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1.
J Biol Chem ; 298(6): 102037, 2022 06.
Article in English | MEDLINE | ID: mdl-35595095

ABSTRACT

NAD+ is a versatile biomolecule acting as a master regulator and substrate in various cellular processes, including redox regulation, metabolism, and various signaling pathways. In this article, we concisely and critically review the role of NAD+ in mechanisms promoting genome maintenance. Numerous NAD+-dependent reactions are involved in the preservation of genome stability, the cellular DNA damage response, and other pathways regulating nucleic acid metabolism, such as gene expression and cell proliferation pathways. Of note, NAD+ serves as a substrate to ADP-ribosyltransferases, sirtuins, and potentially also eukaryotic DNA ligases, all of which regulate various aspects of DNA integrity, damage repair, and gene expression. Finally, we critically analyze recent developments in the field as well as discuss challenges associated with therapeutic actions intended to raise NAD+ levels.


Subject(s)
DNA , Genomic Instability , NAD , ADP Ribose Transferases/metabolism , DNA/chemistry , DNA Ligases/metabolism , NAD/metabolism , Signal Transduction , Sirtuins/metabolism
2.
Food Chem Toxicol ; 138: 111245, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32145355

ABSTRACT

It appears that electronic cigarettes (EC) are a less harmful alternative to conventional cigarette (CC) smoking, as they generate substantially lower levels of harmful carcinogens and other toxic compounds. Thus, switching from CC to EC may be beneficial for smokers. However, recent accounts of EC- or vaping-associated lung injury (EVALI) has raised concerns regarding their adverse health effects. Additionally, the increasing popularity of EC among vulnerable populations, such as adolescents and pregnant women, calls for further EC safety evaluation. In this state-of-the-art review, we provide an update on recent findings regarding the neurological effects induced by EC exposure. Moreover, we discuss possible neurotoxic effects of nicotine and numerous other chemicals which are inherent both to e-liquids and EC aerosols. We conclude that in recognizing pertinent issues associated with EC usage, both government and scientific researchers must address this public health issue with utmost urgency.


Subject(s)
Electronic Nicotine Delivery Systems , Neurotoxicity Syndromes , Nicotine/toxicity , Adolescent , Aerosols/adverse effects , Animals , Brain/drug effects , Female , Free Radicals/toxicity , Humans , Metals, Heavy/toxicity , Nanoparticles/toxicity , Pregnancy , Public Health , Smokers , Smoking , Trace Elements/toxicity , Vaping/adverse effects
3.
Toxicol Lett ; 324: 95-103, 2020 May 15.
Article in English | MEDLINE | ID: mdl-32017979

ABSTRACT

Sulfur mustard (SM) is a toxicant and chemical warfare agent with strong vesicant properties. The mechanisms behind SM-induced toxicity are not fully understood and no antidote or effective therapy against SM exists. Both, the risk of SM release in asymmetric conflicts or terrorist attacks and the usage of SM-derived nitrogen mustards as cancer chemotherapeutics, render the mechanisms of mustard-induced toxicity a highly relevant research subject. Herein, we review a central role of the abundant cellular molecule nicotinamide adenine dinucleotide (NAD+) in molecular mechanisms underlying SM toxicity. We also discuss the potential beneficial effects of NAD+ precursors in counteracting SM-induced damage.


Subject(s)
Chemical Warfare Agents/toxicity , Mustard Gas/toxicity , NAD/physiology , Animals , Dietary Supplements , Humans , NAD/administration & dosage , Niacinamide/administration & dosage , Oxidative Stress/drug effects , Poly(ADP-ribose) Polymerases/metabolism , Reactive Nitrogen Species/metabolism , Sirtuins/antagonists & inhibitors
4.
Environ Res ; 177: 108637, 2019 10.
Article in English | MEDLINE | ID: mdl-31416010

ABSTRACT

Climate change is one of the biggest and most urgent challenges for the 21st century. Rising average temperatures and ocean levels, altered precipitation patterns and increased occurrence of extreme weather events affect not only the global landscape and ecosystem, but also human health. Multiple environmental factors influence the onset and severity of human diseases and changing climate may have a great impact on these factors. Climate shifts disrupt the quantity and quality of water, increase environmental pollution, change the distribution of pathogens and severely impacts food production - all of which are important regarding public health. This paper focuses on brain health and provides an overview of climate change impacts on risk factors specific to brain diseases and disorders. We also discuss emerging hazards in brain health due to mitigation and adaptation strategies in response to climate changes.


Subject(s)
Brain Diseases/epidemiology , Climate Change , Environmental Exposure/statistics & numerical data , Ecosystem , Environmental Pollution/statistics & numerical data , Humans , Public Health
5.
Front Genet ; 10: 165, 2019.
Article in English | MEDLINE | ID: mdl-30891065
6.
J Mol Neurosci ; 67(2): 312-342, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30604380

ABSTRACT

Sex differences in brain physiology and by inference various pathologies are generally recognized, however frequently ignored in epidemiological and experimental studies, leading to numerous data gaps. As a consequence, the mechanisms underlying sexual dimorphism of neurological diseases remain largely unknown. Several cellular and molecular pathways linked to the etiology and pathogenesis of various brain disorders have been recently described as sex-specific. Here, we review the evidence for sex differences in brain redox homeostasis, which is an important factor in brain physiology and disease. First, we focus on sex-specific differences in the healthy brain regarding popular redox balance markers, including reactive oxygen and nitrogen species, oxidative damage, and antioxidant status. We also review the modulatory effect of steroid sex hormones on these markers. Lastly, we approach the sex-specific changes in brain redox homeostasis in disease and discuss the possibility that differential redox response contributes to the sexual dimorphism of neurological disorders.


Subject(s)
Brain/metabolism , Neurodegenerative Diseases/metabolism , Oxidative Stress , Reactive Oxygen Species/metabolism , Animals , Female , Homeostasis , Humans , Male , Mitochondria/metabolism , Neurodegenerative Diseases/etiology , Sex Factors
7.
Neurotox Res ; 35(1): 208-216, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30155682

ABSTRACT

Methylmercury (MeHg), an abundant environmental pollutant, has long been known to adversely affect neurodevelopment in both animals and humans. Several reports from epidemiological studies, as well as experimental data indicate sex-specific susceptibility to this neurotoxicant; however, the molecular bases of this process are still not clear. In the present study, we used Caenorhabditis elegans (C. elegans), to investigate sex differences in response to MeHg toxicity during development. Worms at different developmental stage (L1, L4, and adult) were treated with MeHg for 1 h. Lethality assays revealed that male worms exhibited significantly higher resistance to MeHg than hermaphrodites, when at L4 stage or adults. However, the number of worms with degenerated neurons was unaffected by MeHg, both in males and hermaphrodites. Lower susceptibility of males was not related to changes in mercury (Hg) accumulation, which was analogous for both wild-type (wt) and male-rich him-8 strain. Total glutathione (GSH) levels decreased upon MeHg in him-8, but not in wt. Moreover, the sex-dependent response of the cytoplasmic thioredoxin system was observed-males exhibited significantly higher expression of thioredoxin TRX-1, and thioredoxin reductase TRXR-1 expression was downregulated upon MeHg treatment only in hermaphrodites. These outcomes indicate that the redox status is an important contributor to sex-specific sensitivity to MeHg in C. elegans.


Subject(s)
Methylmercury Compounds/toxicity , Sex Characteristics , Age Factors , Animals , Animals, Genetically Modified , Caenorhabditis elegans , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cytoplasm/drug effects , Cytoplasm/metabolism , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/pathology , Female , Glutathione/metabolism , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Male , Neurodegenerative Diseases/chemically induced , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Thioredoxin-Disulfide Reductase/metabolism , Thioredoxins/metabolism
8.
Neurotoxicology ; 68: 189-202, 2018 09.
Article in English | MEDLINE | ID: mdl-30138651

ABSTRACT

Methylmercury (MeHg) is an environmental pollutant linked to many neurological defects, especially in developing individuals. The thioredoxin (TRX) system is a key redox regulator affected by MeHg toxicity, however the mechanisms and consequences of MeHg-induced dysfunction are not completely understood. This study evaluated the role of the TRX system in C. elegans susceptibility to MeHg during development. Worms lacking or overexpressing proteins from the TRX family were exposed to MeHg for 1 h at different developmental stage: L1, L4 and adult. Worms without cytoplasmic thioredoxin system exhibited age-specific susceptibility to MeHg when compared to wild-type (wt). This susceptibility corresponded partially to decreased total glutathione (GSH) levels and enhanced degeneration of dopaminergic neurons. In contrast, the overexpression of the cytoplasmic system TRX-1/TRXR-1 did not provide substantial protection against MeHg. Moreover, transgenic worms exhibited decreased protein expression for cytoplasmic thioredoxin reductase (TRXR-1). Both mitochondrial thioredoxin system TRX-2/TRXR-2, as well as other thioredoxin-like proteins: TRX-3, TRX-4, TRX-5 did not show significant role in C. elegans resistance to MeHg. Based on the current findings, the cytoplasmic thioredoxin system TRX-1/TRXR-1 emerges as an important age-sensitive protectant against MeHg toxicity in C. elegans.


Subject(s)
Caenorhabditis elegans Proteins/metabolism , Cytoplasm/metabolism , Methylmercury Compounds/toxicity , Thioredoxins/metabolism , Animals , Animals, Genetically Modified , Caenorhabditis elegans , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Glutathione/metabolism , Mitochondria/metabolism
9.
Toxicol Appl Pharmacol ; 354: 126-135, 2018 09 01.
Article in English | MEDLINE | ID: mdl-29550512

ABSTRACT

Due to many advantages Caenorhabditis elegans (C. elegans) has become a preferred model of choice in many fields, including neurodevelopmental toxicity studies. This review discusses the benefits of using C. elegans as an alternative to mammalian systems and gives examples of the uses of the nematode in evaluating the effects of major known neurodevelopmental toxins, including manganese, mercury, lead, fluoride, arsenic and organophosphorus pesticides. Reviewed data indicates numerous similarities with mammals in response to these toxins. Thus, C. elegans studies have the potential to predict possible effects of developmental neurotoxicants in higher animals, and may be used to identify new molecular pathways behind neurodevelopmental disruptions, as well as new toxicants.


Subject(s)
Caenorhabditis elegans/drug effects , Neurons/drug effects , Neurotoxicity Syndromes/etiology , Toxicity Tests/methods , Animals , Caenorhabditis elegans/growth & development , Caenorhabditis elegans/metabolism , Humans , Models, Animal , Neurons/metabolism , Neurons/pathology , Neurotoxicity Syndromes/metabolism , Neurotoxicity Syndromes/pathology , Neurotoxicity Syndromes/physiopathology , Risk Assessment , Species Specificity
10.
Toxicol Rep ; 4: 245-259, 2017.
Article in English | MEDLINE | ID: mdl-28959646

ABSTRACT

Sunscreen application is the main strategy used to prevent the maladies inflicted by ultraviolet (UV) radiation. Despite the continuously increasing frequency of sunscreen use worldwide, the prevalence of certain sun exposure-related pathologies, mainly malignant melanoma, is also on the rise. In the past century, a variety of protective agents against UV exposure have been developed. Physical filters scatter and reflect UV rays and chemical filters absorb those rays. Alongside the evidence for increasing levels of these agents in the environment, which leads to indirect exposure of wildlife and humans, recent studies suggest a toxicological nature for some of these agents. Reviews on the role of these agents in developmental and endocrine impairments (both pathology and related mechanisms) are based on both animal and human studies, yet information regarding the potential neurotoxicity of these agents is scant. In this review, data regarding the neurotoxicity of several organic filters: octyl methoxycinnamate, benzophenone-3 and -4, 4-methylbenzylidene camphor, 3-benzylidene camphor and octocrylene, and two allowed inorganic filters: zinc oxide and titanium dioxide, is presented and discussed. Taken together, this review advocates revisiting the current safety and regulation of specific sunscreens and investing in alternative UV protection technologies.

11.
Article in English | MEDLINE | ID: mdl-28339349

ABSTRACT

Triclosan (TCS) is an antibacterial agent that has been used in many products since 1960s. Given its broad usage as an antiseptic TCS is present ubiquitously in the environment. Trace levels of TCS continue to be detected in many organisms, and it has been shown to be particularly toxic to aquatic species. The mechanisms underlying TCS-mediated toxicity include hormone dyshomeostasis, induction of oxidative stress, apoptosis and inflammation. Although TCS has been considered to be non-toxic to mammals, the adverse effects of continuous, long-term and low concentration exposure remain unknown. Epidemiological studies revealed that levels of TCS in human tissues, urine, plasma and breast milk correlate with the usage of this antimicrobial. This led to concerns regarding TCS safety and potential toxicity in humans, with special emphasis on early development. The Food and Drug Administration (FDA) recently issued a directive banning the use of TCS in consumer soaps, justifying the move attributed to data gaps on its effectiveness and safety, indicating the need for more studies addressing this chemical-mediated effects on various tissues including the central nervous system (CNS). The aim of this review was to (1) summarize the current findings on the neurotoxic effects of TCS and given the paucity of data, to (2) broaden the discussion to other effects of TCS, which might plausibly be related to neuronal functions.


Subject(s)
Anti-Infective Agents, Local/toxicity , Environmental Pollutants/toxicity , Neurotoxins/toxicity , Triclosan/toxicity , Animals , Humans , Mice , Rats
12.
Neurotoxicology ; 56: 118-126, 2016 09.
Article in English | MEDLINE | ID: mdl-27456245

ABSTRACT

Methylmercury (MeHg) is a ubiquitous environmental contaminant and neurotoxin, particularly hazardous to developing and young individuals. MeHg neurotoxicity during early development has been shown to be sex-dependent via disturbances in redox homeostasis, a key event mediating MeHg neurotoxicity. Therefore, we investigated if MeHg-induced changes in key systems of antioxidant defense are sex-dependent. C57BL/6J mice were exposed to MeHg during the gestational and lactational periods, modeling human prenatal and neonatal exposure routes. Dams were exposed to 5ppm MeHg via drinking water from early gestational period until postnatal day 21 (PND21). On PND21 a pair of siblings (a female and a male) from multiple (5-6) litters were euthanized and tissue samples were taken for analysis. Cytoplasmic and nuclear extracts were isolated from fresh cerebrum and cerebellum and used to determine thioredoxin (Trx) and glutathione (GSH) levels, as well as thioredoxin reductase (TrxR) and glutathione peroxidase (GPx) activities. The remaining tissue was used for mRNA analysis. MeHg-induced antioxidant response was not uniform for all the analyzed antioxidant molecules, and sexual dimorphism in response to MeHg treatment was evident for TrxR, Trx and GPx. The pattern of response, namely a decrease in males and an increase in females, may impart differential and sex-specific susceptibility to MeHg. GSH levels were unchanged in MeHg treated animals and irrespective of sex. Trx was reduced only in nuclear extracts from male cerebella, exemplifying a structure-specific response. Results from the gene expression analysis suggest posttranscriptional mechanism of sex-specific regulation of the antioxidant response upon MeHg treatment. The study demonstrates for the first time sex-and structure-specific changes in the response of the thioredoxin system to MeHg neurotoxicity and suggests that these differences in antioxidant responses might impart differential susceptibility to developmental MeHg exposure.


Subject(s)
Antioxidants/metabolism , Brain , Gene Expression Regulation, Developmental/drug effects , Methylmercury Compounds/pharmacology , Prenatal Exposure Delayed Effects/chemically induced , Sex Characteristics , Animals , Animals, Newborn , Brain/drug effects , Brain/growth & development , Brain/pathology , Female , Glutathione/genetics , Glutathione/metabolism , Glutathione Peroxidase/genetics , Glutathione Peroxidase/metabolism , Male , Mice , Mice, Inbred C57BL , Pregnancy , Prenatal Exposure Delayed Effects/pathology , RNA, Messenger/metabolism , Thioredoxin-Disulfide Reductase/genetics , Thioredoxin-Disulfide Reductase/metabolism , Thioredoxins/genetics , Thioredoxins/metabolism
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