Methylmercury (MeHg) is a toxic chemical compound naturally produced mainly in the aquatic environment through the methylation of inorganic mercury catalyzed by aquatic microorganisms. MeHg is ...biomagnified in the aquatic food chain and, consequently, piscivorous fish at the top of the food chain possess huge amounts of MeHg (at the ppm level). Some populations that have fish as main protein's source can be exposed to exceedingly high levels of MeHg and develop signs of toxicity. MeHg is toxic to several organs, but the central nervous system (CNS) represents a preferential target, especially during development (prenatal and early postnatal periods). Though the biochemical events involved in MeHg-(neuro)toxicity are not yet entirely comprehended, a vast literature indicates that its pro-oxidative properties explain, at least partially, several of its neurotoxic effects. As result of its electrophilicity, MeHg interacts with (and oxidize) nucleophilic groups, such as thiols and selenols, present in proteins or low-molecular weight molecules. It is noteworthy that such interactions modify the redox state of these groups and, therefore, lead to oxidative stress and impaired function of several molecules, culminating in neurotoxicity. Among these molecules, glutathione (GSH; a major thiol antioxidant) and thiol- or selenol-containing enzymes belonging to the GSH antioxidant system represent key molecular targets involved in MeHg-neurotoxicity. In this review, we firstly present a general overview concerning the neurotoxicity of MeHg. Then, we present fundamental aspects of the GSH-antioxidant system, as well as the effects of MeHg on this system.
•MeHg is toxic to several organs, but the CNS represents a preferential target, especially during development.•MeHg interacts with (and oxidize) nucleophilic groups present in proteins or low-molecular weight molecules.•GSH and enzymes belonging to the GSH antioxidant system represent molecular targets involved in MeHg-neurotoxicity.•MeHg x GSH or MeHg x GPxs interaction decreases the cellular capacity to detoxify oxidants, favoring toxicity.•MeHg excretion is significantly favored by its interaction with GSH.
Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS) which initiates rapid signal transmission in the synapse before its re-uptake into the surrounding glia, ...specifically astrocytes. The astrocytic glutamate transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) and their human homologs excitatory amino acid transporter 1 (EAAT1) and 2 (EAAT2), respectively, are the major transporters which take up synaptic glutamate to maintain optimal extracellular glutamic levels, thus preventing accumulation in the synaptic cleft and ensuing excitotoxicity. Growing evidence has shown that excitotoxicity is associated with various neurological disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), manganism, ischemia, schizophrenia, epilepsy, and autism. While the mechanisms of neurological disorders are not well understood, the dysregulation of GLAST/GLT-1 may play a significant role in excitotoxicity and associated neuropathogenesis. The expression and function of GLAST/GLT-1 may be dysregulated at the genetic, epigenetic, transcriptional or translational levels, leading to high levels of extracellular glutamate and excitotoxicity. Consequently, understanding the regulatory mechanisms of GLAST/GLT-1 has been an area of interest in developing therapeutics for the treatment of neurological disorders. Pharmacological agents including β-lactam antibiotics, estrogen/selective estrogen receptor modulators (SERMs), growth factors, histone deacetylase inhibitors (HDACi), and translational activators have shown significant efficacy in enhancing the expression and function of GLAST/GLT-1 and glutamate uptake both in vitro and in vivo. This comprehensive review will discuss the regulatory mechanisms of GLAST/GLT-1, their association with neurological disorders, and the pharmacological agents which mediate their expression and function.
This article is part of the issue entitled ‘Special Issue on Neurotransmitter Transporters’.
•Excitotoxicity plays a critical role in neurological and neurodegenerative disorders.•Glutamate transporters GLT-1 and GLAST are essential in preventing excitotoxicity.•GLT-1/GLAST expression can be modulated by drugs at multiple levels of gene expression.•Pharmacological agents can target GLT-1/GLAST to treat neurological disorders.
Manganese (Mn) is an essential mineral. It is present in virtually all diets at low concentrations. The principal route of intake for Mn is via food consumption, but in occupational cohorts, ...inhalation exposure may also occur (this subject will not be dealt with in this review). Humans maintain stable tissue levels of Mn. This is achieved via tight homeostatic control of both absorption and excretion. Nevertheless, it is well established that exposure to high oral, parenteral or ambient air concentrations of Mn can result in elevations in tissue Mn levels. Excessive Mn accumulation in the central nervous system (CNS) is an established clinical entity, referred to as manganism. It resembles idiopathic Parkinson’s disease (IPD) in its clinical features, resulting in adverse neurological effects both in laboratory animals and humans. This review focuses on an area that to date has received little consideration, namely the potential exposure of parenterally fed neonates to exceedingly high Mn concentrations in parenteral nutrition solutions, potentially increasing their risk for Mn-induced adverse health sequelae. The review will consider (1) the essentiality of Mn; (2) the concentration ranges, means and variation of Mn in various foods and infant formulas; (3) the absorption, distribution, and elimination of Mn after oral exposure and (4) the factors that raise a theoretical concern that neonates receiving total parenteral nutrition (TPN) are exposed to excessive dietary Mn.
Astaxanthin (ATX) is a red pigment carotenoid present in shrimp, salmon, crab, and asteroidean. Several studies have corroborated the anti-oxidant efficacy of ATX. In addition, ATX has ...anti-inflammatory, anti-apoptotic and anti-proliferative properties. In the present review, we discuss the role of Nrf2 in mediating the anti-cancer, anti-aging, neuroprotective, lung-protective, skin-protective, cardioprotective, hepatoprotective, anti-diabetic and muscloprotective effects of ATX.
Quercetin is a flavonoid with notable pharmacological effects and promising therapeutic potential. It is widely distributed among plants and found commonly in daily diets predominantly in fruits and ...vegetables. Neuroprotection by quercetin has been reported in several in vitro studies. It has been shown to protect neurons from oxidative damage while reducing lipid peroxidation. In addition to its antioxidant properties, it inhibits the fibril formation of amyloid-β proteins, counteracting cell lyses and inflammatory cascade pathways. In this review, we provide a synopsis of the recent literature exploring the relationship between quercetin and cognitive performance in Alzheimer's disease and its potential as a lead compound in clinical applications.
Thymoquinone (TQ, 2-methyl-5-isopropyl-1, 4-benzoquinone), a monoterpene molecule present in Nigella sativa L., has an anti-inflammatory, anti-oxidant, and anti-apoptotic properties in several ...disorders such as asthma, hypertension, diabetes, inflammation, bronchitis, headache, eczema, fever, dizziness and influenza. TQ exerts its anti-inflammatory and anti-oxidant effects via several molecular pathways, including the release of cytokines, and activation of cyclooxygenase-2 (COX2), nuclear factor erythroid 2–related factor 2 (Nrf2), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), nuclear factor kappa-light-chain-enhancer of activated B (NF-Κβ). In this review, recent reports on the anti-inflammatory efficacy of TQ in heart disorders, respiratory diseases, neuroinflammation, diabetes and arthritis are summarized. We suggest that further investigation is necessary to better characterize the efficacy of TQ as a therapeutic agent.
Manganese Is Essential for Neuronal Health Horning, Kyle J; Caito, Samuel W; Tipps, K. Grace ...
Annual review of nutrition,
07/2015, Letnik:
35, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The understanding of manganese (Mn) biology, in particular its cellular regulation and role in neurological disease, is an area of expanding interest. Mn is an essential micronutrient that is ...required for the activity of a diverse set of enzymatic proteins (e.g., arginase and glutamine synthase). Although necessary for life, Mn is toxic in excess. Thus, maintaining appropriate levels of intracellular Mn is critical. Unlike other essential metals, cell-level homeostatic mechanisms of Mn have not been identified. In this review, we discuss common forms of Mn exposure, absorption, and transport via regulated uptake exchange at the gut and blood-brain barrier and via biliary excretion. We present the current understanding of cellular uptake and efflux as well as subcellular storage and transport of Mn. In addition, we highlight the Mn-dependent and Mn-responsive pathways implicated in the growing evidence of its role in Parkinson's disease and Huntington's disease. We conclude with suggestions for future focuses of Mn health-related research.
Autism Spectrum Disorder (ASD) remains one of the most detrimental neurodevelopmental conditions in society today. Common symptoms include diminished social and communication ability. Investigations ...on autism etiology remain largely ambiguous. Previous studies have highlighted exposure to lead (Pb) may play a role in ASD. In addition, lead has been shown to be one of the most prevalent metal exposures associated with neurological deficits. A semi-systematic review was conducted using public databases in order to evaluate the extent of lead's role in the etiology of autism. This review examines the relationship between autistic comorbid symptoms-such as deterioration in intelligence scores, memory, language ability, and social interaction-and lead exposure. Specifically, the mechanisms of action of lead exposure, including changes within the cholinergic, dopaminergic, glutamatergic, gamma aminobutyric acid (GABA)ergic systems, are discussed. The goal of this review is to help illustrate the connections between lead's mechanistic interference and the possible furthering of the comorbidities of ASD. Considerations of the current data and trends suggest a potential strong role for lead in ASD.
Astaxanthin (AST) is a red pigmented carotenoid with significant antioxidant, anti-inflammatory, anti-proliferative, and anti-apoptotic properties. In this study, we summarize the available ...literature on the anti-inflammatory efficacy of AST in various chronic and acute disorders, such as neurodegenerative, renal-, hepato-, skin- and eye-related diseases, as well as gastrointestinal disorders. In addition, we elaborated on therapeutic efficacy of AST and the role of several pathways, including PI3K/AKT, Nrf2, NF-κB, ERK1/2, JNK, p38 MAPK, and JAK-2/STAT-3 in mediating its effects. However, additional experimental and clinical studies should be performed to corroborate the anti-inflammatory effects and protective effects of AST against inflammatory diseases in humans. Nevertheless, this review suggests that AST with its demonstrated anti-inflammatory property may be a suitable candidate for drug design with novel technology.
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•AST can modulate inflammatory signaling pathways and downregulate the expression of inflammatory cytokines.•AST maybe a suitable candidate for treating chronic inflammatory diseases.•AST has protective effects against skin and gastric diseases and also arterial stiffness via modulating inflammation.•AST could enhance the immune system in healthy men and women.
Cancer is one of the most extreme medical conditions in both developing and developed countries around the world, causing millions of deaths each year. Chemotherapy and/or radiotherapy are key for ...treatment approaches, but both have numerous adverse health effects. Furthermore, the resistance of cancerous cells to anticancer medication leads to treatment failure. The rising burden of cancer overall requires novel efficacious treatment modalities. Natural medications offer feasible alternative options against malignancy in contrast to western medication. Furanocoumarins' defensive and restorative impacts have been observed in leukemia, glioma, breast, lung, renal, liver, colon, cervical, ovarian, and prostate malignancies. Experimental findings have shown that furanocoumarins activate multiple signaling pathways, leading to apoptosis, autophagy, antioxidant, antimetastatic, and cell cycle arrest in malignant cells. Additionally, furanocoumarins have been shown to have chemo preventive and chemotherapeutic synergistic potential when used in combination with other anticancer drugs. Here, we address different pathways which are activated by furanocoumarins and their therapeutic efficacy in various tumors. Ideally, this review will trigger interest in furanocoumarins and their potential efficacy and safety as a cancer lessening agents.
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