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.

Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.

Extrapineal melatonin: sources, regulation, and potential functions.

Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports implicating melatonin as an immunomodulatory compound, it still remains unclear how melatonin regulates immunity. While some authors argue that melatonin is an immunostimulant, many studies have also described anti-inflammatory properties. The data reviewed in this paper support the idea of melatonin as an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses, such as acute inflammation. The clinical relevance of the multiple functions of melatonin under different immune conditions, such as infection, autoimmunity, vaccination and immunosenescence, is also reviewed.

/pdf/melatonin-buffering-the-immune-system-1mr2908lga.pdf

Melatonin: buffering the immune system.

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

Molecular Targets of Cannabidiol in Neurological Disorders

https://www.alchimiaweb.com/blogfr/wp-content/uploads/2015/11/Cannabidiol-CBD-and-its-analogs-A-review-of-their-effects-on-inflammation-CBD-REVIEW-2015.pdf

Cannabidiol (CBD) and its analogs: a review of their effects on inflammation.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by chronic relapsing intestinal inflammation It has been a worldwide health-care problem with a continually increasing incidence It is thought that IBD results from an aberrant and continuing immune response to the microbes in the gut, catalyzed by the genetic susceptibility of the individual Although the etiology of IBD remains largely unknown, it involves a complex interaction between the genetic, environmental or microbial factors and the immune responses Of the four components of IBD pathogenesis, most rapid progress has been made in the genetic study of gut inflammation The latest internationally collaborative studies have ascertained 163 susceptibility gene loci for IBD The genes implicated in childhood-onset and adult-onset IBD overlap, suggesting similar genetic predispositions However, the fact that genetic factors account for only a portion of overall disease variance indicates that microbial and environmental factors may interact with genetic elements in the pathogenesis of IBD Meanwhile, the adaptive immune response has been classically considered to play a major role in the pathogenesis of IBD, as new studies in immunology and genetics have clarified that the innate immune response maintains the same importance in inducing gut inflammation Recent progress in understanding IBD pathogenesis sheds lights on relevant disease mechanisms, including the innate and adaptive immunity, and the interactions between genetic factors and microbial and environmental cues In this review, we provide an update on the major advances that have occurred in above areas

Inflammatory bowel disease: pathogenesis.

Melatonin is a hormone with endocrine, paracrine and autocrine actions. It is involved in the regulation of multiple functions, including the control of the gastrointestinal (GI) system under physiological and pathophysiological conditions. Since the gut contains at least 400 times more melatonin than the pineal gland, a review of the functional importance of melatonin in the gut seems useful, especially in the context of recent clinical trials. Melatonin exerts its physiological effects through specific membrane receptors, named melatonin-1 receptor (MT1), MT2 and MT3. These receptors can be found in the gut and their involvement in the regulation of GI motility, inflammation and pain has been reported in numerous basic and clinical studies. Stable levels of melatonin in the lower gut that are unchanged following a pinealectomy suggest local synthesis and, furthermore, implicate physiological importance of endogenous melatonin in the GI tract. Presently, only a small number of human studies report possible beneficial and also possible harmful effects of melatonin in case reports and clinical trials. These human studies include patients with lower GI diseases, especially patients with irritable bowel syndrome, inflammatory bowel disease and colorectal cancer. In this review, we summarize the presently available information on melatonin effects in the lower gut and discuss available in vitro and in vivo data. We furthermore aim to evaluate whether melatonin may be useful in future treatment of symptoms or diseases involving the lower gut.

Distribution, function and physiological role of melatonin in the lower gut

Colorectal cancer (CRC) has become the fourth leading cause of cancer-related death in the worldwide. It is urgent to find more effective therapeutic strategies for it. Reactive oxygen species (ROS) play multiple roles in normal cellular physiology processes. Thus, a certain level of ROS is essential to keep normal cellular function. However, the accumulation of ROS shows dual roles for cells, which is mainly dependent on the concentration of ROS, the origin of the cancer cell and the activated signaling pathways during tumor progression. In general, moderate level of ROS leads to cell damage, DNA mutation and inflammation, which promotes the initiation and development of cancer. Excessive high level of ROS induces cancer cell death, showing an anti-cancer role. ROS are commonly higher in CRC cells than their normal counterpart cells. Therefore, it is possible that ROS induce cell death in cancer cells while not affecting the normal cells, demonstrating lower side effects. Besides, ROS also play a role in tumor microenvironment and drug resistance. These multiple roles of ROS make them a promising therapeutic target for cancer. To explore potential ROS-target therapies against CRC, it is worth to comprehensively understanding the role of ROS in CRC and therapy. In this review, we mainly discuss the strategies of ROS in CRC therapy, including direct CRC cell target and indirect tumor environment target. In addition, the influences of ROS in drug resistance will also been discussed.

Reactive oxygen species and colorectal cancer.

Berberine is an isoquinoline alkaloid present in several plant species, including Coptis sp. and Berberis sp. In traditional medicine, extracts of berberine are used in the treatment of diarrhea of different origins. Recent studies have shown that berberine and its derivatives have significant biological effects on gastrointestinal (GI) and other functions and may become therapeutics for the treatment of diarrhea, gastroenteritis, diabetes, hyperlipidemia, cardiovascular diseases and inflammatory conditions. This paper summarizes the current knowledge on the actions of berberine in the GI tract. Binding and target sites, activated intracellular pathways, as well as the absorption and metabolism of berberine are discussed. Effects that may be useful in future clinical treatment, like antidiarrheal, anti-inflammatory and antitumor effects are critically reviewed and potential clinical applications are presented in detail.

/pdf/effects-of-berberine-in-the-gastrointestinal-tract-a-review-4rtnoui4eg.pdf

Yong-Yu Li

Papers

Inflammatory bowel disease: pathogenesis.

Distribution, function and physiological role of melatonin in the lower gut

Reactive oxygen species and colorectal cancer.

Effects of berberine in the gastrointestinal tract - a review of actions and therapeutic implications

A role for O-1602 and G protein-coupled receptor GPR55 in the control of colonic motility in mice.