Cellular and Molecular Mechanisms Mediating Methylmercury Neurotoxicity and Neuroinflammation
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SUBMITTER: Novo J
PROVIDER: S-EPMC8003103 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The extent to which postnatal methylmercury exposure contributes to neurobehavioral delays is uncertain. Confounding may occur because the child's dietary exposure likely correlates with the mother's. This conundrum was examined in the Faroese birth cohort 1 born in 1986-1987. Exposure parameters included mercury concentrations in maternal hair at parturition, cord blood, and child blood and hair at the age-7 clinical examination (N=923). In regression analyses, the child's current blood-mercury at age 7 (N=694) showed only weak associations with the neuropsychological test variables, but visuospatial memory revealed a significant negative association. Mutual adjustment caused decreases of the apparent effect of the prenatal exposure. However, such adjustment may lead to underestimations due to the presence of correlated, error-prone exposure variables. In structural equation models, all methylmercury exposure parameters were instead entered into a latent exposure variable that reflected the total methylmercury load. This latent exposure showed significant associations with neurodevelopmental deficits, with prenatal exposure providing the main information. However, postnatal methylmercury exposure appeared to contribute to neurotoxic effects, in particular in regard to visuospatial processing and memory. Thus, addition in the regression analysis of exposure information obtained at a different point in time was not informative and should be avoided. Further studies with better information on exposure profiles are needed to characterize the effects of postnatal methylmercury exposure.
| S-EPMC4066386 | biostudies-literature
Project description:Methylmercury, a worldwide contaminant of fish and seafood, can cause adverse effects on the developing nervous system. However, long-chain n-3 polyunsaturated fatty acids in seafood provide beneficial effects on brain development. Negative confounding will likely result in underestimation of both mercury toxicity and nutrient benefits unless mutual adjustment is included in the analysis.We examined these associations in 176 Faroese children, in whom prenatal methylmercury exposure was assessed from mercury concentrations in cord blood and maternal hair. The relative concentrations of fatty acids were determined in cord serum phospholipids. Neuropsychological performance in verbal, motor, attention, spatial, and memory functions was assessed at 7 years of age. Multiple regression and structural equation models (SEMs) were carried out to determine the confounder-adjusted associations with methylmercury exposure.A short delay recall (in percent change) in the California Verbal Learning Test (CVLT) was associated with a doubling of cord blood methylmercury (-18.9, 95% confidence interval [CI]=-36.3, -1.51). The association became stronger after the inclusion of fatty acid concentrations in the analysis (-22.0, 95% confidence interval [CI]=-39.4, -4.62). In structural equation models, poorer memory function (corresponding to a lower score in the learning trials and short delay recall in CVLT) was associated with a doubling of prenatal exposure to methylmercury after the inclusion of fatty acid concentrations in the analysis (-1.94, 95% CI=-3.39, -0.49).Associations between prenatal exposure to methylmercury and neurobehavioral deficits in memory function at school age were strengthened after fatty acid adjustment, thus suggesting that n-3 fatty acids need to be included in analysis of similar studies to avoid underestimation of the associations with methylmercury exposure.
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Project description:Alzheimer's disease (AD) is the most common neurodegenerative disorder, which is clinically associated with a global cognitive decline and progressive loss of memory and reasoning. According to the prevailing amyloid cascade hypothesis of AD, increased soluble amyloid-? (A?) oligomer levels impair the synaptic functions and augment calcium dyshomeostasis, neuroinflammation, oxidative stress as well as the formation of neurofibrillary tangles at specific brain regions. Emerging new findings related to synaptic dysfunction and initial steps of neuroinflammation in AD have been able to delineate the underlying molecular mechanisms, thus reinforcing the development of new treatment strategies and biomarkers for AD beyond the conventional A?- and tau-targeted approaches. Particularly, the identification and further characterization of disease-associated microglia and their RNA signatures, AD-associated novel risk genes, neurotoxic astrocytes, and in the involvement of complement-dependent pathway in synaptic pruning and loss in AD have set the outstanding basis for further preclinical and clinical studies. Here, we discuss the recent development and the key findings related to the novel molecular mechanisms and targets underlying the synaptotoxicity and neuroinflammation in AD.
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Project description:We evaluated the mechanism by which high-molecular-weight hyaluronan (HMWH) attenuates nociceptor sensitization, in the setting of inflammation. HMWH attenuated mechanical hyperalgesia induced by the inflammatory mediator prostaglandin E2 (PGE2) in male and female rats. Intrathecal administration of an oligodeoxynucleotide antisense (AS-ODN) to mRNA for cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, and intradermal administration of A5G27, a CD44 receptor antagonist, both attenuated antihyperalgesia induced by HMWH. In male rats, HMWH also signals via Toll-like receptor 4 (TLR4), and AS-ODN for TLR4 mRNA administered intrathecally, attenuated HMWH-induced antihyperalgesia. Since HMWH signaling is dependent on CD44 clustering in lipid rafts, we pretreated animals with methyl-β-cyclodextrin (MβCD), which disrupts lipid rafts. MβCD markedly attenuated HMWH-induced antihyperalgesia. Inhibitors for components of intracellular signaling pathways activated by CD44, including phospholipase C and phosphoinositide 3-kinase (PI3K), also attenuated HMWH-induced antihyperalgesia. Furthermore, in vitro application of HMWH attenuated PGE2-induced sensitization of tetrodotoxin-resistant sodium current, in small-diameter dorsal root ganglion neurons, an effect that was attenuated by a PI3K inhibitor. Our results indicate a central role of CD44 signaling in HMWH-induced antihyperalgesia and suggest novel therapeutic targets, downstream of CD44, for the treatment of pain generated by nociceptor sensitization.SIGNIFICANCE STATEMENT High-molecular-weight-hyaluronan (HMWH) is used to treat osteoarthritis and other pain syndromes. In this study we demonstrate that attenuation of inflammatory hyperalgesia by HMWH is mediated by its action at cluster of differentiation 44 (CD44) and activation of its downstream signaling pathways, including RhoGTPases (RhoA and Rac1), phospholipases (phospholipases Cε and Cγ1), and phosphoinositide 3-kinase, in nociceptors. These findings contribute to our understanding of the antihyperalgesic effect of HMWH and support the hypothesis that CD44 and its downstream signaling pathways represent novel therapeutic targets for the treatment of inflammatory pain.
| S-EPMC7486649 | biostudies-literature
Project description:Mechanical forces direct a host of cellular and tissue processes. Although much emphasis has been placed on cell-adhesion complexes as force sensors, the forces must nevertheless be transmitted through the cortical cytoskeleton. Yet how the actin cortex senses and transmits forces and how cytoskeletal proteins interact in response to the forces is poorly understood. Here, by combining molecular and mechanical experimental perturbations with theoretical multiscale modelling, we decipher cortical mechanosensing from molecular to cellular scales. We show that forces are shared between myosin II and different actin crosslinkers, with myosin having potentiating or inhibitory effects on certain crosslinkers. Different types of cell deformation elicit distinct responses, with myosin and ?-actinin responding to dilation, and filamin mainly reacting to shear. Our observations show that the accumulation kinetics of each protein may be explained by its molecular mechanisms, and that protein accumulation and the cell's viscoelastic state can explain cell contraction against mechanical load.
| S-EPMC3838893 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects upper motor neurons (MNs) comprising the corticospinal tract and lower MNs arising from the brain stem nuclei and ventral roots of the spinal cord, leading to fatal paralysis. Currently, there are no effective therapies for ALS. Increasing evidence indicates that neuroinflammation plays an important role in ALS pathogenesis. The neuroinflammation in ALS is characterized by infiltration of lymphocytes and macrophages, activation of microglia and reactive astrocytes, as well as the involvement of complement. In this review, we focus on the key cellular players of neuroinflammation during the pathogenesis of ALS by discussing not only their detrimental roles but also their immunomodulatory actions. We will summarize the pharmacological therapies for ALS that target neuroinflammation, as well as recent advances in the field of stem cell therapy aimed at modulating the inflammatory environment to preserve the remaining MNs in ALS patients and animal models of the disease.
| S-EPMC5567007 | biostudies-literature
Project description:BackgroundHarmful algal blooms (HABs) produce potent neurotoxins that threaten human health, but current regulations may not be protective of sensitive populations. Early life exposure to low levels of the HAB toxin domoic acid (DomA) produces long-lasting behavioral deficits in rodent and primate models; however, the mechanisms involved are unknown. The zebrafish is a powerful in vivo vertebrate model system for exploring cellular processes during development and thus may help to elucidate mechanisms of DomA developmental neurotoxicity.ObjectivesWe used the zebrafish model to investigate how low doses of DomA affect the developing nervous system, including windows of susceptibility to DomA exposure, structural and molecular changes in the nervous system, and the link to behavioral alterations.MethodsTo identify potential windows of susceptibility, DomA (0.09-0.18 ng) was delivered to zebrafish through caudal vein microinjection during distinct periods in early neurodevelopment. Following exposure, structural and molecular targets were identified using live imaging of transgenic fish and RNA sequencing. To assess the functional consequences of exposures, we quantified startle behavior in response to acoustic/vibrational stimuli.ResultsLarvae exposed to DomA at 2 d postfertilization (dpf), but not at 1 or 4 dpf, showed consistent deficits in startle behavior at 7 dpf, including lower responsiveness and altered kinematics. Similarly, myelination in the spinal cord was disorganized after exposure at 2 dpf but not 1 or 4 dpf. Time-lapse imaging revealed disruption of the initial stages of myelination. DomA exposure at 2 dpf down-regulated genes required for maintaining myelin structure and the axonal cytoskeleton.DiscussionThese results in zebrafish reveal a developmental window of susceptibility to DomA-induced behavioral deficits and identify altered gene expression and disrupted myelin structure as possible mechanisms. The results establish a zebrafish model for investigating the mechanisms of developmental DomA toxicity, including effects with potential relevance to exposed sensitive human populations. https://doi.org/10.1289/EHP6652.
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Project description:Breast cancers contain regions of intratumoral hypoxia in which reduced O(2) availability activates the hypoxia-inducible factors HIF-1 and HIF-2, which increase the transcription of genes encoding proteins that are required for many important steps in cancer progression. Recently, HIFs have been shown to play critical roles in the metastasis of breast cancer to the lungs through the transcriptional activation of genes encoding angiopoietin-like 4 and L1 cell adhesion molecule, which promote the extravasation of circulating cancer cells from the lung vasculature, and the lysyl oxidase family members LOX, LOXL2, and LOXL4, which promote invasion and metastatic niche formation. Digoxin, a drug that inhibits HIF-1 activity, blocks primary tumor growth, vascularization, invasion, and metastasis in ex vivo and in vivo assays.
| S-EPMC3449282 | biostudies-literature
Project description:Hemozoin produced by Plasmodium falciparum during malaria infection has been linked to the neurological dysfunction in cerebral malaria. In this study, we determined whether a synthetic form of hemozoin (sHZ) produces neuroinflammation and neurotoxicity in cellular models. Incubation of BV-2 microglia with sHZ (200 and 400 µg/ml) induced significant elevation in the levels of TNFα, IL-6, IL-1β, NO/iNOS, phospho-p65, accompanied by an increase in DNA binding of NF-κB. Treatment of BV-2 microglia with sHZ increased protein levels of NLRP3 with accompanying increase in caspase-1 activity. In the presence of NF-κB inhibitor BAY11-7082 (10 µM), there was attenuation of sHZ-induced release of pro-inflammatory cytokines, NO/iNOS. In addition, increase in caspase-1/NLRP3 inflammasome activation was blocked by BAY11-7082. Pre-treatment with BAY11-7082 also reduced both phosphorylation and DNA binding of the p65 sub-unit. The NLRP3 inhibitor CRID3 (100 µM) did not prevent sHZ-induced release of TNFα and IL-6. However, production of IL-1β, NO/iNOS as well as caspase-1/NLRP3 activity was significantly reduced in the presence of CRID3. Incubation of differentiated neural progenitor (ReNcell VM) cells with sHZ resulted in a reduction in cell viability, accompanied by significant generation of cellular ROS and increased activity of caspase-6, while sHZ-induced neurotoxicity was prevented by N-acetylcysteine and Z-VEID-FMK. Taken together, this study shows that the synthetic form of hemozoin induces neuroinflammation through the activation of NF-κB and NLRP3 inflammasome. It is also proposed that sHZ induces ROS- and caspase-6-mediated neurotoxicity. These results have thrown more light on the actions of malarial hemozoin in the neurobiology of cerebral malaria.
| S-EPMC6764936 | biostudies-literature
Project description:Aging is the most prominent risk factor for late-onset Alzheimer's disease. Aging associates with a chronic inflammatory state both in the periphery and in the central nervous system, the evidence thereof and the mechanisms leading to chronic neuroinflammation being discussed. Nonetheless, neuroinflammation is significantly enhanced by the accumulation of amyloid beta and accelerates the progression of Alzheimer's disease through various pathways discussed in the present review. Decades of clinical trials targeting the 2 abnormal proteins in Alzheimer's disease, amyloid beta and tau, led to many failures. As such, targeting neuroinflammation via different strategies could prove a valuable therapeutic strategy, although much research is still needed to identify the appropriate time window. Active research focusing on identifying early biomarkers could help translating these novel strategies from bench to bedside.
| S-EPMC9915182 | biostudies-literature