Cancer is a disease caused by the accumulation of genetic and epigenetic changes in two types of genes: tumor suppressor genes (TSGs) and proto-oncogenes. Extensive research has been conducted over the last few decades to elucidate the role of TSGs in cancer development. In cancer, loss of TSG function occurs via the deletion or inactivation of two alleles, according to Knudson’s two-hit model hypothesis. It has become clear that mutations in TSGs are recessive at the level of an individual cell; therefore, a single mutation in a TSG is not sufficient to cause carcinogenesis. However, many studies have identified candidate TSGs that do not conform with this standard definition, including genes inactivated by epigenetic silencing rather than by deletion. In addition, proteasomal degradation by ubiquitination, abnormal cellular localization, and transcriptional regulation are also involved in the inactivation of TSGs. This review incorporates these novel additional mechanisms of TSG inactivation into the existing two-hit model and proposes a revised multiple-hit model that will enable the identification of novel TSGs that can be used as prognostic and predictive biomarkers of cancer.

In this study, the hepatoprotective effects of apple polyphenols (AP, Appjfnol) against CCl(4)-induced acute liver damage in Kunming mice as well as the possible mechanisms were investigated. Mice were treated with AP (200, 400, and 800 mg/kg, ig) for seven consecutive days prior to the administration of CCl(4) (0.1%, intraperitoneally). The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) concentrations in the hepatic homogenate, and histopathological changes in mouse liver sections were determined. Levels of ferrous sulfate-L-cysteine (FeSO(4)-L-Cys)-induced lipid peroxidation and 1,1-diphenyl-2-picrylhydrazyl (DPPH) were also determined in vitro. AP significantly prevented the increase in serum ALT and AST levels in acute liver injury induced by CCl(4) and produced a marked amelioration in the histopathological hepatic lesions coupled to weight loss. The extent of MDA formation was reduced; the SOD activity was enhanced, and the GSH concentration was increased in the hepatic homogenate in AP-treated groups compared with the CCl(4)-intoxicated group. AP also exhibited antioxidant effects on FeSO(4)-L-Cys-induced lipid peroxidation in rat liver homogenate and DPPH free radical scavenging activity in vitro. These results indicate that AP has a significant protective effect against acute hepatotoxicity induced by CCl(4) in mice, which may be due to its free radical scavenging effect, inhibition of lipid peroxidation, and its ability to increase antioxidant activity.

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Accumulated data have shown the neuroactive properties of oxytocin (OT), a neurohypophyseal neuropeptide, and its capability of reducing the abuse potential of drugs. The present study investigated the effect of OT on methamphetamine (MAP)-induced hyperactivity in mice and its possible mechanism of action. Locomotor activity was measured after administered with MAP using an infrared sensor. High-performance liquid chromatography with electrochemical detection (HPLC-ECD) was used to detect the content of monoamines and their metabolites in the striatum and accumbens and prefrontal cortex in mice after the behavioral test. OT (0.1, 0.5, and 2.5 microg/mouse, i.c.v.) had no effect on locomotor activity in naïve mice, but inhibited, in a dose-dependent manner, the hyperactivity induced by acute administration of MAP. Atosiban (Ato) (2.0 microg/mouse, i.c.v.), the selective inhibitor of OT receptor, attenuated the inhibitory effect of OT on MAP. A marked reduction of the ratios of 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) to dopamine (DA) was observed in the striatum and accumbens of mice after acute administration of MAP. OT (2.5 microg, i.c.v.) significantly inhibited the reduction of DOPAC/DA and HVA/DA ratios. However, Ato decreased the ratio of DOPAC/DA significantly in mice compared with OT (2.5 microg) in combination with MAP. There was no significant change in serotonin (5-HT) metabolism in mice after a single administration of MAP. These results suggested that OT inhibited the MAP-induced hyperactivity by altering the DA turnover in the mesolimbic region of mice.

DNA methyltransferases are an essential class of modifiers in epigenetics. In mammals, DNMT1, DNMT3A and DNMT3B participate in DNA methylation to regulate normal biological functions, such as embryo development, cell differentiation and gene transcription. Aberrant functions of DNMTs are frequently associated with tumorigenesis. DNMT aberrations usually affect tumor-related factors, such as hypermethylated suppressor genes and genomic instability, which increase the malignancy of tumors, worsen the prognosis for patients, and greatly increase the difficulty of cancer therapy. However, the impact of DNMTs on tumors is still controversial, and therapeutic approaches targeting DNMTs are still under exploration. Here, we summarize the biological functions and paradoxes associated with DNMTs and we discuss some emerging strategies for targeting DNMTs in tumors, which may provide novel ideas for cancer therapy.

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This study provides direct evidence that ethanol can induce oxidative DNA damage in human peripheral lymphocytes in vitro, and its mechanism may be associated with the metabolism of ethanol by the ADH1B/ALDH2 pathway. Moreover, ethanol-induced DNA damage can be auto-repaired by human peripheral lymphocytes possibly mediated by the BER system.