Showing papers by "Dun Xian Tan published in 2009"

Kynuramines, metabolites of melatonin and other indoles: the resurrection of an almost forgotten class of biogenic amines

Abstract: Kynuramines represent their own class of biogenic amines. They are formed either by decarboxylation of kynurenines or pyrrole ring cleavage of indoleamines. N(2)-formylated compounds formed in this last reaction can be deformylated either enzymatically by arylamine formamidases or hemoperoxidases, or photochemically. The earlier literature mainly focussed on cardiovascular effects of kynuramine, 5-hydroxykynuramine and their N(1),N(1)-dimethylated analogs, including indirect effects via release of catecholamines or acetylcholine and interference with serotonin receptors. After the discovery of N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) and N(1)-acetyl-5-methoxykynuramine (AMK) as major brain metabolites of melatonin, these compounds became of particular interest. They were shown to be produced enzymatically, pseudoenzymatically, by various free radical-mediated and via photochemical processes. In recent years, AFMK and AMK were shown to scavenge reactive oxygen and nitrogen species, thereby forming several newly discovered 3-indolinone, cinnolinone and quinazoline compounds, and to protect tissues from damage by reactive intermediates in various models. AMK is of special interest due to its properties as a potent cyclooxygenase inhibitor, NO scavenger forming a stable nitrosation product, inhibitor and/or downregulator of neuronal and inducible NO synthases, and a mitochondrial metabolism modulator. AMK easily interacts with aromates, forms adducts with tyrosyl and tryptophanyl residues, and may modify proteins.

Melatonin and Reproduction Revisited

Abstract: This brief review summarizes new findings related to the reported beneficial effects of melatonin on reproductive physiology beyond its now well-known role in determining the sexual status in both long-day and short-day seasonally breeding mammals. Of particular note are those reproductive processes that have been shown to benefit from the ability of melatonin to function in the reduction of oxidative stress. In the few species that have been tested, brightly colored secondary sexual characteristics that serve as a sexual attractant reportedly are enhanced by melatonin administration. This is of potential importance inasmuch as the brightness of ornamental pigmentation is also associated with animals that are of the highest genetic quality. Free radical damage is commonplace during pregnancy and has negative effects on the mother, placenta, and fetus. Because of its ability to readily pass through the placenta, melatonin easily protects the fetus from oxidative damage, as well as the maternal tissues and placenta. Examples of conditions in which oxidative and nitrosative stress can be extensive during pregnancy include preeclampsia and damage resulting from anoxia or hypoxia that is followed by reflow of oxygenated blood into the tissue. Given the uncommonly low toxicity of melatonin, clinical trials are warranted to document the protection by melatonin against pathophysiological states of the reproductive system in which free radical damage is known to occur. Finally, the beneficial effects of melatonin in improving the outcomes of in vitro fertilization and embryo transfer should be further tested and exploited. The information in this article has applicability to human and veterinary medicine.

Phytomelatonin: a review

Abstract: Melatonin (N-acetyl-5-methoxytryptamine) has been detected in a number of plant species. Indeed, there exists evidence that this classically-considered animal indole is actually both synthesized in and taken up by plants. Among the actions that melatonin may carry out in plant tissues, its role as an antioxidant or growth promoter is most strongly supported by the experimental evidence. Other suggested functional implications include the co-ordination of photoperiodic responses and regulation of plant reproductive physiology, defence of plant cells against apoptosis induced by harsh environmental conditions, its participation as a free radical scavenging agent and/or up-regulator of certain protective enzymes in the senescent process. This review presents a detailed summary of the investigations that have been performed to date in the plant melatonin (phytomelatonin) field. The purpose of this summary is to bring the reader up to date on what is known about melatonin in plants and to encourage plant scientists to investigate this novel research topic; this would certainly assist in solving the numerous questions that still remain regarding the role of melatonin in plants.

Melatonin: An Established Antioxidant Worthy of Use in Clinical Trials

Abstract: Oxidative stress plays a key role in the pathogenesis of aging and many metabolic diseases; therefore, an effective antioxidant therapy would be of great importance in these circumstances. Nutritional, environmental, and chemical factors can induce the overproduction of the superoxide anion radical in both the cytosol and mitochondria. This is the first and key event that leads to the activation of pathways involved in the development of several metabolic diseases that are related to oxidative stress. As oxidation of essential molecules continues, it turns to nitrooxidative stress because of the involvement of nitric oxide in pathogenic processes. Once peroxynitrite forms, it damages via two distinctive mechanisms. First, it has direct toxic effects leading to lipid peroxidation, protein oxidation, and DNA damage. This mechanism involves the induction of several transcription factors leading to cytokine-induced chronic inflammation. Classic antioxidants, including vitamins A, C, and E, have often failed to exhibit beneficial effects in metabolic diseases and aging. Melatonin is a multifunctional indolamine that counteracts virtually all pathophysiologic steps and displays significant beneficial actions against peroxynitrite-induced cellular toxicity. This protection is related to melatonin’s antioxidative and antiinflammatory properties. Melatonin has the capability of scavenging both oxygen- and nitrogen-based reactants, including those formed from peroxynitrite, and blocking transcriptional factors, which induce proinflammatory cytokines. Accumulating evidence suggests that this nontoxic indolamine may be useful either as a sole treatment or in conjunction with other treatments for inhibiting the biohazardous actions of nitrooxidative stress.

The changing biological roles of melatonin during evolution: From an antioxidant to signals of darkness, sexual selection and fitness

Abstract: Melatonin is a molecule present in a multitude of taxa and may be ubiquitous in organisms. It has been found in bacteria, unicellular eukaryotes, macroalgae, fungi, plants and animals. A primary biological function of melatonin in primitive unicellular organisms is in antioxidant defence to protect against toxic free radical damage. During evolution, melatonin has been adopted by multicellular organisms to perform many other biological functions. These functions likely include the chemical expression of darkness in vertebrates, environmental tolerance in fungi and plants, sexual signaling in birds and fish, seasonal reproductive regulation in photoperiodic mammals, and immunomodulation and anti-inflammatory activity in all vertebrates tested. Moreover, its waning production during aging may indicate senescence in terms of a bio-clock in many organisms. Conversely, high melatonin levels can serve as a signal of vitality and health. The multiple biological functions of melatonin can partially be attributed to its unconventional metabolism which is comprised of multi-enzymatic, pseudo-enzymatic and non-enzymatic pathways. As a result, several bioactive metabolites of melatonin are formed during its metabolism and some of the presumed biological functions of melatonin reported to date may, in fact, be mediated by these metabolites. The changing biological roles of melatonin seem to have evolved from its primary function as an antioxidant.

Melatonin in plants.

Abstract: Once thought to be exclusively a molecule of the animal kingdom, melatonin has now been found to exist in plants as well. Among a number of actions, melatonin is a direct free radical scavenger and an indirect antioxidant. Melatonin directly detoxifies the hydroxyl radical (*OH), hydrogen peroxide, nitric oxide, peroxynitrite anion, peroxynitrous acid, and hypochlorous acid. The products from each of these reactions have been identified in pure chemical systems and in at least one case in vivo; the interaction product of melatonin with the OH, i.e., cyclic 3-hydroxymelatonin, is found in the urine of humans and rats. Some of the products that are produced when melatonin detoxifies reactive species are also highly efficient scavengers. As a result, a cascade of scavenging reactions may enhance the antioxidant capacity of melatonin. Additionally, melatonin increases the activity of several antioxidative enzymes, thereby improving its ability to protect macromolecules from oxidative stress. Melatonin is endogenously produced and is also consumed in edible plants. In animal experiments, feeding melatonin-containing foods raised blood levels of the indole. Because physiologic concentrations of melatonin in the blood are known to correlate with the total antioxidant capacity of the serum, consuming foodstuffs containing melatonin may be helpful in lowering oxidative stress.

Role of melatonin in metabolic regulation.

Abstract: Although the human genome has remained unchanged over the last 10,000 years, our lifestyle has become progressively more divergent from those of our ancient ancestors. This maladaptive change became apparent with the Industrial Revolution and has been accelerating in recent decades. Socially, we are people of the 21st century, but genetically we remain similar to our early ancestors. In conjunction with this discordance between our ancient, genetically-determined biology and the nutritional, cultural and activity patterns in contemporary Western populations, many diseases have emerged. Only a century ago infectious disease was a major cause of mortality, whereas today non-infectious chronic diseases are the greatest cause of death in the world. Epidemics of metabolic diseases (e.g., cardiovascular diseases, type 2 diabetes, obesity, metabolic syndrome and certain cancers) have become major contributors to the burden of poor health and they are presently emerging or accelerating, in most developing countries. One major lifestyle consequence is light at night and subsequent disrupted circadian rhythms commonly referred to as circadian disruption or chronodisruption. Mounting evidence reveals that particularly melatonin rhythmicity has crucial roles in a variety of metabolic functions as an anti-oxidant, anti-inflammatory chronobiotic and possibly as an epigenetic regulator. This paper provides a brief outline about metabolic dysregulation in conjunction with a disrupted melatonin rhythm.

Role of melatonin in the epigenetic regulation of breast cancer

Abstract: The oncostatic properties of melatonin as they directly or indirectly involve epigenetic mechanisms of cancer are reviewed with a special focus on breast cancer. Five lines of evidence suggest that melatonin works via epigenetic processes: (1) melatonin influences transcriptional activity of nuclear receptors (ERα, GR and RAR) involved in the regulation of breast cancer cell growth; (2) melatonin down-regulates the expression of genes responsible for the local synthesis or activation of estrogens including aromatase, an effect which may be mediated by methylation of the CYP19 gene or deacetylation of CYP19 histones; (3) melatonin inhibits telomerase activity and expression induced by either natural estrogens or xenoestrogens; (4) melatonin modulates the cell cycle through the inhibition of cyclin D1 expression; (5) melatonin influences circadian rhythm disturbances dependent on alterations of the light/dark cycle (i.e., light at night) with the subsequent deregulation of PER2 which acts as a tumor suppressor gene.

Combination of melatonin and a peroxisome proliferator-activated receptor-γ agonist induces apoptosis in a breast cancer cell line

Abstract: Nuclear receptors (NRs) and ligand-dependent transcription factors play multiple essential roles in development, homeostasis, reproduction, and immune function. NRs influence transcription via several mechanisms and can both activate or inhibit gene expression. The NRs include steroidal transcription factors such as estrogen, glucocorticoids, retinoid acid receptor (RAR), retinoid X receptor (RXR), and peroxisome proliferator-activated receptors (PPARs) [1]. Half of the NRs are so-called orphan receptors because the identity of their ligand, if any, is unknown. Two prime examples are the PPARs and RXRs, which were discovered as orphan NRs, but for which ligands have now been tentatively suggested, although the definitive identity of their physiological, endogenous ligands is somewhat controversial [1]. From emerging evidence regarding the genomic actions of melatonin, it is now clear that this indolamine is an endogenous ligand of RXRs [2–4]. PPARc and RXR play crucial roles in inducing apoptosis in a variety of human cancer cells including colon [5] and breast cancer [6, 7] cell lines. As several exogenous retinoic acid (RA) derivatives (e.g., 9-cis–trans RA and all-trans RA) are considered ligands for RXRs, recent studies have been performed using a combination of PPARc agonists including rosiglitizone, ciglitizone, and troglitazone and RA derivatives [5–7]. In light of recent evidence, we tested whether the combination of a PPARc agonist and melatonin would induce apoptosis in the MDA-MB-231 human breast cancer cell line. Cells were cultured at 37 C in a water-saturated atmosphere with 5% CO2-95% air. The culture medium was renewed each day. Cells were treated either with vehicle alone, 100 lm troglitazone, 1 mm melatonin, or with troglitazone + melatonin for 72 hr. The 3-(4,5-dimethythiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, used to assess cell viability, is based on the ability of viable cells to convert MTT into a blue formazan product. In contrast to normal cells, the nuclei of apoptotic cells have highly condensed chromatin that is uniformly stained by Hoechst 33342; use of this method allows one to observe the morphological changes in the nuclei of apoptotic cells [8]. The addition of melatonin or troglitazone alone to cultured cells caused 16% and 47% reductions in the number of cells, respectively (Fig. 1). The combination of the two agents resulted in a 84% reduction in cell number. After exposure to melatonin and troglitazone for 72 hr, remaining cells underwent apoptosis which was characterized morphologically by chromatin condensation and nuclear fragmentation (Fig. 1). Clearly, the combination of the PPARc agonist and melatonin caused a very

Pineal Gland and Melatonin

Abstract: This article succinctly summarizes what is known about the pineal gland and its secretory product melatonin. The pineal gland, a small dorsal outgrowth of the brain stem, is an end organ of the visual system; its function is determined by light and darkness as perceived by the retinas. The neural connections between the eyes and the pineal gland involve the peripheral sympathetic nervous system and an important synaptic relay in the suprachiasmatic nuclei, the biological clock. During darkness at night, the pineal gland, in response to norepinephrine released onto pineal cells by postganglionic sympathetic nerve fibers, produces melatonin and discharges it into the blood; as a consequence, blood levels of melatonin are elevated at night. The 24 h cycle of blood melatonin functions in the regulation of circadian rhythms and in promoting nighttime sleep. In addition, melatonin inhibits growth of some tumors, has modulatory effects on the immune system, and functions as a direct free-radical scavenger and as an indirect antioxidant. Some of melatonin’s actions are mediated via specific receptors while others are receptor independent.