Showing papers by "Dun Xian Tan published in 2017"

Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas

Abstract: Melatonin is an ancient antioxidant. After its initial development in bacteria, it has been retained throughout evolution such that it may be or may have been present in every species that have existed. Even though it has been maintained throughout evolution during the diversification of species, melatonin’s chemical structure has never changed; thus, the melatonin present in currently living humans is identical to that present in cyanobacteria that have existed on Earth for billions of years. Melatonin in the systemic circulation of mammals quickly disappears from the blood presumably due to its uptake by cells, particularly when they are under high oxidative stress conditions. The measurement of the subcellular distribution of melatonin has shown that the concentration of this indole in the mitochondria greatly exceeds that in the blood. Melatonin presumably enters mitochondria through oligopeptide transporters, PEPT1, and PEPT2. Thus, melatonin is specifically targeted to the mitochondria where it seems to function as an apex antioxidant. In addition to being taken up from the circulation, melatonin may be produced in the mitochondria as well. During evolution, mitochondria likely originated when melatonin-forming bacteria were engulfed as food by ancestral prokaryotes. Over time, engulfed bacteria evolved into mitochondria; this is known as the endosymbiotic theory of the origin of mitochondria. When they did so, the mitochondria retained the ability to synthesize melatonin. Thus, melatonin is not only taken up by mitochondria but these organelles, in addition to many other functions, also probably produce melatonin as well. Melatonin’s high concentrations and multiple actions as an antioxidant provide potent antioxidant protection to these organelles which are exposed to abundant free radicals.

Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis.

Abstract: There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. In many cases, the molecular mechanisms underpinning these inhibitory actions have been proposed. What is rather perplexing, however, is the large number of processes by which melatonin reportedly restrains cancer development and growth. These diverse actions suggest that what is being observed are merely epiphenomena of an underlying more fundamental action of melatonin that remains to be disclosed. Some of the arresting actions of melatonin on cancer are clearly membrane receptor-mediated while others are membrane receptor-independent and involve direct intracellular actions of this ubiquitously-distributed molecule. While the emphasis of melatonin/cancer research has been on the role of the indoleamine in restraining breast cancer, this is changing quickly with many cancer types having been shown to be susceptible to inhibition by melatonin. There are several facets of this research which could have immediate applications at the clinical level. Many studies have shown that melatonin’s co-administration improves the sensitivity of cancers to inhibition by conventional drugs. Even more important are the findings that melatonin renders cancers previously totally resistant to treatment sensitive to these same therapies. Melatonin also inhibits molecular processes associated with metastasis by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growths at distant sites. This is of particular importance since cancer metastasis often significantly contributes to death of the patient. Another area that deserves additional consideration is related to the capacity of melatonin in reducing the toxic consequences of anti-cancer drugs while increasing their efficacy. Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level. Even if the only beneficial actions of melatonin in cancer patients are its ability to attenuate acute and long-term drug toxicity, melatonin should be used to improve the physical wellbeing of the patients. The experimental findings, however, suggest that the advantages of using melatonin as a co-treatment with conventional cancer therapies would far exceed improvements in the wellbeing of the patients.

Melatonin alleviates cadmium-induced liver injury by inhibiting the TXNIP-NLRP3 inflammasome

Abstract: Cadmium (Cd) is a persistent environmental and occupational contaminant that accumulates in the liver and induces oxidative stress and inflammation. Melatonin possesses potent hepatoprotective properties against the development and progression of acute and chronic liver injury. Nevertheless, the molecular mechanism underlying the protective effects of melatonin against Cd-induced hepatotoxicity remains obscure. In the present study, we aimed to investigate the effects of melatonin on Cd-induced liver inflammation and hepatocyte death. Male C57BL/6 mice were intraperitoneally injected with melatonin (10 mg/kg) once a day for 3 days before exposure to CdCl2 (2.0 mg/kg). We found that Cd induced hepatocellular damage and inflammatory infiltration as well as increased serum ALT/AST enzymes. In addition, we showed that Cd triggered an inflammatory cell death, which is mediated by the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Moreover, melatonin treatment significantly alleviated Cd-induced liver injury by decreasing serum ALT/AST levels, suppressing pro-inflammatory cytokine production, inhibiting NLRP3 inflammasome activation, ameliorating oxidative stress and attenuating hepatocyte death. Most importantly, melatonin markedly abrogated Cd-induced TXNIP overexpression and decreased the interaction between TXNIP and NLRP3 in vivo and in vitro. However, treatment with siRNA targeting TXNIP blocked the protective effects of melatonin in Cd-treated primary hepatocytes. Collectively, our results suggest that melatonin confers protection against Cd-induced liver inflammation and hepatocyte death via inhibition of the TXNIP-NLRP3 inflammasome pathway. This article is protected by copyright. All rights reserved.

Melatonin and sirtuins: A “not-so unexpected” relationship

Abstract: Epigenetic modifications, including methylation or acetylation as well as post-transcriptional modifications, are mechanisms used by eukaryotic cells to increase the genome diversity in terms of differential gene expression and protein diversity. Among these modifying enzymes, sirtuins, a class III histone deacetylase (HDAC) enzymes, are of particular importance. Sirtuins regulate the cell cycle, DNA repair, cell survival, and apoptosis, thus having important roles in normal and cancer cells. Sirtuins can also regulate metabolic pathways by changing preference for glycolysis under aerobic conditions as well as glutaminolysis. These actions make sirtuins a major target in numerous physiological processes as well as in other contexts such as calorie restriction-induced anti-aging, cancer, or neurodegenerative disease. Interestingly, melatonin, a nighttime-produced indole synthesized by pineal gland and many other organs, has important cytoprotective effects in many tissues including aging, neurodegenerative diseases, immunomodulation, and cancer. The pleiotropic actions of melatonin in different physiological and pathological conditions indicate that may be basic cellular targeted for the indole. Thus, much research has focused attention on the potential mechanisms of the indole in modulating expression and/or activity of sirtuins. Numerous findings report a rise in activity, especially on SIRT1, in a diversity of cells and animal models after melatonin treatment. This contrasts, however, with data reporting an inhibitory effect of melatonin on this sirtuin in some tumor cells. This review tabulates and discusses the recent findings relating melatonin with sirtuins, particularly SIRT1 and mitochondrial SIRT3, showing the apparent dichotomy with the differential actions documented in normal and in cancer cells.

Natural Variation in Banana Varieties Highlights the Role of Melatonin in Postharvest Ripening and Quality.

Abstract: This study aimed to investigate the role of melatonin in postharvest ripening and quality in various banana varieties with contrasting ripening periods. During the postharvest life, endogenous melatonin showed similar performance with ethylene in connection to ripening. Compared with ethylene, melatonin was more correlated with postharvest banana ripening. Exogenous application of melatonin resulted in a delay of postharvest banana ripening. Moreover, this effect is concentration-dependent, with 200 and 500 μM treatments more effective than 50 μM treatment. Exogenous melatonin also led to elevated endogenous melatonin content, reduced ethylene production through regulation of the expression of MaACO1 and MaACS1, and delayed sharp changes of quality indices. Taken together, this study highlights that melatonin is an indicator for banana fruit ripening in various varieties, and the repression of ethylene biosynthesis and postharvest ripening by melatonin can be used for biological control of postharvest fru...

Melatonin Improves Waterlogging Tolerance of Malus baccata (Linn.) Borkh. Seedlings by Maintaining Aerobic Respiration, Photosynthesis and ROS Migration.

Abstract: Waterlogging, one of the notorious abiotic stressors, retards the growth of apple plants and reduces their production. Thus, it is an urgent agenda for scientists to identify the suitable remedies for this problem. In the current study, we found that melatonin significantly improved the tolerance of apple seedlings against waterlogging stress. This was indicated by the reduced chlorosis and wilting of the seedlings after melatonin applications either by leaf spray or root irrigation. The mechanisms involve in that melatonin functions to maintain aerobic respiration, preserves photosynthesis and reduces oxidative damage of the plants which are under waterlogging stress. Melatonin application also enhances the gene expression of its synthetic enzymes (MbT5H1, MbAANAT3, MbASMT9) and increases melatonin production. This is the first report of a positive feedback that exogenous melatonin application promotes the melatonin synthesis in plants. A post-transcriptional regulation apparently participated in this regulation. When exogenous melatonin meets the requirement of the plants it is found that the protein synthesis of MbASMT9 was suppressed. Taken together, the results showed that melatonin was an effective molecule to protect plant, particularly apple plant, against waterlogging stress.

Selective inhibition of Ebola entry with selective estrogen receptor modulators by disrupting the endolysosomal calcium.

Abstract: The Ebola crisis occurred in West-Africa highlights the urgency for its clinical treatments. Currently, no Food and Drug Administration (FDA)-approved therapeutics are available. Several FDA-approved drugs, including selective estrogen receptor modulators (SERMs), possess selective anti-Ebola activities. However, the inhibitory mechanisms of these drugs remain elusive. By analyzing the structures of SERMs and their incidental biological activity (cholesterol accumulation), we hypothesized that this incidental biological activity induced by SERMs could be a plausible mechanism as to their inhibitory effects on Ebola infection. Herein, we demonstrated that the same dosages of SERMs which induced cholesterol accumulation also inhibited Ebola infection. SERMs reduced the cellular sphingosine and subsequently caused endolysosomal calcium accumulation, which in turn led to blocking the Ebola entry. Our study clarified the specific anti-Ebola mechanism of SERMs, even the cationic amphiphilic drugs (CADs), this mechanism led to the endolysosomal calcium as a critical target for development of anti-Ebola drugs.

Melatonin antagonizes interleukin-18-mediated inhibition on neural stem cell proliferation and differentiation.

Abstract: Neural stem cells (NSCs) are self-renewing, pluripotent and undifferentiated cells which have the potential to differentiate into neurons, oligodendrocytes and astrocytes. NSC therapy for tissue regeneration, thus, gains popularity. However, the low survivals rate of the transplanted cell impedes its utilities. In this study, we tested whether melatonin, a potent antioxidant, could promote the NSC proliferation and neuronal differentiation, especially, in the presence of the pro-inflammatory cytokine interleukin-18 (IL-18). Our results showed that melatonin per se indeed exhibited beneficial effects on NSCs and IL-18 inhibited NSC proliferation, neurosphere formation and their differentiation into neurons. All inhibitory effects of IL-18 on NSCs were significantly reduced by melatonin treatment. Moreover, melatonin application increased the production of both brain-derived and glial cell-derived neurotrophic factors (BDNF, GDNF) in IL-18-stimulated NSCs. It was observed that inhibition of BDNF or GDNF hindered the protective effects of melatonin on NSCs. A potentially protective mechanism of melatonin on the inhibition of NSC's differentiation caused IL-18 may attribute to the up-regulation of these two major neurotrophic factors, BNDF and GNDF. The findings indicate that melatonin may play an important role promoting the survival of NSCs in neuroinflammatory diseases.

Circadian Dysregulation and Melatonin Rhythm Suppression in the Context of Aging

Abstract: Fifty years ago, little was known of the role of the prevailing light:dark environment in terms of its impact on the circadian pathophysiology of organisms. In the intervening years the field of photoperiodic regulation of the master circadian oscillator, i.e., the suprachiasmatic nucleus (SCN), has advanced at a rapid pace. The importance of the regulatory actions of the light:dark cycle, and particularly of perturbed light:dark cycles, not only on the SCN but also on the circadian production of pineal melatonin as well as the cyclic metabolism of cells throughout the body are by no means trivial. When the regular cyclic information generated and dispensed by the SCN is dysregulated, the negative consequences in terms of cellular and organismal physiology can be dire to the extent that the rate of aging and the onset and progression of a variety of age-related diseases have now been at least provisionally linked to circadian disruption and/or melatonin suppression. While the findings are not definitive, there is certainly credible data to warrant the conclusion that regular circadian rhythms at multiple levels, including a stable day:night melatonin cycle, enhance life quality and potentially delay senescence and forestall diseases normally associated with advanced age. As a result, the prolonged health span may also predispose to a longer life span. In view of the critical role of an abnormal or unusual light environment in terms of perturbing essential circadian physiological events, serious consideration should be given to rational thought about the misuse of artificial light and the consequences thereof.