ABSTRACT
The objective of the present study was to retrospectively evaluate hair mercury (Hg) content in reproductive-age women living in Central Russia (Moscow and Moscow region), and to calculate the potential costs of the potential Hg-induced IQ loss in a hypothetical national birth cohort. MATERIALS AND METHODS: A total of 36,263 occupationally non-exposed women aged between 20 and 40 years living in Moscow (n = 30,626) or Moscow region (n = 5637) in the period between 2005 and 2021 participated in this study. Hair Hg content was evaluated with inductively coupled plasma-mass spectrometry (ICP-MS). Hair Hg levels in reproductive-age women were used for assessment of the potential IQ loss and its costs. RESULTS: The results demonstrate that hair Hg content in the periods between 2010 and 2015, and 2016-2021 was significantly lower than that in 2005-2009 by 26â¯% and 51â¯%, respectively. The highest hair Hg level was observed in women in 2005 (0.855⯵g/g), being more than 2.5-fold higher than the lowest value observed in 2020 (0.328⯵g/g). Multiple regression analysis revealed a significant inverse association between the year of analysis and hair Hg content (ß = -0.288; p < 0.001). The calculations demonstrate that in 2005 the costs of IQ loss in children exceeded 1.0 (1.6) billion USD, whereas in 2020 the costs of IQ loss accounted to approximately 0.15 (0.28) billion USD. CONCLUSION: Taken together, our data demonstrate that Hg accumulation in reproductive-age women reduced significantly in Russia from 2005 to 2021 resulting in predicted economic benefits by decreasing the costs of Hg-induced IQ loss.
Subject(s)
Hair , Mercury , Humans , Female , Hair/chemistry , Mercury/analysis , Adult , Russia , Young Adult , Intelligence/drug effects , Retrospective StudiesABSTRACT
The objective of the present review was to provide a timely update on the molecular mechanisms underlying the beneficial role of Se in Alzheimer's disease pathogenesis, and discuss the potential role of gut microbiota modulation in this neuroprotective effect. The existing data demonstrate that selenoproteins P, M, S, R, as well as glutathione peroxidases and thioredoxin reductases are involved in regulation of Aß formation and aggregation, tau phosphorylation and neurofibrillary tangles formation, as well as mitigate the neurotoxic effects of Aß and phospho-tau. Correspondingly, supplementation with various forms of Se in cellular and animal models of AD was shown to reduce Aß formation, tau phosphorylation, reverse the decline in brain antioxidant levels, inhibit neuronal oxidative stress and proinflammatory cytokine production, improve synaptic plasticity and neurogenesis, altogether resulting in improved cognitive functions. In addition, most recent findings demonstrate that these neuroprotective effects are associated with Se-induced modulation of gut microbiota. In animal models of AD, Se supplementation was shown to improve gut microbiota biodiversity with a trend to increased relative abundance of Lactobacillus, Bifidobacterium, and Desulfivibrio, while reducing that of Lachnospiracea_NK4A136, Rikenella, and Helicobacter. Moreover, the relative abundance of Se-affected taxa was significantly associated with Aß accumulation, tau phosphorylation, neuronal oxidative stress, and neuroinflammation, indicative of the potential role of gut microbiota to mediate the neuroprotective effects of Se in AD. Hypothetically, modulation of gut microbiota along with Se supplementation may improve the efficiency of the latter in AD, although further detailed laboratory and clinical studies are required.
ABSTRACT
Aluminum (Al) is known to induce neurotoxic effects, potentially contributing to Alzheimer's disease (AD) pathogenesis. Recent studies suggest that epigenetic modification may contribute to Al neurotoxicity, although the mechanisms are still debatable. Therefore, the objective of the present study was to summarize existing data on the involvement of epigenetic mechanisms in Al-induced neurotoxicity, especially AD-type pathology. Existing data demonstrate that Al exposure induces disruption in DNA methylation, histone modifications, and non-coding RNA expression in brains. Alterations in DNA methylation following Al exposure were shown to be mediated by changes in expression and activity of DNA methyltransferases (DNMTs) and ten-eleven translocation proteins (TETs). Al exposure was shown to reduce histone acetylation by up-regulating expression of histone deacetylases (HDACs) and impair histone methylation, ultimately contributing to down-regulation of brain-derived neurotrophic factor (BDNF) expression and activation of nuclear factor κB (NF-κB) signaling. Neurotoxic effects of Al exposure were also associated with aberrant expression of non-coding RNAs, especially microRNAs (miR). Al-induced patterns of miR expression were involved in development of AD-type pathology by increasing amyloid ß (Aß) production through up-regulation of Aß precursor protein (APP) and ß secretase (BACE1) expression (down-regulation of miR-29a/b, miR-101, miR-124, and Let-7c expression), increasing in neuroinflammation through NF-κB signaling (up-regulation of miR-9, miR-125b, miR-128, and 146a), as well as modulating other signaling pathways. Furthermore, reduced global DNA methylation, altered histone modification, and aberrant miRNA expression were associated with cognitive decline in Al-exposed subjects. However, further studies are required to evaluate the contribution of epigenetic mechanisms to Al-induced neurotoxicity and/or AD development.
ABSTRACT
Glioblastoma (GBM) is an aggressive form of cancer affecting the Central Nervous System (CNS) of thousands of people every year. Redox alterations have been shown to play a key role in the development and progression of these tumors as Reactive Oxygen Species (ROS) formation is involved in the modulation of several signaling pathways, transcription factors, and cytokine formation. The second-generation oral alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic drug used to treat of GBM, though patients often develop primary and secondary resistance, reducing its efficacy. Antioxidants represent promising and potential coadjutant agents as they can reduce excessive ROS formation derived from chemo- and radiotherapy, while decreasing pharmacological resistance. S-allyl-cysteine (SAC) has been shown to inhibit the proliferation of several types of cancer cells, though its precise antiproliferative mechanisms remain poorly investigated. To date, SAC effects have been poorly explored in GBM cells. Here, we investigated the effects of SAC in vitro, either alone or in combination with TMZ, on several toxic and modulatory endpoints-including oxidative stress markers and transcriptional regulation-in two glioblastoma cell lines from rats, RG2 and C6, to elucidate some of the biochemical and cellular mechanisms underlying its antiproliferative properties. SAC (1-750 µM) decreased cell viability in both cell lines in a concentration-dependent manner, although C6 cells were more resistant to SAC at several of the tested concentrations. TMZ also produced a concentration-dependent effect, decreasing cell viability of both cell lines. In combination, SAC (1 µM or 100 µM) and TMZ (500 µM) enhanced the effects of each other. SAC also augmented the lipoperoxidative effect of TMZ and reduced cell antioxidant resistance in both cell lines by decreasing the TMZ-induced increase in the GSH/GSSG ratio. In RG2 and C6 cells, SAC per se had no effect on Nrf2/ARE binding activity, while in RG2 cells TMZ and the combination of SAC + TMZ decreased this activity. Our results demonstrate that SAC, alone or in combination with TMZ, exerts antitumor effects mediated by regulatory mechanisms of redox activity responses. SAC is also a safe drug for testing in other models as it produces non-toxic effects in primary astrocytes. Combined, these effects suggest that SAC affords antioxidant properties and potential antitumor efficacy against GBM.
ABSTRACT
BACKGROUND: Recent studies indicated that bioactive lipids of phosphatidylcholines (PCs) and lysophosphatidylcholines (LysoPCs) predict unhealthy metabolic phenotypes, but results remain inconsistent. To fill this knowledge gap, we investigated whether essential trace elements affect PC-Lyso PC remodeling pathways and the risk of insulin resistance (IR). METHODS: Anthropometric and blood biochemical data (glucose, insulin, and lipoprotein-associated phospholipase A2 (Lp-PLA2)) were obtained from 99 adults. Blood essential/probably essential trace elements and lipid metabolites were respectively measured by inductively coupled plasma mass spectrometry (ICP-MS), and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). RESULT AND CONCLUSION: Except for LysoPC (O-18:0/0:0), an inverse V shape was observed between body weight and PC and LysoPC species. A Pearson correlation analysis showed that essential/probably-essential metals (Se, Cu, and Ni: r=-0.4â¼-0.7) were negatively correlated with PC metabolites but positively correlated with LysoPC (O-18:0/0:0) (Se, Cu, and Ni: r=0.85-0.64). Quantile-g computation showed that one quantile increase in essential metals was associated with a 2.16-fold increase in serum Lp-PLA2 (ß=2.16 (95â¯% confidence interval (CI): 0.34, 3.98), p=0.023), which are key enzymes involved in PC/Lyso PC metabolism. An interactive analysis showed that compared to those with the lowest levels (reference), individuals with the highest levels of serum PCs (pooled, M2) and the lowest essential/probably essential metals (M1) were associated with a healthier body composition and had a 76â¯% decreased risk of IR (odds ratio (OR)=0.24 (95â¯% CI: 0.06, 0.90), p<0.05). In contrast, increased exposure to LysoPC(O-18:0/0:0) (M2) and essential metals (M2) exhibited an 8.22-times highest risk of IR (OR= 8.22 (2.07, 32.57), p<0.05) as well as an altered body composition. In conclusion, overexposure to essential/probably essential trace elements may promote an unhealthy body weight and IR through modulating PC/LysoPC remodeling pathways.
Subject(s)
Body Composition , Insulin Resistance , Phosphatidylcholines , Trace Elements , Humans , Male , Phosphatidylcholines/blood , Phosphatidylcholines/metabolism , Female , Trace Elements/blood , Trace Elements/metabolism , Adult , Middle Aged , Lysophosphatidylcholines/blood , Lysophosphatidylcholines/metabolismABSTRACT
The objective of the present study was to evaluate hair levels of toxic and essential trace elements and minerals in male and female patients with chronic gout. A total of 223 examinees aged from 27 to 82 years old including 116 healthy controls (64 women and 52 men) and 107 patients with gout (56 women and 51 men) were enrolled in the current cross-sectional study. Analysis of hair toxic and essential trace element and mineral content was performed using inductively-coupled plasma mass-spectrometry. The obtained data demonstrate that hair B, Fe, I, and Mo levels in gout patients were 67%, 8%, 46%, and 21% higher in comparison to the respective control values. Hair Cr and V content in patients was more than twofold higher than in the controls. Hair Mg and Zn levels were found to be 34% and 11% lower when compared to the respective control values. Hair toxic metal and metalloid content was also significantly affected in gout patients. Specifically, hair Al, As, and Pb levels were 24%, 43%, and 33% higher in gout patients than in healthy controls, respectively. Analysis of covariance demonstrated that sex also had a significant influence on hair trace element and mineral levels in gout patients. Specifically, gout-associated overaccumulation of hair trace elements including was more profound in male than in female patients. It is assumed that trace element dysregulation may contribute to gout development and progression, especially in men. However, further studies are required to elucidate this association and the underlying molecular mechanisms.
ABSTRACT
PURPOSE OF REVIEW: Deficiencies in micronutrients persist as widespread global challenges, where supplementation remains a crucial therapeutic approach. This review aims to elucidate the intricate relationships between micronutrient supplementation - specifically iron, selenium (Se), and vitamin D (Vit D) - and gut microbiota composition, investigating their collective impact on host health and disease susceptibility. RECENT FINDINGS: Maintaining balanced iron levels is essential for gut microbiota equilibrium and host health, as both iron deficiency and excess disrupt gut bacterial balance, affecting colon health. Se supplementation can restore and improve the gut microbial balance, influencing health outcomes not only in the gut but also in areas such as neuroprotection in the brain, testicular health, and metabolic syndrome. Clinical and experimental models demonstrate that Vit D modulates the gut microbiome, enhancing anti-inflammatory effects, supporting metabolic health, and potentially reducing the risk of gut-related behavioral changes and diseases. SUMMARY: Findings of this review emphasize that balanced iron levels are essential for maintaining a healthy gut microbiota composition and underscore the beneficial effects of Se and Vit D in modulating the gut microbiome. The interactions between micronutrients and the gut microbiome are complex but may have a broad spectrum of health outcomes.
Subject(s)
Dietary Supplements , Gastrointestinal Microbiome , Iron , Micronutrients , Selenium , Vitamin D , Humans , Gastrointestinal Microbiome/drug effects , Vitamin D/pharmacology , Vitamin D/administration & dosage , Selenium/administration & dosage , Selenium/pharmacology , Micronutrients/pharmacology , AnimalsABSTRACT
The objective of the present study was to review the molecular mechanisms of the adverse effects of environmental pollutants on chondrocytes and extracellular matrix (ECM). Existing data demonstrate that both heavy metals, including cadmium (Cd), lead (Pb), and arsenic (As), as well as organic pollutants, including polychlorinated dioxins and furans (PCDD/Fs) and polychlorinated biphenyls (PCB), bisphenol A, phthalates, polycyclic aromatic hydrocarbons (PAH), pesticides, and certain other organic pollutants that target cartilage ontogeny and functioning. Overall, environmental pollutants reduce chondrocyte viability through the induction apoptosis, senescence, and inflammatory response, resulting in cell death and impaired ECM production. The effects of organic pollutants on chondrocyte development and viability were shown to be mediated by binding to the aryl hydrocarbon receptor (AhR) signaling and modulation of non-coding RNA expression. Adverse effects of pollutant exposures were observed in articular and growth plate chondrocytes. These mechanisms also damage chondrocyte precursors and subsequently hinder cartilage development. In addition, pollutant exposure was shown to impair chondrogenesis by inhibiting the expression of Sox9 and other regulators. Along with altered Runx2 signaling, these effects also contribute to impaired chondrocyte hypertrophy and chondrocyte-to-osteoblast trans-differentiation, resulting in altered endochondral ossification. Several organic pollutants including PCDD/Fs, PCBs and PAHs, were shown to induce transgenerational adverse effects on cartilage development and the resulting skeletal deformities. Despite of epidemiological evidence linking human environmental pollutant exposure to osteoarthritis or other cartilage pathologies, the data on the molecular mechanisms of adverse effects of environmental pollutant exposure on cartilage tissue were obtained from studies in laboratory rodents, fish, or cell cultures and should be carefully extrapolated to humans, although they clearly demonstrate that cartilage should be considered a putative target for environmental pollutant toxicity.
Subject(s)
Chondrocytes , Environmental Pollutants , Osteoarthritis , Humans , Environmental Pollutants/toxicity , Chondrocytes/drug effects , Chondrocytes/pathology , Chondrocytes/metabolism , Osteoarthritis/pathology , Osteoarthritis/chemically induced , Animals , Chondrogenesis/drug effects , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism , Cartilage/drug effects , Cartilage/pathology , Cartilage/metabolism , Receptors, Aryl Hydrocarbon/metabolism , Receptors, Aryl Hydrocarbon/genetics , Metals, Heavy/toxicity , Signal Transduction/drug effectsABSTRACT
The objective of the present narrative review was to synthesize existing clinical and epidemiological findings linking manganese (Mn) exposure biomarkers to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), and to discuss key pathophysiological mechanisms of neurodevelopmental disorders that may be affected by this metal. Existing epidemiological data demonstrated both direct and inverse association between Mn body burden and ASD, or lack of any relationship. In contrast, the majority of studies revealed significantly higher Mn levels in subjects with ADHD, as well as direct relationship between Mn body burden with hyperactivity and inattention scores in children, although several studies reported contradictory results. Existing laboratory studies demonstrated that impaired attention and hyperactivity in animals following Mn exposure was associated with dopaminergic dysfunction and neuroinflammation. Despite lack of direct evidence on Mn-induced neurobiological alterations in patients with ASD and ADHD, a plethora of studies demonstrated that neurotoxic effects of Mn overexposure may interfere with key mechanisms of pathogenesis inherent to these neurodevelopmental disorders. Specifically, Mn overload was shown to impair not only dopaminergic neurotransmission, but also affect metabolism of glutamine/glutamate, GABA, serotonin, noradrenaline, thus affecting neuronal signaling. In turn, neurotoxic effects of Mn may be associated with its ability to induce oxidative stress, apoptosis, and neuroinflammation, and/or impair neurogenesis. Nonetheless, additional detailed studies are required to evaluate the association between environmental Mn exposure and/or Mn body burden and neurodevelopmental disorders at a wide range of concentrations to estimate the potential dose-dependent effects, as well as environmental and genetic factors affecting this association.
ABSTRACT
The existing data demonstrate that probiotic supplementation affords protective effects against neurotoxicity of exogenous (e.g., metals, ethanol, propionic acid, aflatoxin B1, organic pollutants) and endogenous (e.g., LPS, glucose, Aß, phospho-tau, α-synuclein) agents. Although the protective mechanisms of probiotic treatments differ between various neurotoxic agents, several key mechanisms at both the intestinal and brain levels seem inherent to all of them. Specifically, probiotic-induced improvement in gut microbiota diversity and taxonomic characteristics results in modulation of gut-derived metabolite production with increased secretion of SFCA. Moreover, modulation of gut microbiota results in inhibition of intestinal absorption of neurotoxic agents and their deposition in brain. Probiotics also maintain gut wall integrity and inhibit intestinal inflammation, thus reducing systemic levels of LPS. Centrally, probiotics ameliorate neurotoxin-induced neuroinflammation by decreasing LPS-induced TLR4/MyD88/NF-κB signaling and prevention of microglia activation. Neuroprotective mechanisms of probiotics also include inhibition of apoptosis and oxidative stress, at least partially by up-regulation of SIRT1 signaling. Moreover, probiotics reduce inhibitory effect of neurotoxic agents on BDNF expression, on neurogenesis, and on synaptic function. They can also reverse altered neurotransmitter metabolism and exert an antiamyloidogenic effect. The latter may be due to up-regulation of ADAM10 activity and down-regulation of presenilin 1 expression. Therefore, in view of the multiple mechanisms invoked for the neuroprotective effect of probiotics, as well as their high tolerance and safety, the use of probiotics should be considered as a therapeutic strategy for ameliorating adverse brain effects of various endogenous and exogenous agents.
ABSTRACT
Manganese (Mn) overexposure has been associated with the development of neurological damage reminiscent of Parkinson's disease, while the underlying mechanisms have yet to be fully characterized. This study aimed to investigate the mechanisms leading to injury in dopaminergic neurons induced by Mn and identify novel treatment approaches. In the in vivo and in vitro models, ICR mice and dopaminergic neuron-like PC12 cells were exposed to Mn, respectively. We treated them with anti-ferroptotic agents ferrostatin-1 (Fer-1), deferoxamine (DFO), HIF-1α activator dimethyloxalylglycine (DMOG) and inhibitor LW6. We also used p53-siRNA to verify the mechanism underlying Mn-induced neurotoxicity. Fe and Mn concentrations increased in ICR mice brains overexposed to Mn. Additionally, Mn-exposed mice exhibited movement impairment and encephalic pathological changes, with decreased HIF-1α, SLC7A11, and GPX4 proteins and increased p53 protein levels. Fer-1 exhibited protective effects against Mn-induced both behavioral and biochemical changes. Consistently, in vitro, Mn exposure caused ferroptosis-related changes and decreased HIF-1α levels, all ameliorated by Fer-1. Upregulation of HIF-1α by DMOG alleviated the Mn-associated ferroptosis, while LW6 exacerbated Mn-induced neurotoxicity through downregulating HIF-1α. p53 knock-down also rescued Mn-induced ferroptosis without altering HIF-1α protein expression. Mn overexposure resulted in ferroptosis in dopaminergic neurons, mediated through the HIF-1α/p53/SLC7A11 pathway.
Subject(s)
Amino Acid Transport System y+ , Brain , Ferroptosis , Hypoxia-Inducible Factor 1, alpha Subunit , Manganese , Mice, Inbred ICR , Tumor Suppressor Protein p53 , Animals , Ferroptosis/drug effects , PC12 Cells , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Mice , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Manganese/toxicity , Brain/drug effects , Amino Acid Transport System y+/metabolism , Amino Acid Transport System y+/genetics , Rats , Male , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/pathology , Cyclohexylamines/pharmacology , Phenylenediamines/toxicity , Phenylenediamines/pharmacology , Deferoxamine/pharmacology , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Amino Acids, DicarboxylicABSTRACT
The objective of the present review is to discuss epidemiological evidence demonstrating the association between toxic metal (Cd, Pb, Hg, As, Sn, Ti, Tl) exposure and retinal pathology, along with the potential underlying molecular mechanisms. Epidemiological studies demonstrate that Cd, and to a lesser extent Pb exposure, are associated with age-related macular degeneration (AMD), while the existing evidence on the levels of these metals in patients with diabetic retinopathy is scarce. Epidemiological data on the association between other toxic metals and metalloids including mercury (Hg) and arsenic (As), are limited. Clinical reports and laboratory in vivo studies have shown structural alterations in different layers of retina following metal exposure. Examination of retina samples demonstrate that toxic metals can accumulate in the retina, and the rate of accumulation appears to increase with age. Experimental studies in vivo and in vitro studies in APRE-19 and D407 cells demonstrate that toxic metal exposure may cause retinal damage through oxidative stress, apoptosis, DNA damage, mitochondrial dysfunction, endoplasmic reticulum stress, impaired retinogenesis, and retinal inflammation. However, further epidemiological as well as laboratory studies are required for understanding the underlying molecular mechanisms and identifying of the potential therapeutic targets and estimation of the dose-response effects.
Subject(s)
Metals, Heavy , Retina , Humans , Retina/drug effects , Retina/pathology , Retina/metabolism , Metals, Heavy/toxicity , Animals , Oxidative Stress/drug effects , Macular Degeneration/chemically inducedABSTRACT
THE OBJECTIVE: Of the present study was to assess essential trace element and mineral levels in serum, hair, and urine of healthy first-year students from Turkmenistan (n = 73) in comparison to students from Iran (n = 78) or Russia (n = 95). MATERIALS AND METHODS: Examination of foreign students was performed within two days after arrival to Russia during medical examination prior admission to RUDN University. Serum, hair, and urine trace element and mineral levels were assessed with inductively coupled plasma-mass spectrometry (ICP-MS). RESULTS: The data demonstrate that the levels of trace elements and minerals in students from Turkmenistan share high similarity to elemental profiles of students from Iran. In comparison to students from Russia, subjects originating from Iran and Turkmenistan are characterized by lower serum cobalt (Co), chromium (Cr), copper (Cu), manganese (Mn), molybdenum (Mo), selenium (Se), vanadium (V), zinc (Zn) levels, higher urinary Cr, Cu, Fe, Mn, V, and Zn, lower urinary Co and hair Mo, Se, and Zn content. Concomitantly, students from Turkmenistan were characterized by lower urinary Cr and Cu, serum Cu and V levels, higher circulating Zn concentration, as well as the lower hair Cr, Cu, iodine (I) and magnesium (Mg) content in comparison to Iranian subjects. The discriminant analysis demonstrated that hair, serum, and urinary trace element and mineral levels contributed to complete discrimination between the groups of students from different countries. CONCLUSIONS: The high similarity of trace element and mineral status of students from Turkmenistan and Iran is expected to be mediated by similar geochemical conditions in the bordering countries.
Subject(s)
Minerals , Students , Trace Elements , Humans , Trace Elements/blood , Trace Elements/urine , Trace Elements/analysis , Iran , Russia , Male , Female , Minerals/blood , Minerals/urine , Minerals/analysis , Turkmenistan , Hair/chemistry , Young AdultABSTRACT
Mitochondrial dysfunction plays a key role in the development of neurodegenerative disorders. In contrast, the regulation of the endocannabinoid system has been shown to promote neuroprotection in different neurotoxic paradigms. The existence of an active form of the cannabinoid receptor 1 (CB1R) in mitochondrial membranes (mitCB1R), which might exert its effects through the same signaling mechanisms as the cell membrane CB1R, has been shown to regulate mitochondrial activity. Although there is evidence suggesting that some cannabinoids may induce protective effects on isolated mitochondria, substantial evidence on the role of cannabinoids in mitochondria remains to be explored. In this work, we developed a toxic model of mitochondrial dysfunction induced by exposure of brain mitochondria to the succinate dehydrogenase inhibitor 3-nitropropionic acid (3-NP). Mitochondria were also pre-incubated with the endogenous agonist anandamide (AEA) and the synthetic CB1R agonist WIN 55212-2 to evaluate their protective effects. Mitochondrial reduction capacity, reactive oxygen species (ROS) formation, and mitochondrial swelling were assessed as toxic markers. While 3-NP decreased the mitochondrial reduction capacity and augmented mitochondrial ROS formation and swelling, both AEA and WIN 55212-2 ameliorated these toxic effects. To explore the possible involvement of mitCB1R activation on the protective effects of AEA and WIN 55212-2, mitochondria were also pre-incubated in the presence of the selective CB1R antagonist AM281, which completely reverted the protective effects of the cannabinoids to levels similar to those evoked by 3-NP. These results show partial protective effects of cannabinoids, suggesting that mitCB1R activation may be involved in the recovery of compromised mitochondrial activity, related to reduction of ROS formation and further prevention of mitochondrial swelling.
ABSTRACT
Neurodegenerative disorders are chronic brain diseases that affect humans worldwide. Although many different factors are thought to be involved in the pathogenesis of these disorders, alterations in several key elements such as the ubiquitin-proteasome system (UPS), the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, and the endocannabinoid system (ECS or endocannabinoidome) have been implicated in their etiology. Impairment of these elements has been linked to the origin and progression of neurodegenerative disorders, while their potentiation is thought to promote neuronal survival and overall neuroprotection, as proved with several experimental models. These key neuroprotective pathways can interact and indirectly activate each other. In this review, we summarize the neuroprotective potential of the UPS, ECS, and Nrf2 signaling, both separately and combined, pinpointing their role as a potential therapeutic approach against several hallmarks of neurodegeneration.
Subject(s)
Neurodegenerative Diseases , Proteasome Endopeptidase Complex , Humans , Proteasome Endopeptidase Complex/metabolism , Ubiquitin/metabolism , NF-E2-Related Factor 2/metabolism , Cytoplasm/metabolism , Neurodegenerative Diseases/metabolismABSTRACT
The objective of the present study is assessment of serum trace element and amino acid levels in non-alcoholic fatty liver disease (NAFLD) patients with subsequent evaluation of its independent associations with markers of liver injury and metabolic risk. MATERIALS AND METHODS: 140 women aged 20-90 years old with diagnosed NAFLD and 140 healthy women with a respective age range were enrolled in the current study. Analysis of serum and hair levels of trace elements and minerals was performed with inductively-coupled plasma mass-spectrometry (ICP-MS). Serum amino acid concentrations were evaluated by high-pressure liquid chromatography (HPLC) with UV-detection. In addition, routine biochemical parameters including liver damage markers, alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT), were assessed spectrophotometrically. RESULTS: The findings demonstrated that patients with NAFLD were characterized by higher ALT, GGT, lactate dehydrogenase (LDH) and cholinesterase (CE) activity, as well as increased levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and uric acid. NAFLD patients were characterized by reduced serum and hair Co, Se, and Zn levels, as well as hair Cu content and serum Mn concentrations in comparison to controls. Circulating Ala, Cit, Glu, Gly, Ile, Leu, Phe, and Tyr levels in NAFLD patients exceeded those in the control group. Multiple linear regression demonstrated that serum and hair trace element levels were significantly associated with circulating amino acid levels after adjustment for age, BMI, and metabolic parameters including liver damage markers. CONCLUSION: It is proposed that altered trace element handling may contribute to NAFLD pathogenesis through modulation of amino acid metabolism.
Subject(s)
Non-alcoholic Fatty Liver Disease , Trace Elements , Adult , Humans , Female , Young Adult , Middle Aged , Aged , Aged, 80 and over , Trace Elements/analysis , Amino Acids , Minerals , CholesterolABSTRACT
INRODUCTION: Cobalt (Co) is known to interfere with iron (Fe) metabolism that is essential for differentiating male germ cells. Our aim was to study the effect of developmental chronic cobalt exposure on mouse testis through changes in iron homeostasis in adulthood. METHODS: Pregnant ICR mice were exposed to 75 mg (low dose) or 125 mg (high dose)/kg b.w. cobalt chloride (CoCl2) with drinking water for 3 days before delivery and treatment continued until postnatal day 90 of the pups. Age-matched control animals obtained regular tap water. Testes of control and Co-treated mice were processed for immunohistochemistry and inductively coupled plasma mass spectrometry. Sperm count was performed. RESULTS: Chronic CoCl2 administration resulted in significant dose-dependent Co accumulation in sera and testes of the exposed mice. Fe content also showed a significant increase in sera and testes compared to the untreated controls. Surprisingly, testes of low dose-treated mice had â¼ 2.7-fold higher Fe content compared to those exposed to the high dose. A significant dose-dependent reduction in relative testis weight by 18.8% and by 37.7% was found after treatment with low and high dose CoCl2, respectively was found. Our study demonstrated that developmental chronic exposure to CoCl2 affected cellular composition of the testis manifested by germ cell loss and low sperm count, accompanied by altered androgen response in Sertoli cells (loss of stage-specific expression of androgen receptor). A possible mechanism involved is iron accumulation in the testis that was associated with altered ferroportin-hepcidin localization in seminiferous tubules depleted in germ cells. As a protective mechanism for germ cells in condition of iron excess, ferroportin was distributed in Sertoli cells around elongating spermatids. Similar changes in expression of transferrin receptor 1 (TfR1) and divalent metal transporter 1 (DMT1) implied that both factors of testicular Fe homeostasis are closely related. Outside the seminiferous tubules, Leydig cells localized ferroportin, hepcidin, DMT1 and TfR1 thus they could be considered as a main site for iron metabolism. CONCLUSION: Our data suggest that Co exerts its effects on the testis by indirect mechanism possibly through alteration in Fe homeostasis.
Subject(s)
Hepcidins , Testis , Pregnancy , Female , Male , Mice , Animals , Hepcidins/metabolism , Mice, Inbred ICR , Semen/metabolism , Cobalt/pharmacology , Cobalt/metabolism , Iron/metabolismABSTRACT
Mercury is a ubiquitous environmental contaminant and can be found in inorganic (Hg0, Hg+ and Hg2+) and organic forms (chiefly CH3Hg+ or MeHg+). The main route of human, mammals and bird exposure occurs via predatory fish ingestion. Occupational exposure to Hg0 (and Hg2+) can also occur; furthermore, in gold mining areas the exposure to inorganic Hg can also be high. The toxicity of electrophilic forms of Hg (E+Hg) is mediated by disruption of thiol (-SH)- or selenol (-SeH)-containing proteins. The therapeutic approaches to treat methylmercury (MeHg+), Hg0 and Hg2+ are limited. Here we discuss the potential use of ebselen as a potential therapeutic agent to lower the body burden of Hg in man. Ebselen is a safe drug for humans and has been tested in clinical trials (for instance, brain ischemia, noise-induce hearing loss, diabetes complications, bipolar disorders) at doses varying from 400 to 3600 mg per day. Two clinical trials with ebselen in moderate and severe COVID are also approved. Ebselen can be metabolized to an intermediate with -SeH (selenol) functional group, which has a greater affinity to electrophilic Hg (E+Hg) forms than the available thiol-containing therapeutic agents. Accordingly, as observed in vitro and rodent models in vivo, Ebselen exhibited protective effects against MeHg+, indicating its potential as a therapeutic agent to treat MeHg+ overexposure. The combined use of ebselen with thiol-containing molecules (e.g. N-acetylcysteine and enaramide)) is also commented, because they can have synergistic protective effects against MeHg+.