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.

N6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

/pdf/the-role-of-m6a-modification-in-the-biological-functions-and-4yp9ys39cx.pdf

The role of m6A modification in the biological functions and diseases.

Organotypic brain slice cultures: A review.

Parkinson’s disease (PD) is a chronic and progressive neurodegeneration of dopamine neurons in the substantia nigra. The reason for the death of these neurons is unclear; however, studies have demonstrated the potential involvement of mitochondria, endoplasmic reticulum, α-synuclein or dopamine levels in contributing to cellular oxidative stress as well as PD symptoms. Even though those papers had separately described the individual roles of each element leading to neurodegeneration, recent publications suggest that neurodegeneration is the product of various cellular interactions. This review discusses the role of oxidative stress in mediating separate pathological events that together, ultimately result in cell death in PD. Understanding the multi-faceted relationships between these events, with oxidative stress as a common denominator underlying these processes, is needed for developing better therapeutic strategies.

/pdf/oxidative-stress-and-cellular-pathologies-in-parkinson-s-317b2bpokd.pdf

Oxidative stress and cellular pathologies in Parkinson's disease.

Current progress on understanding the impact of mercury on human health.

Epitranscriptomics, also known as “RNA epigenetics”, is a chemical modification for RNA regulation. Ribonucleic acid (RNA) methylation is considered to be a major discovery following the deoxyribonucleic acid (DNA) and histone methylation. Messenger RNA (mRNA) methylation modification accounts for more than 60% of all RNA modifications and N6-methyladenosine (m6A) is known as one of the most common type of eukaryotic mRNA methylation modifications in current. The m6A modification is a dynamic reversible modification, which can directly or indirectly affect biological processes, such as RNA degradation, translation and splicing, and can play important biological roles in vivo. This article introduces the mRNA m6A methylation modification enzymes and binding proteins, and reviews the research progress and related mechanisms of the role of mRNA m6A methylation in the nervous system from the aspects of neural stem cells, learning and memory, brain development, axon growth and glioblastoma.

/pdf/the-role-of-mrna-m-6-a-methylation-in-the-nervous-system-1xki5pm7jy.pdf

The role of mRNA m 6 A methylation in the nervous system

Excessive manganese (Mn) exposure can lead to oxidative injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) exerts an antioxidant response toward various environmental toxicants in the brain. However, the role of Nrf2 against Mn-induced oxidative injury remains largely unexplored. This study investigated the role of melatonin (MLT), an agent that was recently shown to induce the activation of the Kelch-like ECH-associated protein 1 (Keap1)–Nrf2–antioxidant response elements (ARE) pathway against manganism. Mice were randomly divided into six groups, including control, 12.5, 25, 50 mg/kg MnCl2, MLT control, and MLT + 50 mg/kg MnCl2. The following were determined: behavioral activity; pathological changes; immunofluorescence staining of Neuronal Nuclei and glial fibrillary acidic protein; cell apoptosis; the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH); the immunohistochemical expression; and the protein levels of Nrf2, Keap1, and downstream enzymes. Mn-induced motor disorders, pathological damage, neuron degeneration, astrocytes activation, apoptosis, ROS and MDA generation, and GSH depletion. Nrf2, keap1, heme oxygenase-1 and NAD(P)H dehydrogenase, and quinone 1 showed a biphasic expression trend, which was most evidenced in the 12.5 mg/kg MnCl2 group. Changes in γ-glutamylcysteine synthetase, glutathione peroxidase 1, glutathionine S-transferase, glutathione reductase, and superoxide dismutase decreased in a concentration-dependent manner as a result of Mn exposure. MLT antagonized oxidative injury through the activation of the Keap1–Nrf2–ARE signaling pathway. In conclusion, disturbance of the Keap1–Nrf2–ARE signaling pathway partly caused oxidative injury. MLT can activate Nrf2 and its downstream enzymes and reverse Mn-induced oxidative injury.

Melatonin Antagonizes Mn-Induced Oxidative Injury Through the Activation of Keap1–Nrf2–ARE Signaling Pathway in the Striatum of Mice

Methyl-mercury (MeHg) is a dangerous environmental contamination biotransformed from mercury or inorganic mercury compounds in waterways, which induces severe toxic effects in central nervous syste...

Methyl-mercury induces apoptosis through ROS-mediated endoplasmic reticulum stress and mitochondrial apoptosis pathways activation in rat cortical neurons.

Oxidative stress involvement in manganese-induced alpha-synuclein oligomerization in organotypic brain slice cultures.

Methylmercury (MeHg) is a prominent environmental neurotoxicant, which induces oxidative damage and an indirect excitotoxicity caused by altered glutamate (Glu) metabolism. However, the interaction between oxidative damage and excitotoxicity in MeHg-exposed rats has not been fully recognized. Here, we explored the interaction between oxidative damage and excitotoxicity and evaluated the preventive effects of sulforaphane (SFN) on MeHg-induced neurotoxicity in rat cerebral cortex. Seventy-two rats were randomly assigned to four groups: control group, MeHg-treated groups (4 and 12 μmol/kg), and SFN pretreatment group. After treatment (28 days), the rats were killed and the cerebral cortex was analyzed. Then, Hg, glutathione (GSH), malondialdehyde (MDA), protein sulfhydryl, protein carbonyl, 8-hydroxy-2-deoxyguanosine (8-OHdG), and the levels of reactive oxygen species (ROS) and apoptosis were examined. Glu and glutamine (Gln) levels, glutamine synthetase (GS), phosphate-activated glutaminase (PAG), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), Na+-K+-ATPase and Ca2+-ATPase activities, intracellular Ca2+ levels, and the mRNA and protein expressions of Nrf2, Nrf2-regulated gene products, and N-methyl-D-aspartate receptors (NMDARs) were investigated in rat cerebral cortex. In our study, MeHg exposure not only induced Hg accumulation, apoptosis, ROS formation, GSH depletion, inhibition of antioxidant enzyme activities, and activation of Nrf2-ARE pathway signaling but also caused lipid, protein, and DNA peroxidative damage in a dose-dependent manner in rat cerebral cortex. Moreover, MeHg treatment significantly altered Gln/Glu cycling and NMDAR expression and resulted in calcium overloading. Furthermore, the present study also indicated that SFN pretreatment significantly reinforced the activation of the Nrf2-ARE pathway, which could prevent the toxic effects of MeHg exposure. Collectively, MeHg initiates multiple additive or synergistic disruptive mechanisms that lead to oxidative damage and excitotoxicity in rat cerebral cortex; pretreatment with SFN might prevent the MeHg-induced neurotoxicity by reinforcing the activation of the Nrf2-ARE pathway and then downregulating the interaction between oxidative damage and excitotoxicity pathways.

Zhaofa Xu

Papers

The role of mRNA m 6 A methylation in the nervous system

Melatonin Antagonizes Mn-Induced Oxidative Injury Through the Activation of Keap1–Nrf2–ARE Signaling Pathway in the Striatum of Mice

Methyl-mercury induces apoptosis through ROS-mediated endoplasmic reticulum stress and mitochondrial apoptosis pathways activation in rat cortical neurons.

Oxidative stress involvement in manganese-induced alpha-synuclein oligomerization in organotypic brain slice cultures.

Sulforaphane Prevents Methylmercury-Induced Oxidative Damage and Excitotoxicity Through Activation of the Nrf2-ARE Pathway.