Hua Wang

Melatonin attenuates lipopolysaccharide (LPS)-induced apoptotic liver damage in d-galactosamine-sensitized mice

D-Galactosamine (GalN) depletes UTP primarily in liver, resulting in decreased RNA synthesis in hepatocytes. When given together with a sublethal dose of lipopolysaccharide (LPS), GalN highly sensitizes animals to produce apoptotic liver injury with severe hepatic congestion, resulting in rapid death. Melatonin is a cytokine modulator, antioxidant and anti-apoptotic agent. In the present study, we investigated the effect of melatonin on LPS-induced apoptotic liver damage in GalN-sensitized mice. Female CD-1 mice were intraperitoneally (i.p.) injected with melatonin (5.0mg/kg) 30min before GalN/LPS (700mg10microg/kg, i.p.), another two doses of melatonin (2.5mg/kg, i.p.) being administered 1 and 2h after GalN/LPS. Results showed that serum alanine aminotransferase (ALT) activities were markedly increased 8h after GalN/LPS treatment, massive hemorrhage being observed in histological sections of liver from GalN/LPS-treated mice. Melatonin significantly attenuated GalN/LPS-induced elevation of serum ALT. In parallel, melatonin distinctly improved GalN/LPS-induced congestion. Additional experiment showed that melatonin significantly attenuated GalN/LPS-induced hepatic apoptosis, measured by inhibition of caspase-3 activities and attenuation of DNA laddering. Furthermore, melatonin markedly increased hepatic Se-dependent glutathione peroxidase (GSH-Px) and glutathione reductase (GSH-Rd) activities and attenuated hepatic glutathione (GSH) depletion in GalN/LPS-treated mice. Increases in serum tumor necrosis factor alpha (TNF-alpha), which were observed in GalN/LPS-treated mice, were significantly reduced by melatonin. However, melatonin had no effect on LPS-evoked nitric oxide production in GalN-sensitized mice. Taken together, these results indicate that melatonin protected against LPS-induced liver damage in GalN-sensitized mice through its strong ROS-scavenging, antiinflammatory and antiapoptotic effects.

Melatonin pretreatment attenuates 2-bromopropane-induced testicular toxicity in rats

2-Bromopropane (2-BP) was used as an alternative for ozone-depleting solvents, which caused reproductive disorders in male workers and laboratory animals. A recent study indicated that 2-BP impaired antioxidant cellular defences and enhanced lipid peroxidation (LPO). Melatonin is a powerful endogenous antioxidant. We hypothesized that reactive oxygen species (ROS) and lipid peroxidation are involved in 2-BP-induced testicular toxicities. To test the hypothesis, we investigated the effects of melatonin on 2-BP-induced testicular toxicities. Rats were intraperitoneally injected with 2-BP (1g/kg) with or without melatonin (5mg/kg), then sacrificed on 7th day after 2-BP injection. Epididymal and testicular tissues were examined for biochemical and histopathological changes. Apoptotic cells in testis were detected by TUNEL staining and immunohistochemistry for active caspase-3. Exposure to 2-BP significantly decreased epididymal sperm count and morphological normal sperms. 2-BP also induced vacuolation and atrophy of the seminiferous tubules, reduction of spermatogonia and apoptosis of germ cells. 2-BP significantly increased TBARS levels in plasma and epididymis, and decreased GSH content in testis and epididymis. Pretreatment with melatonin counteracted 2-BP-induced oxidative stress, ameliorated apoptosis in testis and attenuated histopathological damage in testis. In addition, pretreatment with melatonin significantly attenuated 2-BP-induced sperm morphological changes. We conclude that pretreatment with melatonin attenuates 2-BP-induced testicular toxicity through its ROS scavenging and anti-apoptotic effects.

The role of methyl-CpG binding protein 2 in liver fibrosis

Liver injury is induced by various insults such as alcohol abuse, if insults persist, may result in the formation of liver fibrosis. Hepatic stellate cell (HSC) activation and transdifferentiation into hepatic myofibroblast, accompanied with potent pro-inflammatory and pro-fibrogenic activities and the down-regulation of anti-inflammatory anti-fibrogenic in gene expression in coordination with epigenetic modifications at the level of the chromatin structure, are pivotal events in liver fibrogenesis. In this review we focus on the role of the methyl-CpG binding protein 2 (MeCP2) transcriptional regulation of different target genes and the interaction MeCP2 with microRNAs (miRNAs) during liver fibrosis. In addition, we address different signaling pathways interacted with MeCP2 regulated HSC activation. Such approaches provide valuable insights into the potential targets of liver fibrosis, and are useful pointers for the development of future therapeutic strategies.

Apoptosis contributes to testicular toxicity induced by two isomers of bromopropanes

The aim of this study was to investigate the different testicular toxicity and the role of apoptosis in the possible mechanism induced by the two isomers of bromopropanes (BPs) in the same dosage. Following the 14-day treatment with a single dose of 1-BP and 2-BP (1 g/kg), male rats were killed and a series of experiments were performed. 1-BP and 2-BP both significantly decreased the epididymal sperm count, while only 2-BP induced an increase in sperms with abnormal heads. Morphological evaluation showed that 1-BP did not cause morphological changes in seminiferous epithelium, but 2-BP treatment resulted in the disappearance of spermatogonia, atrophy of the seminiferous tubules and degeneration of germ cells. 2-BP significantly increased the TUNEL-positive cells and the activation of caspase-3 and decreased the genes and proteins expression of Bax, Bcl-2 and p53. In contrast, there were no significant changes in the expression of apoptosis-related genes and proteins in 1-BP group, though the TUNEL-positive cells were significantly increased. Taken together, this study indicated that those two isomers both have toxicity in male rats, however, the testicular toxicity and the role of apoptosis in the toxic mechanism induced by 1-BP and 2-BP may be different.