Melatonin is uncommonly effective in reducing oxidative stress under a remarkably large number of circumstances. It achieves this action via a variety of means: direct detoxification of reactive oxygen and reactive nitrogen species and indirectly by stimulating antioxidant enzymes while suppressing the activity of pro-oxidant enzymes. In addition to these well-described actions, melatonin also reportedly chelates transition metals, which are involved in the Fenton/Haber-Weiss reactions; in doing so, melatonin reduces the formation of the devastatingly toxic hydroxyl radical resulting in the reduction of oxidative stress. Melatonin's ubiquitous but unequal intracellular distribution, including its high concentrations in mitochondria, likely aid in its capacity to resist oxidative stress and cellular apoptosis. There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant. Melatonin's capacity to prevent oxidative damage and the associated physiological debilitation is well documented in numerous experimental ischemia/reperfusion (hypoxia/reoxygenation) studies especially in the brain (stroke) and in the heart (heart attack). Melatonin, via its antiradical mechanisms, also reduces the toxicity of noxious prescription drugs and of methamphetamine, a drug of abuse. Experimental findings also indicate that melatonin renders treatment-resistant cancers sensitive to various therapeutic agents and may be useful, due to its multiple antioxidant actions, in especially delaying and perhaps treating a variety of age-related diseases and dehumanizing conditions. Melatonin has been effectively used to combat oxidative stress, inflammation and cellular apoptosis and to restore tissue function in a number of human trials; its efficacy supports its more extensive use in a wider variety of human studies. The uncommonly high-safety profile of melatonin also bolsters this conclusion. It is the current feeling of the authors that, in view of the widely diverse beneficial functions that have been reported for melatonin, these may be merely epiphenomena of the more fundamental, yet-to-be identified basic action(s) of this ancient molecule.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jpi.12360

Melatonin as an antioxidant: under promises but over delivers.

Melatonin is remarkably functionally diverse with actions as a free radical scavenger and antioxidant, circadian rhythm regulator, anti-inflammatory and immunoregulating molecule, and as an oncostatic agent. We hypothesize that the initial and primary function of melatonin in photosynthetic cyanobacteria, which appeared on Earth 3.5-3.2 billion years ago, was as an antioxidant. The evolution of melatonin as an antioxidant by this organism was necessary as photosynthesis is associated with the generation of toxic-free radicals. The other secondary functions of melatonin came about much later in evolution. We also surmise that mitochondria and chloroplasts may be primary sites of melatonin synthesis in all eukaryotic cells that possess these organelles. This prediction is made on the basis that mitochondria and chloroplasts of eukaryotes developed from purple nonsulfur bacteria (which also produce melatonin) and cyanobacteria when they were engulfed by early eukaryotes. Thus, we speculate that the melatonin-synthesizing actions of the engulfed bacteria were retained when these organelles became mitochondria and chloroplasts, respectively. That mitochondria are likely sites of melatonin formation is supported by the observation that this organelle contains high levels of melatonin that are not impacted by blood melatonin concentrations. Melatonin has a remarkable array of means by which it thwarts oxidative damage. It, as well as its metabolites, is differentially effective in scavenging a variety of reactive oxygen and reactive nitrogen species. Moreover, melatonin and its metabolites modulate a large number of antioxidative and pro-oxidative enzymes, leading to a reduction in oxidative damage. The actions of melatonin on radical metabolizing/producing enzymes may be mediated by the Keap1-Nrf2-ARE pathway. Beyond its direct free radical scavenging and indirect antioxidant effects, melatonin has a variety of physiological and metabolic advantages that may enhance its ability to limit oxidative stress.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jpi.12267

Melatonin: an ancient molecule that makes oxygen metabolically tolerable.

http://www.anuragaja.staff.ipb.ac.id/files/2012/10/Kumar_2010_FC_Phytate-human-rev.pdf

Dietary roles of phytate and phytase in human nutrition: A review

The article gives an overview of phytic acid in food and of its significance for human nutrition. It summarises phytate sources in foods and discusses problems of phytic acid/phytate contents of food tables. Data on phytic acid intake are evaluated and daily phytic acid intake depending on food habits is assessed. Degradation of phytate during gastro-intestinal passage is summarised, the mechanism of phytate interacting with minerals and trace elements in the gastro-intestinal chyme described and the pathway of inositol phosphate hydrolysis in the gut presented. The present knowledge of phytate absorption is summarised and discussed. Effects of phytate on mineral and trace element bioavailability are reported and phytate degradation during processing and storage is described. Beneficial activities of dietary phytate such as its effects on calcification and kidney stone formation and on lowering blood glucose and lipids are reported. The antioxidative property of phytic acid and its potentional anticancerogenic activities are briefly surveyed. Development of the analysis of phytic acid and other inositol phosphates is described, problems of inositol phosphate determination and detection discussed and the need for standardisation of phytic acid analysis in foods argued.

https://wiebaktmee.nl/cms/pdf/Schlemmer%20_Mol_Nutr_Food_res_2009_Phytate_in_foods_and_significance_for_humans.pdf

Phytate in foods and significance for humans: food sources, intake, processing, bioavailability, protective role and analysis.

https://link.springer.com/content/pdf/10.1007%2Fs13311-015-0377-3.pdf

Molecular Targets of Cannabidiol in Neurological Disorders

Simple classification of renal calculi closely related to their micromorphology and etiology.

Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases

Oxidative damage is related to aging and a wide range of human disorders. Mitochondria are in large part responsible for free radical production and they are also main targets of the attack of these toxic molecules. The resulting deleterious effects of the damage to mitochondria can be prevented by antioxidants. Melatonin is an endogenously-produced indoleamine that modulates numerous functions, including mitochondria-related functions; this result from its capacity to penetrate all morphophysiological barriers and to enter all subcellular compartments due to its amphiphilic nature. Furthermore, this indoleamine and its metabolites are powerful antioxidants and scavengers of free radicals, protecting cellular membranes, the electron transport chain and mitochondrial DNA from oxidative damage. These properties may make melatonin a potent protector against a variety of free radical-related diseases. By comparison, other conventional antioxidants have less efficacy due to their limited access to the mitochondria. In recent years, research has focused on the advancement of mitochondria-targeted antioxidants, such as MitoQ (composed by the lipophilic triphenylphosphonium cation conjugated to the endogenous antioxidant coenzyme Q10) and MitoE (composed by the triphenylphosphonium cation attached to the antioxidant α-tocopherol). Mitochondria-targeted antioxidants accumulate in several hundred-fold greater concentrations within mitochondria and protect these critical organelles from oxidative damage. Melatonin also seems to be a mitochondria-targeted antioxidant and has similar protective actions as the synthetic antioxidants. Further work is required to determine the therapeutic properties of these antioxidants in ameliorating diseases related to mitochondrial dysfunction.

Protective Effects of Melatonin and Mitochondria-targeted Antioxidants Against Oxidative Stress: A Review

This is a comparative study of the effects of phytate and pyrophosphate and other polyphosphates on the crystallization of hydroxyapatite and brushite, the most frequent calcium phosphates involved in calcium oxalate urolithiasis. Brushite and hydroxyapatite crystal formation was studied in synthetic urine, through kinetic-turbidimetric measurements that allowed evaluation of the inhibitory effects on crystallization of insoluble salts. The effectiveness in preventing brushite crystallization decreases in the sequence phytate > polyphosphate > EDTPO > etidronate > pyrophosphate > triphosphate > medronate; whereas the order of effectiveness in preventing hydroxyapatite crystallization was EDTPO > etidronate=pyrophosphate > triphosphate > medronate > polyphosphate > phytate. Phytate, a natural inhibitor in urine, most effectively blocked brushite precipitation (1.21·10−5 M prevented crystallization during time periods of at least 1 h), and pyrophosphate was the natural inhibitor that most effectively blocked hydroxyapatite precipitation (2.87·10−6 M prevented crystallization during time periods of at least 1 h). This demonstrates that low excretion of these substances would pose a risk of renal lithiasis.

Effects of phytate and pyrophosphate on brushite and hydroxyapatite crystallization. Comparison with the action of other polyphosphates.

The aim of this paper is to study the variations in the percentage of the different types of renal stones with age and sex. Renal calculi were classified according to their composition and structure. Stone formers were divided according to age and sex, and the percentage of each kind of calculi in the different considered age periods for men and women were determined. It was found that calcium oxalate dihydrate calculi decreased with age, but only in men. These calculi were also clearly predominant in men. Hydroxyapatite calculi decreased with age in both men and women, but they were predominant in women. Uric acid calculi increased with age in both men and women, but were predominant in men. Finally, it was found that calcium oxalate monohydrate unattached calculi increased with age in both men and women. As a main novelty, the study here presented demonstrates the importance of distinguishing between calcium oxalate monohydrate papillary stones and calcium oxalate monohydrate unattached stones, since the etiologic factors responsible for their origin must be clearly different.

M. Ramis

Papers

Simple classification of renal calculi closely related to their micromorphology and etiology.

Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases

Protective Effects of Melatonin and Mitochondria-targeted Antioxidants Against Oxidative Stress: A Review

Effects of phytate and pyrophosphate on brushite and hydroxyapatite crystallization. Comparison with the action of other polyphosphates.

Type of renal calculi: variation with age and sex