Doxorubicin (DOX)-related cardiotoxicity has been recognized as a serious complication of cancer chemotherapy. Effective targeted strategies for myocardial protection in addition to DOX treatment are urgently needed. The purpose of this paper was to determine the therapeutic effect of berberine (Ber) on DOX-triggered cardiomyopathy and explore the underlying mechanism. Our data showed that Ber markedly prevented cardiac diastolic dysfunction and fibrosis, reduced cardiac malondialdehyde (MDA) level and increased antioxidant superoxide dismutase (SOD) activity in DOX-treated rats. Moreover, Ber effectively rescued the DOX-induced production of reactive oxygen species (ROS) and MDA, mitochondrial morphological damage and membrane potential loss in neonatal rat cardiac myocytes and fibroblasts. This effect was mediated by increases in the nuclear accumulation of nuclear erythroid factor 2-related factor 2 (Nrf2) and levels of heme oxygenase-1 (HO-1) and mitochondrial transcription factor A (TFAM). We also found that Ber suppressed the differentiation of cardiac fibroblasts (CFs) into myofibroblasts, as indicated by decreased expression of α-smooth muscle actin (α-SMA), collagen I and collagen III in DOX-treated CFs. Pretreatment with Ber inhibited ROS and MDA production and increased SOD activity and the mitochondrial membrane potential in DOX-challenged CFs. Further investigation indicated that the Nrf2 inhibitor trigonelline reversed the protective effect of Ber on both cardiomyocytes and CFs after DOX stimulation. Taken together, these findings demonstrated that Ber effectively alleviated DOX-induced oxidative stress and mitochondrial damage by activating the Nrf2-mediated pathway, thereby leading to the prevention of myocardial injury and fibrosis. The current study suggests that Ber is a potential therapeutic agent for DOX-induced cardiotoxicity that exerts its effects by activating Nrf2.

Geranylgeranylacetone (GGA), an inducer of heat shock proteins, exerts anticancer activity in some tumours. However, the effect of GGA on human osteosarcoma (OS) has not been reported. This work is designed to evaluate the effect of GGA on the proliferation and apoptosis of human OS cells and to explore the underlying mechanisms. It was found that GGA markedly inhibited the proliferation and induced apoptosis of U‐2 OS cells in a dose‐dependent manner and also up‐regulated the expression of heat shock protein 70 (Hsp70). The degradation and ubiquitination of protein arginine N‐methyltransferase 1 (PRMT1) were obviously enhanced in U‐2 OS cells with CHIP overexpression and GGA treatment. The expression of PRMT1 was reversed in GGA‐treated cell after CHIP knockdown. The turnover of PRMT1 was obviously faster in cells overexpressing CHIP than that in control cells. The methylation and activity of STAT3 were induced by PRMT1, resulting in the inhibition of FAS transcription. Overexpression of PRMT1 reversed the effect of GGA on activation of apoptosis‐related proteins and U‐2 OS cell apoptosis. The expressions of PRMT1 were significantly up‐regulated in OS tissues compared with the adjacent normal tissues and benign bone tumours. In conclusion, GGA promotes the degradation of PRMT1 through the Hsp70‐CHIP‐mediated proteasome pathway, thereby inducing the FAS‐triggered cell apoptosis. Inhibition of PRMT1 may be a potential therapeutic strategy for OS patients.

The E6 protein of the human papillomavirus (HPV) underpins important protein interaction networks between the virus and host to promote viral infection.Through its interaction with E6AP, a host E3 ubiquitin (UB) ligase, E6 stirs the protein ubiquitination pathways toward the oncogenic transformation of the infected cells. For a systematic measurement of E6 reprogramming of the substrate

Dexmedetomidine (DEX), a selective α2 adrenergic receptor (AR) agonist, is commonly used as a sedative drug during critical illness. In the present study, we explored a novel accelerative effect of DEX on cardiac fibroblast (CF) differentiation mediated by LPS and clarified its potential mechanism. LPS apparently increased the expression of α-SMA and collagen I/III and the phosphorylation of p38 and Smad-3 in the CFs of mice. These effects were significantly enhanced by DEX through increasing α2A-AR expression in CFs after LPS stimulation. The CFs from α2A-AR knockout mice were markedly less sensitive to DEX treatment than those of wild-type mice. Inhibition of protein kinase C (PKC) abolished the enhanced effects of DEX on LPS-induced differentiation of CFs. We also found that the α-SMA level in the second-passage CFs was much higher than that in the nonpassage and first-passage CFs. However, after LPS stimulation, the TNF-α released from the nonpassage CFs was much higher than that in the first- and second-passage CFs. DEX had no effect on LPS-induced release of TNF-α and IL-6 from CFs. Further investigation indicated that DEX promoted cardiac fibrosis and collagen I/III synthesis in mice exposed to LPS for four weeks. Our results demonstrated that DEX effectively accelerated LPS-induced differentiation of CFs to myofibroblasts through the PKC-p38-Smad2/3 signaling pathway by activating α2A-AR.

Karyopherin α (KPNA) proteins are involved in nucleocytoplasmic trafficking and are critical for protein subcellular localization. Recent studies have suggested that KPNA proteins are abnormally expressed in various solid tumors. The objective of this study was to investigate the expression of KPNA1 and KPNA2 in cervical cancer tissue with different histologic grades and cell lines, as well as the effects of the KPNA1 expression level on Hela cell proliferation. We collected the medical data of 106 patients with cervical cancer and investigated the protein expression of KPNA1 and KPNA2 by immunohistochemistry and western blot. The results revealed a significantly lower expression of KPNA1 in cervical cancer compared to normal tissue. Conversely, stronger staining intensity for KPNA2 was observed in cervical tumor samples. The expression levels of KPNA1 and KPNA2 were significantly associated with the tumor histologic grade. The weakest KPNA1 expression and strongest staining for KPNA2 were observed in grade III tumor tissue. The expression levels of KPNA1 were lower in Hela and C33A cells compared with normal human cervical epithelial cells; however, the expression of KPNA2 exhibited an opposite trend. The up-regulation of KPNA1 significantly suppressed the proliferation of Hela cells and relevant proteins expression, as well as promoted transportation of IRF3 into nucleus. Our results suggest the downregulation of KPNA1 expression is related to the malignant degree of cervical cancer and is closely associated with the proliferation of cervical cancer cells.