Melatonin, the chief product secreted by pineal gland, is capable of reducing free radical damage by acting directly as a free radical scavenger, and indirectly, by stimulating of antioxidant enzymes. Cyclosporine A (CsA) is the most widely used immunosuppressive drug, but its therapeutic use has several side effects including, i.e. nephrotoxicity and cardiotoxicity. This study was designed to examine the beneficial effects of melatonin in preventing CsA-induced cardiotoxicity. Additionally, we investigated the ability of melatonin to protect the rat heart via melatonin receptor. In one group of Wistar rats, melatonin (1 mg/kg/day i.p.) was administered concurrently with CsA (15 mg/kg/day s.c.) for 21 days. In another group of animals, melatonin was injected with CsA and luzindole, an antagonist of melatonin receptors. Oxidative stress in heart tissue homogenates was estimated using thiobarbituric acid reactive substances (TBARS), reduced glutathione levels and antioxidant enzyme activities including catalase and superoxide dismutase. CsA administration for 21 days produced elevated levels of TBARS, marked depletion of cardiac antioxidant enzymes and caused morphological alterations in myocardial fibers. Melatonin markedly reduced TBARS levels, increased the antioxidant enzyme levels and normalized altered cardiac morphology. The protective effects of melatonin were lost when the animals received the melatonin receptor antagonist. In conclusion our study shows that, (a) melatonin significantly reduces CsA cardiotoxicity, and (b) the reduction in CsA-induced cardiotoxicity was mediated by the binding of melatonin to its membrane receptors.

Melatonin is known to exert antitumour activity in several types of human cancers, but the underlying mechanisms as well as the efficacy of different doses of melatonin are not well defined. Here, we test the hypothesis whether melatonin in the nanomolar range is effective in exerting antitumour activity in vivo and examine the correlation with the hypoxia signalling mechanism, which may be a major molecular mechanism by which melatonin antagonizes cancer. To test this hypothesis, LNCaP human prostate cancer cells were xenografted into seven-wk-old Foxn1nu/nu male mice that were treated with melatonin (18 i.p. injections of 1 mg/kg in 41 days). Saline-treated mice served as control. We found that the melatonin levels in plasma and xenografted tissue were 4× and 60× higher, respectively, than in control samples. Melatonin tended to restore the redox imbalance by increasing expression of Nrf2. As part of the phenotypic response to these perturbations, xenograft microvessel density was less in melatonin-treated animals, indicative of lower angiogenesis, and the xenograft growth rate was slower (P < 0.0001). These changes were accompanied by a reduced expression of Ki67, elevated expression of HIF-1α and increased phosphorylation of Akt in melatonin than saline-treated mice. We conclude that the beneficial effect of melatonin in reducing cancer growth in vivo was evident at melatonin plasma levels as low as 4 nm and was associated with decreased angiogenesis. Higher HIF-1α expression in xenograft tissue indicates that the antitumour effect cannot be due to a postulated antihypoxic effect, but may stem from lower angiogenesis potential.

In the therapeutic strategies, the role of diet is a well-established factor that can also have an important role in liver diseases. Melatonin, identified in animals, has many antioxidant properties and it was after discovered also in plants, named phytomelatonin. These substances have a positive effect during aging and in pathological conditions too. In particular, it is important to underline that the amount of melatonin produced by pineal gland in human decreases during lifetime and its reduction in blood could be related to pathological conditions in which mitochondria and oxidative stress play a pivotal role. Moreover, it has been indicated that melatonin/phytomelatonin containing foods may provide dietary melatonin, so their ingestion through balanced diets could be sufficient to confer health benefits. In this review, the classification of liver diseases and an overview of the most important aspects of melatonin/phytomelatonin, concerning the differences among their synthesis, their presence in foods and their role in health and diseases, are summarized. The findings suggest that melatonin/phytomelatonin supplementation with diet should be considered important in preventing different disease settings, in particular in liver. Currently, more studies are needed to strengthen the potential beneficial effects of melatonin/phytomelatonin in liver diseases and to better clarify the molecular mechanisms of action.

Tobacco smoking is responsible for death of many people each year and increases the risk of developing numerous disorders, particularly cardiovascular disease and cancer. Among the components of cigarette smoke, nicotine is known to excert proatherosclerotic, prothrombotic and proangiogenic effects on vascular endothelial cells. The current study was designed to investigate the mechanisms by which nicotine induces endothelial dysfunction and further to examine whether melatonin protects against nicotine-induced vasculopathy. Four groups of male rats (controls, melatonin-treated, nicotine treated [100 microg/mL in drinking water], and nicotine plus melatonin [5 mg/kg/day] treated) were used in this study. After 28 days all the animals were killed by decapitation and the aorta was removed. We evaluated the hydroxyproline content, and the different expression of proteins involved in several types of stress (ERK1/2), in fibrosis (TGF-beta1, NF-kappaB) and in recruitment of circulating leukocytes onto the vessel wall, including intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1). These metabolic pathways are important in the development of nicotine-induced atherosclerosis and hypertension. Our results show that nicotine induces marked structural and functional alterations in the aorta. Nicotine receptor binding results in activation and phosphorylation of ERK 1/2. This enzyme, in turn, activates both TGF-beta1 and NF-kappaB; they stimulate respectively the synthesis of type I collagen, responsible of fibrosis, and moreover ICAM-1, VCAM-1 and reactive oxygen species. Based on these findings, melatonin is able to minimize the negative effects of nicotine by blocking the activation of ERK and the other signalling pathways in which this enzyme is involved.