Dichloroacetate enhances the antitumor effect of pirarubicin via regulating the ROS-JNK signaling pathway in liver cancer cells.

Aim: Liver cancer is one of the most common malignancies and has a high recurrence rate. However, current treatment strategies do not achieve satisfactory outcomes in the clinic. To explore a new strategy to enhance the effectiveness of chemotherapy in liver cancer, we investigated whether dichloroacetate (DCA) could enhance the sensitivity of liver cancer cells to pirarubicin (THP). Methods: Liver cancer cells were treated with DCA alone, THP alone, or DCA and THP combined. Cell viability was determined by the CCK-8 assay. Cell apoptosis was analyzed by flow cytometer. Reactive oxygen species (ROS) were detected using a CM-H2DCFDA fluorescence probe. Protein levels were identified by immunoblotting. Results: The results revealed that DCA significantly enhanced the antitumor effect of THP in liver cancer cells. Changes in morphology and adherence ability were observed, as well as decreased cell viability. The results of flow cytometry showed that the combination of THP and DCA significantly increased apoptosis of liver cancer cells. Moreover, compared with THP alone, combination treatment with DCA significantly increased THP-triggered ROS generation in liver cancer cells. The antioxidant N-acetyl-L-cysteine reversed the synergistic effect of DCA and THP on ROS generation, cell viability and apoptosis. Furthermore, phosphorylation of c-Jun N-terminal kinase (JNK) was significantly increased in the DCA and THP combination group. The effects of DCA and THP on cell viability and apoptosis were inhibited by the JNK inhibitor SP600125. Conclusion: The results obtained in the present study indicated that DCA enhanced the antitumor effect of THP in liver cancer cells via regulating the ROS-JNK signaling pathway.

Fluorofenidone inhibits transforming growth factor-beta1-induced cardiac myofibroblast differentiation.

Cardiac myofibroblast differentiation, characterized by expression of alpha-smooth muscle actin (alpha-SMA) and fibrillar collagens, plays a key role in the adverse myocardial remodeling. Fluorofenidone (1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone, AKF-PD) is a novel pyridone antifibrotic agent, which exerts a strong antifibrotic effect. This study investigated the potential role of AKF-PD in suppressing cardiac myofibroblast conversion induced by transforming growth factor-beta1 (TGF-beta1) and the related mitogen-activated protein kinase (MAPK) signaling pathways in neonatal rat cardiac fibroblasts. The MAPK inhibitors used for pathway determination are c-Jun NH(2)-terminal kinase (JNK) inhibitor II (JNK inhibitor), PD98059 (extracellular signal-regulated kinase inhibitor (ERK) inhibitor) and SB203580 (p38 MAPK inhibitor). Cell proliferation was evaluated by multiply-table tournament (MTT) assay. The expressions of fibronectin (FN), alpha-SMA, phosphorylated ERK1/2 (pERK1/2) and ERK1/2 were investigated using Western blot analysis. AKF-PD remarkablely reduced the proliferative response of cardiac fibroblasts by 27.57% compared with TGF-beta1 stimulated group. AKF-PD, PD98059, and JNK inhibitor II completely prevented TGF-beta1-induced FN protein production. In addition, AKF-PD, PD98059 and SB203580 greatly attenuated alpha-SMA expression induced by TGF-beta1. Furthermore, AKF-PD significantly blocked TGF-beta1-induced phosphorylation of ERK. These results indicate that (1) AKF-PD inhibits TGF-beta1-induced myofibroblast differentiation; (2) the anti-fibrotic effects of AKF-PD are partially mediated by ERK phosphorylation.

[Association of metabolic syndrome with serum interleukin-10 and high sensitive C reactive protein(hs-CRP) in old men].

OBJECTIVE: To explore the association of metabolic syndrome(MS) with serum interleukin-10 (IL-10) and high sensitive C reactive protein(hs-CRP) in old men with MS. METHODS: Seventy patients with MS and 30 age-matched controls were enrolled. Blood pressure, waist circumference(WC), weight, height, body mass index(BMI), lipid-profile, fasting plasma glucose(FPG), fasting plasma insulin (FINS), homeostasis model assessment of insulin resistance(HOMA-IR),the serum IL-10, and hs-CRP levels were measured. The concentration of serum IL-10 was measured by enzyme linked immunosorbent assay (ELISA), and serum hs-CRP level by the latex-enhanced immuno- turbidimetric assay. RESULTS: Compared with the control group, the serum IL-10 level in the MS group was significantly lower (P<0.05), and the concentration of hs-CRP was obviously higher (P<0.05). Using Pearson's correlation analysis, the serum IL-10 level was negatively related with HOMA-IR(r=-0.684,P=0.000)and FINS(r=-0.742,P=0.000); hs-CRP was positively related with BMI(r=0.372,P=0.002), HOMA-IR(r=0.276,P=0.021)and FINS(r=0.312,P=0.008)in the MS group. Stepwise regression analysis suggested that FINS might be the influencing factors of IL-10; BMI and FINS might be the influencing factors of hs-CRP in patients with MS. CONCLUSION: In old male patients with MS, the concentration of serum IL-10 decreases, and the serum hs-CRP level increases obviously. This suggests chronic inflammation.