Publications by authors named "Michael Aschner"

768 Publications

RPS6 transcriptional modulation in neural tissues of Nauphoeta cinerea during streptozotocin-associated sugar metabolism impairment.

Comp Biochem Physiol B Biochem Mol Biol 2022 Aug 2:110785. Epub 2022 Aug 2.

Department of Biochemistry and Molecular Biology, Center for Natural and Exact Sciences (CCNE), Federal University of Santa Maria, 97105-900 Santa Maria, RS, Brazil.

The use of insects to model molecular events that characterize degenerative conditions was originally met with scepticism. However, the discovery of insect insulin-like peptides in the 1970's and the demonstration of evolutionary conservation of insulin-related signalling from insects to mammals have highlighted the importance and reduced cost of insect models in biomedical research. Here, we expand on our earlier described modelling of streptozotocin-induced brain glucose metabolic disruption in Nauphoeta cinerea, using RNA-sequencing analysis to study transcriptional and genetic signatures of degeneration and stress signalling when glucose levels are elevated in the brain of the lobster cockroach. Nymphs were randomly divided into three groups: Control (0.8% NaCl), and two single streptozotocin injection doses (74 nmol and 740 nmol). The transcriptional analyses featured a dysregulation of 226 genes at high dose STZ treatment and 278 genes at the low dose. Our mRNA-sequencing data showed that ribosomal protein genes were the most upregulated genes at both 74 and 740 nmol STZ treatment. We therefore used RT-qPCR and relative transcriptional methods to validate our proposed mechanism of brain glucose toxicity-induced degeneration in Nauphoeta cinerea, which involved the upregulation of ribosomal proteins and rpS6 regulators (mTORC1, protein kinases, casein kinase 1 and Death-associated protein kinase), the upregulation of MAPK cascades (RAS, ERK, P38 and JNK), alongside the downregulation of the PI3K/AKT cascade. Taken together, this study highlights the remarkable opportunity for Nauphoeta cinerea use as an experimental organism in hyperglycaemia, degeneration, and stress signalling.
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http://dx.doi.org/10.1016/j.cbpb.2022.110785DOI Listing
August 2022

Therapeutic Potential of Marine Peptides in Prostate Cancer: Mechanistic Insights.

Mar Drugs 2022 Jul 22;20(8). Epub 2022 Jul 22.

Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan.

Prostate cancer (PCa) is the leading cause of cancer death in men, and its treatment is commonly associated with severe adverse effects. Thus, new treatment modalities are required. In this context, natural compounds have been widely explored for their anti-PCa properties. Aquatic organisms contain numerous potential medications. Anticancer peptides are less toxic to normal cells and provide an efficacious treatment approach via multiple mechanisms, including altered cell viability, apoptosis, cell migration/invasion, suppression of angiogenesis and microtubule balance disturbances. This review sheds light on marine peptides as efficacious and safe therapeutic agents for PCa.
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http://dx.doi.org/10.3390/md20080466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330892PMC
July 2022

SHH activation restores interneurons and cognitive function in newborns with intraventricular haemorrhage.

Brain 2022 Jul 22. Epub 2022 Jul 22.

Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA.

Premature infants with germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) suffer from neurobehavioral deficits as they enter childhood and adolescence. Yet the underlying mechanisms remain unclear. Impaired development and function of interneurons contribute to neuropsychiatric disorders. Therefore, we hypothesized that the occurrence of IVH would reduce interneuron neurogenesis in the medial ganglionic eminence and diminish the population of parvalbumin+ and somatostatin+ cortical interneurons. Since Sonic Hedgehog promotes the production of cortical interneurons, we also postulated that the activation of Sonic Hedgehog signaling might restore neurogenesis, cortical interneuron population, and neurobehavioral function in premature newborns with IVH. These hypotheses were tested in a preterm rabbit model of IVH and autopsy samples from human preterm infants. We compared premature newborns with and without IVH for intraneuronal progenitors, cortical interneurons, transcription factors regulating neurogenesis, single-cell transcriptome of medial ganglionic eminence, and neurobehavioral functions. We treated premature rabbit kits with adenovirus expressing Sonic Hedgehog (Ad-Shh) or green fluorescence protein gene (Ad-GFP) to determine the effect of Sonic Hedgehog activation on the interneuron production, cortical interneuron population, and neurobehavior. We discovered that IVH reduced the number of Nkx2.1+ and Dlx2+ progenitors in the medial ganglionic eminence of both humans and rabbits by attenuating their proliferation and inducing apoptosis. Moreover, IVH decreased the population of parvalbumin+ and somatostatin+ neurons in the frontal cortex of both preterm infants and kits relative to controls. Sonic hedgehog expression and the downstream transcription factors, including Nkx2.1, Mash1, Lhx6, and Sox 6, were also reduced in kits with IVH. Consistent with these findings, single-cell transcriptomic analyses of medial ganglionic eminence identified a distinct subpopulation of cells exhibiting perturbation in genes regulating neurogenesis, ciliogenesis, mitochondrial function, and MAPK signaling in rabbits with IVH. More importantly, restoration of Sonic Hedgehog level by Ad-Shh treatment ameliorated neurogenesis, cortical interneuron population, and neurobehavioral function in kits with IVH. Additionally, Sonic hedgehog activation alleviated IVH-induced inflammation and several transcriptomic changes in the medial ganglionic eminence. Taken together, IVH reduced intraneuronal production and cortical interneuron population by downregulating Sonic Hedgehog signaling in both preterm rabbits and humans. Notably, activation of Sonic hedgehog signaling restored interneuron neurogenesis, cortical interneurons, and cognitive function in rabbit kits with IVH. These findings highlight disruption in cortical interneurons in IVH and identify a novel therapeutic strategy to restore cortical interneurons and cognitive function in infants with IVH. These studies can accelerate the development of new therapies to enhance the neurodevelopmental outcome of survivors with IVH.
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http://dx.doi.org/10.1093/brain/awac271DOI Listing
July 2022

Neurotoxicity Evaluation of Nanomaterials Using C. elegans: Survival, Locomotion Behaviors, and Oxidative Stress.

Curr Protoc 2022 Jul;2(7):e496

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York.

Nanomaterials are broadly used in a variety of industries and consumer products. However, studies have demonstrated that many nanomaterials, including metal-containing nanoparticles and nanoplastics, have neurotoxic effects. Caenorhabditis elegans (C. elegans) is a widely used model organism with numerous advantages for research, including transparency, short life span, well-characterized nervous system, complete connectome, available genome, and numerous genetic tools. C. elegans has been extensively used to assess the neurotoxicity of multiple chemicals via survival assays, behavioral tests, neuronal morphology studies, and various molecular and mechanistic analyses. However, detailed protocols describing general assays in C. elegans to examine the neurotoxic effects of nanomaterials are limited. Here, we describe protocols for assessing nanomaterial neurotoxicity in C. elegans. We describe the steps for exposure and subsequent evaluation of survival, locomotion behavior, and oxidative stress. Survival and locomotion behavior are measured in wild-type N2 strains to assess acute neurotoxicity. Oxidative stress is used as an endpoint here since it is one of the most predominant and common changes induced by nanomaterials. VP596 nematodes, which express GFP upon activation of skn-1 (the worm homolog of Nrf2), are evaluated for assays of oxidative stress in response to test nanomaterials. These assays can be readily used to quickly examine the neurotoxicity of nanomaterials in vivo, laying the foundation for mechanistic studies of nanomaterials and their impacts on health and physiology. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Exposure of C. elegans to nanomaterials Basic Protocol 2: Survival assessment Basic Protocol 3: Assessment of locomotion behavior Basic Protocol 4: Analysis of oxidative stress.
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http://dx.doi.org/10.1002/cpz1.496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299521PMC
July 2022

The Human LRRK2 Modulates the Age-Dependent Effects of Developmental Methylmercury Exposure in Caenorhabditis elegans.

Neurotox Res 2022 Jul 15. Epub 2022 Jul 15.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Room 209, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.

Methylmercury (MeHg) neurotoxicity exhibits age-dependent effects with a latent and/or persistent neurotoxic effect on aged animals. Individual susceptibility to MeHg neurotoxicity is governed by both exposure duration and genetic factors that can magnify or mitigate the pathologic processes associated with this exposure. We previously showed the G2019S mutation of leucine-rich repeat kinase 2 (LRRK2) modulates the response of worms to high levels of MeHg, mitigating its effect on neuronal morphology in pre-vesicles in cephalic (CEP) dopaminergic neurons. Here we sought to better understand the long-term effects of MeHg exposure at low levels (100-fold lower than that in our previous report) and the modulatory role of the LRRK2 mutation. Worms exposed to MeHg (10 or 50 nM) at the larval stage (L1 stage) were compared at adult stages (young age: day 1 adult; middle age: day 5 adult; old age: day 10 adult) for the swimming speeds in M9 buffer, moving speeds during locomotion on an OP50-seeded plate, and the numbers of CEP dopaminergic pre-vesicles, vesicular structures originating from the dendrites of CEP for exportation of cellular content. In addition, the expression levels of Caenorhabditis elegans homologs of dopamine transporter (dat-1) and tyrosine hydroxylase (cat-2) were also analyzed at these adult stages. Our data showed that swimming speeds were reduced in wild-type worms at the day 10 adult stage at 50 nM MeHg level; yet, reduced swimming speeds were noted in the G2019S LRRK2 transgenic line upon MeHg exposures as low as 10 nM. Compared to locomotor speeds, swimming speeds appear to be more sensitive to the behavioral effects of developmental MeHg exposures, as the locomotor speeds were largely intact and indistinguishable from controls following MeHg exposures. Furthermore, we showed an age-dependent modulation of dat-1 and cat-2 expressions, which could also be modified by the LRRK2 mutation. Although MeHg exposures did not change the number of pre-vesicles, the LRRK2 mutation was associated with increased numbers of pre-vesicles in aged worms. Our data suggest that the latent behavioral effects of MeHg are sensitized by the G2019S LRRK2 mutation, and the underlying mechanism likely involves age-dependent changes in dopaminergic signaling.
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http://dx.doi.org/10.1007/s12640-022-00547-xDOI Listing
July 2022

Thioredoxin Reductase Inhibitors as Potential Antitumors: Mercury Compounds Efficacy in Glioma Cells.

Front Mol Biosci 2022 23;9:889971. Epub 2022 Jun 23.

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.

Glioblastoma multiforme (GBM) is the most aggressive and common form of glioma. GBM, like many other tumors, expresses high levels of redox proteins, such as thioredoxin (Trx) and thioredoxin reductase (TrxR), allowing tumor cells to cope with high levels of reactive oxygen species (ROS) and resist chemotherapy and radiotherapy. Thus, tackling the activity of these enzymes is a strategy to reduce cell viability and proliferation and most importantly achieve tumor cell death. Mercury (Hg) compounds are among the most effective inhibitors of TrxR and Trx due to their high affinity for binding thiols and selenols. Moreover, organomercurials such as thimerosal, have a history of clinical use in humans. Thimerosal effectively crosses the blood-brain barrier (BBB), thus reaching effective concentrations for the treatment of GBM. Therefore, this study evaluated the effects of thimerosal (TmHg) and its metabolite ethylmercury (EtHg) over the mouse glioma cell line (GL261), namely, the inhibition of the thioredoxin system and the occurrence of oxidative cellular stress. The results showed that both TmHg and EtHg increased oxidative events and triggered cell death primarily by apoptosis, leading to a significant reduction in GL261 cell viability. Moreover, the cytotoxicity of TmHg and ETHg in GL261 was significantly higher when compared to temozolomide (TMZ). These results indicate that EtHg and TmHg have the potential to be used in GBM therapy since they strongly reduce the redox capability of tumor cells at exceedingly low exposure levels.
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http://dx.doi.org/10.3389/fmolb.2022.889971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9260667PMC
June 2022

The Therapeutic Potential of Kaemferol and Other Naturally Occurring Polyphenols Might Be Modulated by Nrf2-ARE Signaling Pathway: Current Status and Future Direction.

Molecules 2022 Jun 28;27(13). Epub 2022 Jun 28.

Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University, P.le Aldo Moro 5, 00185 Rome, Italy.

Kaempferol is a natural flavonoid, which has been widely investigated in the treatment of cancer, cardiovascular diseases, metabolic complications, and neurological disorders. Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor involved in mediating carcinogenesis and other ailments, playing an important role in regulating oxidative stress. The activation of Nrf2 results in the expression of proteins and cytoprotective enzymes, which provide cellular protection against reactive oxygen species. Phytochemicals, either alone or in combination, have been used to modulate Nrf2 in cancer and other ailments. Among them, kaempferol has been recently explored for its anti-cancer and other anti-disease therapeutic efficacy, targeting Nrf2 modulation. In combating cancer, diabetic complications, metabolic disorders, and neurological disorders, kaempferol has been shown to regulate Nrf2 and reduce redox homeostasis. In this context, this review article highlights the current status of the therapeutic potential of kaempferol by targeting Nrf2 modulation in cancer, diabetic complications, neurological disorders, and cardiovascular disorders. In addition, we provide future perspectives on kaempferol targeting Nrf2 modulation as a potential therapeutic approach.
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http://dx.doi.org/10.3390/molecules27134145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268049PMC
June 2022

How Curcumin Targets Inflammatory Mediators in Diabetes: Therapeutic Insights and Possible Solutions.

Molecules 2022 Jun 24;27(13). Epub 2022 Jun 24.

Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University, Piazzale Aldo Moro 5, 00185 Rome, Italy.

Diabetes mellitus is a multifactorial chronic metabolic disorder, characterized by altered metabolism of macro-nutrients, such as fats, proteins, and carbohydrates. Diabetic retinopathy, diabetic cardiomyopathy, diabetic encephalopathy, diabetic periodontitis, and diabetic nephropathy are the prominent complications of diabetes. Inflammatory mediators are primarily responsible for these complications. Curcumin, a polyphenol derived from turmeric, is well known for its anti-oxidant, anti-inflammatory, and anti-apoptotic properties. The regulation of several signaling pathways effectively targets inflammatory mediators in diabetes. Curcumin's anti-inflammatory and anti-oxidative activities against a wide range of molecular targets have been shown to have therapeutic potential for a variety of chronic inflammatory disorders, including diabetes. Curcumin's biological examination has shown that it is a powerful anti-oxidant that stops cells from growing by releasing active free thiol groups at the target location. Curcumin is a powerful anti-inflammatory agent that targets inflammatory mediators in diabetes, and its resistant form leads to better therapeutic outcomes in diabetes complications. Moreover, Curcumin is an anti-oxidant and NF-B inhibitor that may be useful in treating diabetes. Curcumin has been shown to inhibit diabetes-related enzymes, such as a-glucosidase, aldose reductase and aldose reductase inhibitors. Through its anti-oxidant and anti-inflammatory effects, and its suppression of vascular endothelial development and nuclear transcription factors, curcumin has the ability to prevent, or reduce, the course of diabetic retinopathy. Curcumin improves insulin sensitivity by suppressing phosphorylation of ERK/JNK in HG-induced insulin-resistant cells and strengthening the PI3K-AKT-GSK3B signaling pathway. In the present article, we aimed to discuss the anti-inflammatory mechanisms of curcumin in diabetes regulated by various molecular signaling pathways.
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http://dx.doi.org/10.3390/molecules27134058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268477PMC
June 2022

Flavonoids Targeting the mTOR Signaling Cascades in Cancer: A Potential Crosstalk in Anti-Breast Cancer Therapy.

Oxid Med Cell Longev 2022 27;2022:4831833. Epub 2022 Jun 27.

Department of Physiology and Pharmacology "Vittorio Erspamer" Sapienza University, 00185 Rome, Italy.

Cancer is one of the leading causes of death worldwide. Breast cancer is the second leading cause of death in women, with triple-negative breast cancer being the most lethal and aggressive form. Conventional therapies, such as radiation, surgery, hormonal, immune, gene, and chemotherapy, are widely used, but their therapeutic efficacy is limited due to adverse side effects, toxicities, resistance, recurrence, and therapeutic failure. Many molecules have been identified and investigated as potential therapeutic agents for breast cancer, with a focus on various signaling pathways. Flavonoids are a versatile class of phytochemicals that have been used in cancer treatment to overcome issues with traditional therapies. Cell proliferation, growth, apoptosis, autophagy, and survival are all controlled by mammalian target of rapamycin (mTOR) signaling. Flavonoids target mTOR signaling in breast cancer, and when this signaling pathway is regulated or deregulated, various signaling pathways provide potential therapeutic means. The role of various flavonoids as phytochemicals in targeting mTOR signaling pathways in breast cancer is highlighted in this review.
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http://dx.doi.org/10.1155/2022/4831833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9252758PMC
July 2022

Single-cell transcriptomics reveals immune dysregulation mediated by IL-17A in initiation of chronic lung injuries upon real-ambient particulate matter exposure.

Part Fibre Toxicol 2022 06 23;19(1):42. Epub 2022 Jun 23.

Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, China.

Background: Long-term exposure to fine particulate matter (PM) increases susceptibility to chronic respiratory diseases, including inflammation and interstitial fibrosis. However, the regulatory mechanisms by which the immune response mediates the initiation of pulmonary fibrosis has yet to be fully characterized. This study aimed to illustrate the interplay between different cell clusters and key pathways in triggering chronic lung injuries in mice following PM exposure.

Results: Six-week-old C57BL/6J male mice were exposed to PM or filtered air for 16 weeks in a real-ambient PM exposure system in Shijiazhuang, China. The transcriptional profiles of whole lung cells following sub-chronic PM exposure were characterized by analysis of single-cell transcriptomics. The IL-17A knockout (IL-17A) mouse model was utilized to determine whether the IL-17 signaling pathway mediated immune dysregulation in PM-induced chronic lung injuries. After 16-week PM exposure, chronic lung injuries with excessive collagen deposition and increased fibroblasts, neutrophils, and monocytes were noted concurrent with a decreased number of major classes of immune cells. Single-cell analysis showed that activation of the IL-17 signaling pathway was involved in the progression of pulmonary fibrosis upon sub-chronic PM exposure. Depletion of IL-17A led to significant decline in chronic lung injuries, which was mainly triggered by reduced recruitment of myeloid-derived suppressor cells (MDSCs) and downregulation of TGF-β.

Conclusion: These novel findings demonstrate that immunosuppression via the IL-17A pathway plays a critical role in the initiation of chronic lung injuries upon sub-chronic PM exposure.
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http://dx.doi.org/10.1186/s12989-022-00483-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9219231PMC
June 2022

Fasting Enhances the Acute Toxicity of Acrylonitrile in Mice via Induction of CYP2E1.

Toxics 2022 Jun 19;10(6). Epub 2022 Jun 19.

Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China.

Cytochrome P450 2E1 (CYP2E1) plays an essential role in the susceptibility to acute acrylonitrile (AN)-induced toxicity. Here, we investigated the toxicity and mechanism of AN in fasting mice and potential underlying mechanisms. Convulsions, loss of righting reflex, and death 4 h after AN treatment were observed and recorded for each group of mice. Relative to ad lib-fed mice, 48 h fasting significantly increased the acute toxicity of AN, as noted by a more rapid onset of convulsions and death. In addition, fasting significantly enhanced CYP2E1-mediated oxidative metabolism of AN, resulting in increased formation of CN (one of the end-metabolites of AN). Moreover, fasting decreased hepatic GSH content, abrogating the detoxification of GSH. However, trans-1,2-dichloroethylene (DCE), a CYP2E1 inhibitor, altered the level of hepatic CYP2E1 activity in response to fasting, reduced the acute toxic symptoms of AN and the content of CN in AN-treated mice. These data establish that fasting predisposes to AN toxicity, attributable to induced CYP2E1 and reduced hepatic GSH.
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http://dx.doi.org/10.3390/toxics10060337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9228628PMC
June 2022

Smoking is associated with altered serum and hair essential metal and metalloid levels in women.

Food Chem Toxicol 2022 Sep 18;167:113249. Epub 2022 Jun 18.

IM Sechenov First Moscow State Medical University (Sechenov University), 119435, Moscow, Russia; Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, 150003, Yaroslavl, Russia. Electronic address:

The objective of the study was to evaluate the association between smoking and essential metal (Co, Cr, Cu, Fe, Mn, V, Zn) and metalloid (Se) levels in hair and serum of adult women using inductively coupled plasma-mass spectrometry (ICP-MS). In this cross-sectional study, a total of 344 women 20-70 years old including 199 smokers and 145 non-smoking women were enrolled. Serum Cu, Fe, and Zn levels in smoking women were found to be 6%, 8%, and 3% lower of levels in non-smokers, respectively. In contrast, circulating Mn, V, and especially Cr concentrations in smoking women exceeded the respective values in non-smoking women by 5%, 14%, and 54%. Hair Fe and Se levels in smoking women were 17% and 23% lower as compared to non-smoking controls, respectively. In multiple regression models, smoking severity was inversely associated with serum and hair Se concentrations, whereas the relationship to serum and hair Cr was positive. In addition, serum Zn and hair Fe levels were found to be inversely associated with the number of cigarettes per day. These findings hypothesize that health hazards of smoking may be at least in part be mediated by alteration in essential metal and metalloid metabolism.
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http://dx.doi.org/10.1016/j.fct.2022.113249DOI Listing
September 2022

Ferroptosis as a mechanism of non-ferrous metal toxicity.

Arch Toxicol 2022 09 21;96(9):2391-2417. Epub 2022 Jun 21.

Laboratory of Molecular Dietetics, IM Sechenov First Moscow State Medical University (Sechenov University), 119435, Moscow, Russia.

Ferroptosis is a recently discovered form of regulated cell death, implicated in multiple pathologies. Given that the toxicity elicited by some metals is linked to alterations in iron metabolism and induction of oxidative stress and lipid peroxidation, ferroptosis might be involved in such toxicity. Although direct evidence is insufficient, certain pioneering studies have demonstrated a crosstalk between metal toxicity and ferroptosis. Specifically, the mechanisms underlying metal-induced ferroptosis include induction of ferritinophagy, increased DMT-1 and TfR cellular iron uptake, mitochondrial dysfunction and mitochondrial reactive oxygen species (mitoROS) generation, inhibition of Xc-system and glutathione peroxidase 4 (GPX4) activity, altogether resulting in oxidative stress and lipid peroxidation. In addition, there is direct evidence of the role of ferroptosis in the toxicity of arsenic, cadmium, zinc, manganese, copper, and aluminum exposure. In contrast, findings on the impact of cobalt and nickel on ferroptosis are scant and nearly lacking altogether for mercury and especially lead. Other gaps in the field include limited studies on the role of metal speciation in ferroptosis and the critical cellular targets. Although further detailed studies are required, it seems reasonable to propose even at this early stage that ferroptosis may play a significant role in metal toxicity, and its modulation may be considered as a potential therapeutic tool for the amelioration of metal toxicity.
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http://dx.doi.org/10.1007/s00204-022-03317-yDOI Listing
September 2022

Developmental lead exposure affects dopaminergic neuron morphology and modifies basal slowing response in Caenorhabditis elegans: Effects of ethanol.

Neurotoxicology 2022 07 17;91:349-359. Epub 2022 Jun 17.

Instituto de Farmacología Experimental de Córdoba-Consejo Nacional de Investigaciones Técnicas (IFEC-CONICET) and Departamento de Farmacología Otto Orsingher, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA Córdoba, Argentina. Electronic address:

Lead (Pb) and ethanol (EtOH) are neurotoxicants that affect the dopaminergic (DAergic) system. We first sought to assess the morphology of the DAergic neurons in the Caenorhabditis elegans BY200 strain. The results demonstrated dose-dependent damage in these neurons induced by developmental Pb exposure. Secondly, transgenic worms exposed to 24 μM Pb and administered with 200 mM EtOH were evaluated in the basal slowing response (BSR). Pb induced impairment in the BSR in the wild-type strain that did not improve in response to EtOH, an effect also observed in strains that lack the DOP-1, DOP-2, and DOP-3 receptors. The animals that overexpress tyrosine hydroxylase (TH), or lack the vesicular transport (VMAT) showed a Pb-induced impairment in the BSR that seemed to improve after EtOH. Interestingly, a dramatic impairment in the BSR was observed in the Pb group in strains lacking the DOP-4 receptor, resembling the response of the TH-deficient strain, an effect that in both cases showed a non-significant reversal by EtOH. These results suggest that the facilitatory effect of EtOH on the impaired BSR observed in Pb-exposed null mutant strains may be the result of a compensatory effect in the altered DAergic synapse present in these animals.
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http://dx.doi.org/10.1016/j.neuro.2022.06.005DOI Listing
July 2022

The role of aquaporin 4 in brain tumors: implications for pathophysiology, diagnosis and therapy.

Mol Biol Rep 2022 Jun 17. Epub 2022 Jun 17.

Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, I.R. of Iran.

Primary brain tumors are a heterogeneous group of tumors that arise from cells intrinsic to the central nervous system (CNS). Aquaporin-4 (AQP4) has been implicated in the pathogenesis of brain tumors. Previous reports have documented a relationship between AQP4 and several molecular pathways associated with the etiology of brain tumors, such as apoptosis, invasion and cell migration. AQP4 affects apoptosis via cytochrome C, Bad and Bcl-2, as well as invasion and migration via IDO1/TDO-Kyn-AhR axis, lncRNA LINC00461, miR-216a, miRNA-320a and MMPs. In addition, inhibition of AQP4 mitigates the progression of brain tumors. This review summarizes current knowledge and evidence regarding the relationship between AQP4 and brain tumors, and the mechanisms involved.
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http://dx.doi.org/10.1007/s11033-022-07656-yDOI Listing
June 2022

Amyloid Beta Peptide-Mediated Alterations in Mitochondrial Dynamics and its Implications for Alzheimer's Disease.

CNS Neurol Disord Drug Targets 2022 06 16. Epub 2022 Jun 16.

Laboratorio de Aminoácidos Excitadores/Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, Mexico City 14269, Mexico.

Alzheimer's disease (AD) is considered the most frequent neurodegenerative disorder worldwide, compromising cognitive function in patients, with an average incidence of 1-3% in the open population. Protein aggregation into amyloidogenic plaques and neurofibrillary tangles, as well as neurodegeneration in the hippocampal and cortical areas represent the neuropathological hallmarks of this disorder. Mechanisms involved in neurodegeneration include protein misfolding, augmented apoptosis, disrupted molecular signaling pathways and axonal transport, oxidative stress, inflammation, and mitochondrial dysfunction, among others. It is precisely through a disrupted energy metabolism that neural cells trigger toxic mechanisms leading to cell death. In this regard, the study of mitochondrial dynamics constitutes a relevant topic to decipher the role of mitochondrial dysfunction in neurological disorders, especially when considering that amyloid beta peptides can target mitochondria. Specifically, amyloid beta (Aβ) peptide, which is known to accumulate in the brain of AD patients, has been shown to disrupt overall mitochondrial metabolism by impairing energy production, mitochondrial redox activity, and calcium homeostasis, thus highlighting its key role for the AD pathogenesis. In this work, we review and discuss recent evidence supporting the concept that mitochondrial dysfunction mediated by amyloid peptides contributes to the development of AD.
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http://dx.doi.org/10.2174/1871527321666220616094036DOI Listing
June 2022

Resveratrol in cancer treatment with a focus on breast cancer.

Curr Mol Pharmacol 2022 Jun 16. Epub 2022 Jun 16.

Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.

Although considerable advances have been made in the early diagnosis and treatment of breast cancer, it is still one of the major causes of global cancer-related death in women over the last several decades. Phytochemicals have been shown to be promising agents in the prevention and treatment of breast cancer. Resveratrol is an important plant-derived polyphenolic compound, with a variety of potent biological activities. It has been suggested that resveratrol can be used in the prevention and treatment of various types of cancer, including breast cancer. Resveratrol can affect numerous signaling pathways in vitro, leading to the induction of cell cycle arrest and apoptosis, suppression of proliferation, reduction of inflammatory responses, and the inhibition of angiogenesis and metastasis. Nevertheless, studies of resveratrol in animal models of breast cancer have so far been disappointing.
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http://dx.doi.org/10.2174/1874467215666220616145216DOI Listing
June 2022

Role of Nrf2 in bisphenol effects: a review study.

Environ Sci Pollut Res Int 2022 Jun 9. Epub 2022 Jun 9.

Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran.

Bisphenols (BPs), the main endocrine-disrupting chemicals used in polycarbonate plastics, epoxy-phenol resins, and some other manufacturers, have been interestingly focused to find their toxic effects in recent years. Due to the strong relation between bisphenols and some crucial receptors such as ERs, AR, glucocorticoid receptor, THRs, ERRs, hPXR, AhR, and etcetera, the disrupting and oncogenic role of these chemicals on reproductive, respiratory, and circulatory systems and a broad group of body tissues have been investigated. BPs induce oxidant enzymes, exert antioxidant enzymes from body cells, and result in the expression of proinflammatory genes, leading to cell apoptosis and inflammation. To maintain the homeostasis of human body cells, Nrf2, the key regulator of oxidative stress (Ashrafizadeh et al., 2020a; Ashrafizadeh et al., 2020c; Boroumand et al., 2018), confronts BP-induced ROS and RNS through the activation of antioxidant enzymes such as SOD1/2, CAT, GSH, GPX, HO-1, and etcetera. Chemicals and drugs such as LUT, NAC, GEN, L-NMMA, PhSe, and GE can regulate the interactions between BPs and Nrf2. Despite the vital role of controlled levels of Nrf2 as an anti-inflammatory and antiapoptotic element, the uncontrolled activity of this transcription factor could lead to cell proliferation and tumorigenesis through NQO1, SLC7a11, Gclm, HMOX1, NQO1 gene activation, and some other genes. To avoid the excessive activity of Nrf2, some protein complexes like CUL3-RBX1-Keap1 (as the primary regulator), β-TrCP, and WDR23 regulate Nrf2's function. It is necessary to note that BPA, as the most famous member, is further reviewed due to its resemblance to the bisphenol family to each other.
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http://dx.doi.org/10.1007/s11356-022-20996-3DOI Listing
June 2022

Can Berberine Serve as a New Therapy for Parkinson's Disease?

Neurotox Res 2022 Aug 6;40(4):1096-1102. Epub 2022 Jun 6.

Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neurodegeneration and deposition of alpha-synuclein. Mechanisms associated with PD etiology include oxidative stress, apoptosis, autophagy, and abnormalities in neurotransmission, to name a few. Drugs used to treat PD have shown significant limitations in their efficacy. Therefore, recent focus has been placed on the potential of active plant ingredients as alternative, complementary, and efficient treatments. Berberine is an isoquinoline alkaloid that has shown promise as a pharmacological treatment in PD, given its ability to modulate several molecular pathway associated with the disease. Here, we review contemporary knowledge supporting the need to further characterize berberine as a potential treatment for PD.
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http://dx.doi.org/10.1007/s12640-022-00526-2DOI Listing
August 2022

Effects of co-exposure to lead and manganese on learning and memory deficits.

J Environ Sci (China) 2022 Nov 1;121:65-76. Epub 2022 Feb 1.

Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address:

Lead (Pb) and manganese (Mn) are common neurotoxins. However, individuals are subject to co-exposures in real life, and it is therefore important to study these metals in combination. Weaning Sprague-Dawley rats were given ad libitum access to drinking water solutions containing Pb (100 mg/L), Mn (2.5 mg/mL) or a mixture, and each treatment had its own minocycline (50 mg/(kg•day)) supplement group. The results showed a significant difference in spatial memory and induction levels of hippocampal long-term potentiation (LTP) in all exposure groups when compared with controls. The combined-exposure group exhibited the most pronounced effect when compared with each of the single-metal exposure groups. Microglia displayed activation at day 3 after exposure alone or in combination, while astrocytes showed activation at day 5, accompanied by decreased expression levels of GLAST, GLT-1, and GS. Furthermore, the levels of glutamate in the synaptic cleft increased significantly. When microglial activation was inhibited by minocycline, the activation of astrocytes and the expression of GLAST, GLT-1, and GS were both reversed. In addition, upon minocycline treatment, hippocampal LTP impairment and cognitive injury were significantly alleviated in each of the exposure groups. These results suggest that combined exposure to Pb and Mn can cause greater effects on cognition and synaptic plasticity when compared to single-metal exposure groups. The reason may involve abnormal activation of microglia leading to excessive regulation of astrocytes, resulting in glutamate reuptake dysfunction in astrocytes and leading to perturbed cognition and synaptic plasticity.
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http://dx.doi.org/10.1016/j.jes.2021.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9163452PMC
November 2022

Deletion of RE1-silencing transcription factor in striatal astrocytes exacerbates manganese-induced neurotoxicity in mice.

Glia 2022 May 31. Epub 2022 May 31.

Department of Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, USA.

Chronic manganese (Mn) overexposure causes a neurological disorder, referred to as manganism, exhibiting symptoms similar to parkinsonism. Dysfunction of the repressor element-1 silencing transcription factor (REST) is associated with various neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Mn-induced neurotoxicity, but its cellular and molecular mechanisms have yet to be fully characterized. Although neuronal REST is known to be neuroprotective, the role of astrocytic REST in neuroprotection remains to be established. We investigated if astrocytic REST in the striatal region of the mouse brain where Mn preferentially accumulates plays a role in Mn-induced neurotoxicity. Striatal astrocytic REST was deleted by infusion of adeno-associated viral vectors containing sequences of the glial fibrillary acidic protein promoter-driven Cre recombinase into the striatum of REST mice for 3 weeks, followed by Mn exposure (30 mg/kg, daily, intranasally) for another 3 weeks. Striatal astrocytic REST deletion exacerbated Mn-induced impairment of locomotor activity and cognitive function with further decrease in Mn-reduced protein levels of tyrosine hydroxylase and glutamate transporter 1 (GLT-1) in the striatum. Astrocytic REST deletion also exacerbated the Mn-induced proinflammatory mediator COX-2, as well as cytokines such as TNF-α, IL-1β, and IL-6, in the striatum. Mn-induced detrimental astrocytic products such as proinflammatory cytokines on neuronal toxicity were attenuated by astrocytic REST overexpression, but exacerbated by REST inhibition in an in vitro model using primary human astrocytes and Lund human mesencephalic (LUHMES) neuronal culture. These findings indicate that astrocytic REST plays a critical role against Mn-induced neurotoxicity by modulating astrocytic proinflammatory factors and GLT-1.
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http://dx.doi.org/10.1002/glia.24226DOI Listing
May 2022

Benchmark dose approach in investigating the relationship between blood metal levels and reproductive hormones: Data set from human study.

Environ Int 2022 07 21;165:107313. Epub 2022 May 21.

Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia. Electronic address:

The main objective of this research was to conduct a dose-response modeling between the internal dose of measured blood Cd, As, Hg, Ni, and Cr and hormonal response of serum testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The study included 207 male participants from subjects of 5 different cohorts (patients with prostate, testicular, and pancreatic cancer, patients suffering from various thyroid and metabolic disorders, as well as healthy volunteers), enrolled from January 2019 to May 2021 at the Clinical Centre of Serbia in Belgrade, Serbia. Benchmark dose-response modeling analysis was performed with the PROAST software version 70.1, showing the hormone levels as quantal data. The averaging technique was applied to compute the Benchmark dose (BMD) interval (BMDI), with benchmark response set at 10%. Dose-response relationships between metal/metalloid blood concentration and serum hormone levels were confirmed for all the investigated metals/metalloid and hormones. The narrowest BMDI was found for Cd-testosterone and Hg-LH pairs, indicative of high confidence in these estimates. Although further research is needed, the observed findings demonstrate that the BMD approach may prove to be significant in the dose-response modeling of human data.
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http://dx.doi.org/10.1016/j.envint.2022.107313DOI Listing
July 2022

Exposing the role of metals in neurological disorders: a focus on manganese.

Trends Mol Med 2022 Jul 22;28(7):555-568. Epub 2022 May 22.

School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA. Electronic address:

Metals are ubiquitous chemical entities involved in a myriad of biological processes. Despite their integral role in sustaining life, overexposure can lead to deleterious neurological outcomes posing a public health concern. Excess exposure to metals has been associated with aberrant neurodevelopmental and neurodegenerative diseases and prominently contributes to environmental risk for neurological disorders. Here, we use manganese (Mn) to exemplify the gap in our understanding of the mechanisms behind acute metal toxicity and their relationship to chronic toxicity and disease. This challenge frustrates understanding of how individual exposure histories translate into preventing and treating brain diseases from childhood through old age. We discuss ways to enhance the predictive value of preclinical models and define mechanisms of chronic, persistent, and latent neurotoxicity.
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http://dx.doi.org/10.1016/j.molmed.2022.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9233117PMC
July 2022

Sex-dependent metal accumulation and immunoexpression of Hsp70 and Nrf2 in rats' brain following manganese exposure.

Environ Toxicol 2022 Sep 21;37(9):2167-2177. Epub 2022 May 21.

Departments of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA.

Manganese (Mn), although important for multiple cellular processes, has posed environmental health concerns due to its neurotoxic effects. In recent years, there have been extensive studies on the mechanism of Mn-induced neuropathology, as well as the sex-dependent vulnerability to its neurotoxic effects. Nonetheless, cellular mechanisms influenced by sex differences in susceptibility to Mn have yet to be adequately characterized. Since oxidative stress is a key mechanism of Mn neurotoxicity, here, we have probed Hsp70 and Nrf2 proteins to investigate the sex-dependent changes following exposure to Mn. Male and female rats were administered intraperitoneal injections of MnCl (10 mg/kg and 25 mg/kg) 48 hourly for a total of eight injections (15 days). We evaluated changes in body weight, as well as Mn accumulation, Nrf2 and Hsp70 expression across four brain regions; striatum, cortex, hippocampus and cerebellum in both sexes. Our results showed sex-specific changes in body-weight, specifically in males but not in females. Additionally, we noted sex-dependent accumulation of Mn in the brain, as well as in expression levels of Nrf2 and Hsp70 proteins. These findings revealed sex-dependent susceptibility to Mn-induced neurotoxicity corresponding to differential Mn accumulation, and expression of Hsp70 and Nrf2 across several brain regions.
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http://dx.doi.org/10.1002/tox.23583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9357062PMC
September 2022

Oxytocin effect in adult patients with autism: An updated systematic review and meta-analysis of randomized controlled trials.

CNS Neurol Disord Drug Targets 2022 May 17. Epub 2022 May 17.

Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.

Introduction: The efficacy of oxytocin in the treatment of autism spectrum disorder (ASD) has not been fully characterized. This systematic review and meta-analysis study evaluated randomized controlled trials (RCTs) on the treatment of intranasally administered oxytocin for autism.

Method: The study was conducted in accordance with the PRISMA statement. Two authors searched Scopus, PubMed/ Medline, Google Scholar, and Web of Science search engines and databases from inception through December 2020. Quality assessment was carried out by with the "ROB-2, Cochrane collaboration's tool". The random-effects model was used for pooled analyses. I2 and Q tests were used to investigate between study heterogeneity. The visual inspection of funnel plots along with the Egger's regression asymmetry test were used to assess the potential sources of publication bias.

Results: Ten RCTs were selected for the systematic review. No study corroborated the efficacy of oxytocin for the treatment of anxiety and repetitive behavior. One out of 4 studies reported clinical improvement in severity, and 1 out of 6 studies indicated improvement in social function. Our meta-analyses findings suggest that oxytocin shows no significant efficacy in the treatment of anxiety (SMD: -0.168, SE= 0.112; 95% CI: -0.387, 0.050, p = 0.132), repetitive behavior (SMD: -0.078, SE= 0.155; 95% CI: -0.382, 0.225, p = 0.614), social function (SMD: -0.018, SE= 0.133; 95% CI: -0.279, 0.242, p = 0.891) and severity (SMD: -0.084, SE= 132; 95% CI: -0.343, 0.175, p = 0.524) of autism. No significant heterogeneity nor publication bias were observed between studies.

Conclusions: Our findings failed to corroborate the efficacy of oxytocin in the treatment of ASD. Nonetheless, given the several limitations of our study, the results should be interpreted cautiously and stimulate future research on this timely topic.
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http://dx.doi.org/10.2174/1871527321666220517112612DOI Listing
May 2022

Therapeutic Role of Carotenoids in Blood Cancer: Mechanistic Insights and Therapeutic Potential.

Nutrients 2022 May 6;14(9). Epub 2022 May 6.

Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan.

Blood cancers are characterized by pathological disorders causing uncontrolled hematological cell division. Various strategies were previously explored for the treatment of blood cancers, including chemotherapy, Car-T therapy, targeting chimeric antigen receptors, and platelets therapy. However, all these therapies pose serious challenges that limit their use in blood cancer therapy, such as poor metabolism. Furthermore, the solubility and stability of anticancer drugs limit efficacy and bio-distribution and cause toxicity. The isolation and purification of natural killer cells during Car-T cell therapy is a major challenge. To cope with these challenges, treatment strategies from phyto-medicine scaffolds have been evaluated for blood cancer treatments. Carotenoids represent a versatile class of phytochemical that offer therapeutic efficacy in the treatment of cancer, and specifically blood cancer. Carotenoids, through various signaling pathways and mechanisms, such as the activation of AMPK, expression of autophagy biochemical markers (p62/LC3-II), activation of Keap1-Nrf2/EpRE/ARE signaaling pathway, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), increased level of reactive oxygen species, cleaved poly (ADP-ribose) polymerase (c-PARP), c-caspase-3, -7, decreased level of Bcl-xL, cycle arrest at the G0/G1 phase, and decreasing STAT3 expression results in apoptosis induction and inhibition of cancer cell proliferation. This review article focuses the therapeutic potential of carotenoids in blood cancers, addressing various mechanisms and signaling pathways that mediate their therapeutic efficacy.
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http://dx.doi.org/10.3390/nu14091949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9104383PMC
May 2022

Methylcyclopentadienyl Manganese Tricarbonyl Alter Behavior and Cause Ultrastructural Changes in the Substantia Nigra of Rats: Comparison with Inorganic Manganese Chloride.

Neurochem Res 2022 Aug 5;47(8):2198-2210. Epub 2022 May 5.

Department of Toxicology, School of Public Health, Guangxi Medical University, No. 22, Shuang-yong Rd., Nanning, 530021, Guangxi, China.

The antiknock additive methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese(Mn) compound. Mn neurotoxicity caused by occupational Mn exposure (mostly inorganic MnCl) is associated with motor and cognitive disturbances, referred to as Manganism. However, the impact of environmentally relevant Mn exposure on MMT-induced Manganism is poorly understood. In this investigation, we studied the effects of MMT on motor function and brain structure, and compared its effects with those of inorganic MnCl. After adaptive feeding for 7 days, male and female Sprague-Dawley (SD) rats in the MMT-treated groups and positive control group were treated for 8 weeks with MMT (1, 2 and 4 mg/kg/i.g.) or MnCl·4HO (200 mg/kg/i.g.). Mn content in blood, liver, spleen and distinct brain regions was determined by inductively coupled plasma-mass spectrometer (ICP-MS). We found that MMT and MnCl exposure led to slower body-weight-gain in female rats, impaired motor and balance function and spatial learning and memory both in male and female rats. HE staining showed that MMT and MnCl led to altered structure of the substantia nigra pars compacta (SNpc), and Nissl staining corroborated MMT's propensity to damage the SNpc both in male and female rat. In addition, Immunostaining of the SNpc showed decreased TH-positive neurons in MMT- and MnCl-treated rats, concomitant with Iba1 activation in microglia. Moreover, no statistically significant difference was noted between the rats in the H-MMT and MnCl groups. In summary, these findings suggest that MMT and MnCl exposure cause ultrastructural changes in the SNpc neurons culminating in altered motor behavior and cognition, suggesting that altered SNpc structure and function may underline the motor and cognitive deficits inherent to Manganism, and accounting for MMT and MnCl's manifestations of atypical parkinsonism.
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http://dx.doi.org/10.1007/s11064-022-03606-zDOI Listing
August 2022

D-Ribose-LCysteine attenuates manganese-induced cognitive and motor deficit, oxidative damage, and reactive microglia activation.

Environ Toxicol Pharmacol 2022 Jul 2;93:103872. Epub 2022 May 2.

Department of Anatomy, Faculty of Basic Medical Sciences, University of Ilorin, Nigeria. Electronic address:

Due to overexposure, manganese (Mn) accumulation in the brain can trigger the inhibition of glutathione synthesis and lead to increased generation of reactive oxygen species (ROS) and oxidative stress. D-Ribose-L-Cysteine (RibCys) has been demonstrated to effectively support glutathione synthesis to scavenge ROS and protect cells from oxidative damage. In the present study, we examined the effects of RibCys on weight changes, cognitive and motor associated activities, oxidative stress markers, striatal and cortical histology, and microglia activation following Mn exposure. Rats were exposed to either saline, Mn or/and RibCys for two weeks. The Mn exposed rats received RibCys either as pre-, co-, or post-treatments. Mn caused a significant decrease in weight, memory and motor activities, increased lactate dehydrogenase level, overexpression of IBA1 reflecting microglia activation, and distortion of the neuronal cytoarchitecture of the striatum and motor cortex, respectively. Interventions with RibCys mitigated Mn-induced neurotoxic events. Our novel study demonstrates that RibCys effectively ameliorates the neurotoxicity following Mn treatment and maybe a therapeutic strategy against the neurological consequences of Mn overexposurec.
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http://dx.doi.org/10.1016/j.etap.2022.103872DOI Listing
July 2022
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