found early and robust activation of β-catenin pathway as indicated by overexpression of total and activated β-catenin in the TA + APAP-treated mice compared to the DW + APAP-treated mice ( Figure 4A and 4B ).…”

“…Several studies have examined the underlying machineries for tissue regeneration after toxicant-induced and traumatic organ injuries (liver, kidney, lung, heart, and axon). 7 , 11 - 16 Of these cytokine-, chemokine-, growth factor-, neuroendocrine-, mitogenic pathway-, and stem cell-based mechanisms of various organs regeneration, canonical Wnt/β-catenin signaling pathway appears a highly promising one for liver regeneration due to the following compelling evidences: (1) of the several hepatic mitogenic pathways studied, only Wnt/β-catenin pathway was directly correlated with liver regeneration after the APAP treatment 17 ; (2) stimulation of Wnt/β-catenin pathway using a synthetic compound tanshinone IIA stimulated rat hepatic oval cells proliferation, 18 which often contributes toward liver regeneration 19 ; (3) prior treatment with a Wnt/β-catenin agonist reversed the inhibited hepatocyte proliferation in the small-for-size liver graft model in Sprague-Dawley rats 20 ; and (4) Wnt/β-catenin pathway can also protect the liver against oxidative injury by preserving mitochondrial functions. 21 These observations highlight the need to further examine the role of the hepatic Wnt/β-catenin signaling to better understand the toxicodynamics of autoprotection and heteroprotection models of hepatotoxicity.…”

Protective effect of tanshinone IIA against cardiac hypertrophy in spontaneously hypertensive rats through inhibiting the Cys-C/Wnt signaling pathway

“…A previous study demonstrated that the elevation of Cys-C can evoke an inhibition of cathepsin B, and an accumulation of collagen I, collagen III and fibronectin in the ischaemic area of the myocardium, indicating a stimulatory role of Cys-C in cardiac hypertrophy [ 34 ]. Additionally, the activation of Wnt signaling pathway is responsible for the growth of hypertrophy [ 8 , 35 , 36 ]. After treated by tanshinone IIA, the Cys-C and Wnt expressions decreased significantly, suggesting that tanshinone IIA may have a protective effect on cardiac hypertrophy in SHRs through the inhibition of the Cys-C/Wnt signaling pathway.…”