Melatonin in clinical oncology

The aim of this article is provide a survey of the current knowledge relating to the analysis of melatonin and its administration to cancer patients. On the basis of this compilation of data it can be discussed under which conditions melatonin may be used for diagnostic and/or therapeutic purposes in clinical oncology. Melatonin is depressed in patients with cancers of different origins during the phase of primary tumour growth whereas a normal or sometimes elevated pineal melatonin secretory activity is found during early stages of tumour development or when recidivations arise. The clinical studies of Lissoni show that melatonin, particularly if combined with interleukin-2, is able to favourably influence the course of advanced malignant disease leading to a prolonged survival as well as to an improved quality of life. These findings require to be verified by independent and controlled replication studies. If they can be confirmed it should be attempted to administer melatonin to patients with earlier stages of cancer parallel to standard oncological treatment regimens. In such trials it should be tested whether a substitutional therapy in patients with endogenously depressed melatonin may favourably affect the course of the disease both in quantitative (inhibitory effect on tumour growth and spread) and qualitative terms (improved performance status).     

Melatonin and lipid uptake by murine fibroblasts: clinical implications

The current study was undertaken to uncover the role of melatonin in lipid metabolism in the murine fibroblasts. The results show melatonin in vitro enhances lipid accumulation and lipid droplet formation in this cell line. Using oil red O staining, it was found that when oleic acid was present in the culture media, melatonin at doses of 0.1-2mM, significantly increased the lipid concentrations in the cells. However, low levels of melatonin, with or without oleic acid, did not influence lipid metabolism in the cultured fibroblasts. When a non-specific melatonin receptor antagonist, luzindole 10 microM was co-incubated with 1mM melatonin, the stimulatory effects of melatonin on lipid accumulation in these cells was significantly reduced. It appears that the effects of melatonin on lipid metabolism in murine fibroblasts is mediated by melatonin membrane receptors.     

Melatonin and 5-methoxytryptamine in non-metazoans.

Melatonin seems to be an almost ubiquitous substance, which has been detected not only in metazoans, but also in all major non-metazoan taxa investigated, including bacteria, dinoflagellates, euglenoids, trypanosomids, fungi, rhodophyceans, pheophyceans, chlorophyceans and angiosperms. Despite its vast abundance, little is known to date about its functions. Its presence is not necessarily associated with circadian rhythmicity, which is evident in yeast. Circadian rhythms of melatonin have been reported in non-metazoans only for several unicellular organisms and in one angiosperm. In dinoflagellates, which have been studied in the most detail, the effects on enzyme activities and on phase shifting are known, but the most spectacular actions concerning the stimulation of bioluminescence, changes in cytoplasmic pH and induction of resting stages, can be related to a metabolite of melatonin, the 5-methoxytryptamine; therefore, melatonin should also be considered as a source of other agonists.     

REVIEW. Melatonin and the thyroid gland

This review briefly summarizes the published data on relationships observed between melatonin - the main pineal hormone, and the thyroid gland. The prevailing part of the survey is devoted to thyroid growth processes and function. A large experimental evidence exists suggesting the inhibitory action of melatonin on thyroid growth and function; this effect has been revealed by using different experimental models: by chronic and short-term melatonin administration in vivo, by light restriction, which is known to increase the activity of the pineal gland, by pinealectomy, etc., as well as by employing the in vitro conditions. Thus, much information has been accumulated, indicating - in experimental conditions - a mutual relationship between the pineal gland and the thyroid. The confirmation of these relations in clinical studies in humans meets numerous difficulties, resulting - among others - from the fact that, nowadays, human beings, as well as certain animal species, used in experimental studies, have been living far away from their natural and original habitat. It makes almost impossible to compare the results obtained in particular studies performed in different species, on the pineal-thyroid interrelationship.     

Melatonin and the seasonal control of reproduction.

Many mammalian species from temperate latitudes exhibit seasonal variations in breeding activity which are controlled by the annual photoperiodic cycle. Photoperiodic information is conveyed through several neural relays from the retina to the pineal gland where the light signal is translated into a daily cycle of melatonin secretion: high at night, low in the day. The length of the nocturnal secretion of melatonin reflects the duration of the night and it regulates the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Changes in GnRH release induce corresponding changes in luteinising hormone secretion which are responsible for the alternating presence or absence of ovulation in the female, and varying sperm production in the male. It is not yet known where and how this pineal indoleamine acts to exert this effect. Although melatonin binding sites are preferentially localised in the pars tuberalis (PT) of the adenohypophysis, the hypothalamus contains the physiological target sites of melatonin for its action on reproduction. Melatonin does not seem to act directly on GnRH neurons; rather it appears to involve a complex neural circuit of interneurons that includes at least dopaminergic, serotoninergic and excitatory aminoacidergic neurons.     

Streptokinase--biochemistry and clinical application

Plasminogen activation to plasmin is due to enzymatic cleavage of a single peptide bond in the zymogen molecule. Streptokinase is not an enzyme and its activation of plasminogen is indirect. Streptokinase forms stoichiometric complexes with plasmin and plasminogen and these complexes activate plasminogen to plasmin. Streptokinase is species selective in its action.     

褪黑素与衰老

随年龄增长松果腺功能减退、褪黑素分泌降低。施用ＭＴ或松果腺移植可使机体寿命延长。本文从ＭＴ抗氧化、增强免疫和调整生物钟功能等方面,阐明ＭＴ延缓衰老作用的机理。     

Melatonin and aging

Although many theories relating the pineal secretory product melatonin to aging have been put forward, the role of this agent in the aging process is not clear. However, there are several reasons to postulate a role for melatonin in this process. Melatonin levels fall gradually over the life-span. Melatonin is a potent free radical scavenger. Melatonin deficiency is related to suppressed immunocompetence. In at least one animal model melatonin supplementation increased life-span although several other studies have failed. The aging process is multifactorial, and no single element seems to be of basic importance. It seems, however, that although melatonin can not be univocally recognized as a substance delaying aging, some of its actions may be beneficial for the process of aging. However, the precise role of melatonin in the aging process remains to be determined.     

Melatonin in epilepsy: first results of replacement therapy and first clinical results

At a single evening dose of 5-10 mg, melatonin (MLT), the pineal gland hormone, can exert a positive effect on the frequency of epileptic attacks in children with sleep disturbances of various etiologies. We have shown that the sleep behavior can be normalized and an existing epilepsy can be favorably influenced. Pretherapeutic MLT secretion profiles can provide new information concerning the origin and treatment of these disturbances. In vitro experiments suggest that this effect might be the result of the interaction between MLT and MLT-specific receptors in the neocortex. Due to its favorable safety profile, MLT can be liberally administered in the specified doses and be considered as a useful antiepileptic drug.     

Melatonin

Melatonin, originally discovered as a hormone of the pineal gland, is produced by bacteria, protozoa, plants, fungi, invertebrates, and various extrapineal sites of vertebrates, including gut, skin, Harderian gland, and leukocytes. Biosynthetic pathways seem to be identical. Actions are pleiotropic, mediated by membrane and nuclear receptors, other binding sites or chemical interactions. Melatonin regulates the sleep/wake cycle, other circadian and seasonal rhythms, and acts as an immunostimulator and cytoprotective agent. Circulating melatonin is mostly 6-hydroxylated by hepatic P450 monooxygenases and excreted as 6-sulfatoxymelatonin. Pyrrole-ring cleavage is of higher importance in other tissues, especially the brain. The product, N1-acetyl-N2-formyl-5-methoxykynuramine, is formed by enzymatic, pseudoenzymatic, photocatalytic, and numerous free-radical reactions. Additional metabolites result from hydroxylation and nitrosation. The secondary metabolite, N1-acetyl-5-methoxykynuramine, supports mitochondrial function and downregulates cyclooxygenase 2. Antioxidative protection, safeguarding of mitochondrial electron flux, and in particular, neuroprotection, have been demonstrated in many experimental systems. Findings are encouraging to use melatonin as a sleep promoter and in preventing progression of neurodegenerative diseases.     

Melatonin and sleep

Sleep-wake cycle is the predominant example of circadian rhythms. Melatonin is commonly used to treat insomnia and in additional neurodevelopmental disorders in which sleep disturbance is frequent. In mammals, melatonin receptors are present in the membrane and cell nucleus of many tissues and systems where it exhibits various actions, including the regulation of circadian rhythms. The rhythmic pattern of melatonin secretion is imperative since it endows with vital information to the organism concerning time, which permits for alterations of a number of physiological functions consistent with daily and seasonal variations. Melatonin as well has sleep promoting effects demonstrated in changes in brain activation patterns and tiredness generation. The SCN’s (suprachiasmatic nuclei) function and melatonin production capability turns down with age consequently depriving the brain from an important time cue and sleep regulator.     

Melatonin: new applications in clinical and veterinary medicine, plant physiology and industry

Novel functions of melatonin continue to be uncovered. Those summarized in this report include actions at the level of the peripheral reproductive organs and include functions as an antioxidant to protect the maturing oocyte in the vesicular follicle and during ovulation, melatonin actions on the developing fetus particularly in relation to organizing the circadian system, its potential utility in combating the consequences of pre-eclampsia, reducing intrauterine growth restriction, suppressing endometriotic growths and improving the outcomes of in vitro fertilization/embryo transfer. The inhibitory effects of melatonin on many cancer types have been known for decades. Until recently, however, melatonin had not been tested as a protective agent against exocrine pancreatic tumors. This cancer type is highly aggressive and 5 year survival rate in individuals with pancreatic cancer is very low. Recent studies with melatonin indicate it may have utility in the treatment of these otherwise almost untreatable pancreatic cancers. The discovery of melatonin in plants has also opened a vast new field of research which is rapidly being exploited although the specific functions(s) of melatonin in plant organs remains enigmatic. Finally, the described application of melatonin's use as a chemical reductant in industry could well serve as a stimulus to further define the utility of this versatile molecule in new industrial applications.     

Melatonin and childbearing: Part 2. Postimplantation period

In this part of the review, we have tried to consider the dependence of the pineal hormone melatonin in human blood serum. It was established that one of the main functions of melatonin is the synchronization of all organs and the regulation of seasonal and diurnal rhythms of their physiological activity. It is confirmed that pregnancy and childbirth directly depend on the rhythm and level of melatonin secretion in the body. It was also found that melatonin maintains the appropriate proliferative level and immune status of the fetus. Disturbances in the melatonin secretion rhythm in children lead to the development of mental (stress and depression) and physiological (preeclampsia, eclampsia, fetal hypoxia, and miscarriages) pathologies. A drastic decrease in the melatonin concentration initiates the childbirth process. Therefore, the creation of conditions for maintaining a sufficient level of melatonin is required to ensure the birth of healthy offspring.