ArticleJournal of applied toxicology : JAT2011
Manganese modulation of MAPK pathways: effects on upstream mitogen activated protein kinase kinases and mitogen activated kinase phosphatase-1 in microglial cells.
Article in Journal of applied toxicology : JAT, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 28 citations in OpenAlex.
- Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework.Risk analysis : an official publication of the Society for Risk Analysis · 2015Pooled it
- Microglia encapsulation in nanozyme-loaded hydrogels: response to oxidative stress and inflammation.Nanomedicine (London, England) · 2026Article
- Behavioral Alterations in Mice Exposed to Manganese via Drinking Water: Effects of Sex and a Lipopolysaccharide Challenge.Journal of applied toxicology : JAT · 2025Article
- Loss of O-GlcNAcylation modulates mTORC1 and autophagy in β cells, driving diabetes 2 progression.JCI insight · 2024Article
- Neurotoxicity mechanisms of manganese in the central nervous system.Advances in neurotoxicology · 2021Article
- Manganese Accumulation in the Brain via Various Transporters and Its Neurotoxicity Mechanisms.Molecules (Basel, Switzerland) · 2020Review
- Manganese Acts upon Insulin/IGF Receptors to Phosphorylate AKT and Increase Glucose Uptake in Huntington's Disease Cells.Molecular neurobiology · 2020Article
- Microglia amplify inflammatory activation of astrocytes in manganese neurotoxicity.Journal of neuroinflammation · 2017Article
- Inflammatory Activation of Microglia and Astrocytes in Manganese Neurotoxicity.Advances in neurobiology · 2017Review
- Manganese and the Insulin-IGF Signaling Network in Huntington's Disease and Other Neurodegenerative Disorders.Advances in neurobiology · 2017Review
- "Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies".BMC pharmacology & toxicology · 2016Review
- Mitogen-Activated Protein Kinase Phosphatase (MKP)-1 in Nervous System Development and Disease.Molecular neurobiology · 2015Review
- Manganese Is Essential for Neuronal Health.Annual review of nutrition · 2015Review
- Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox.Archives of toxicology · 2013Article
- In vitro manganese exposure disrupts MAPK signaling pathways in striatal and hippocampal slices from immature rats.BioMed research international · 2013Article
- Modulation of interferon-γ-induced glial cell activation by transforming growth factor β1: a role for STAT1 and MAPK pathways.Journal of neurochemistry · 2012Article
- In vivo manganese exposure modulates Erk, Akt and Darpp-32 in the striatum of developing rats, and impairs their motor function.PloS one · 2012Article
- Manganese potentiates LPS-induced heme-oxygenase 1 in microglia but not dopaminergic cells: role in controlling microglial hydrogen peroxide and inflammatory cytokine output.Neurotoxicology · 2011Article
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Multiple studies demonstrate that manganese (Mn) exposure potentiates inflammatory mediator output from activated glia; this increased output is associated with enhanced mitogen activated protein kinase (MAPK: p38, ERK and JNK) activity. We hypothesized that Mn activates MAPK by activating the kinases upstream of MAPK, i.e. MKK-3/6, MKK-1/2 and MKK-4 (responsible for activation of p38, ERK, and JNK, respectively), and/or by inhibiting a major phosphatase responsible for MAPK inactivation, MKP-1. Exposure of N9 microglia to Mn (250 µm), LPS (100 ng ml⁻¹) or Mn + LPS increased MKK-3/6 and MKK-4 activity at 1 h; the effect of Mn + LPS on MKK-4 activation was greater than the rest. At 4 h, Mn, LPS, and Mn + LPS increased MKK-3/6 and MKK-1/2 phosphorylation, whereas MKK-4 was activated only by Mn and Mn + LPS. Besides activating MKK-4 via Ser257/Thr261 phosphorylation, Mn (4 h) prevented MKK-4's phosphorylation on Ser80, which negatively regulates MKK-4 activity. Exposure to Mn or Mn + LPS (1 h) decreased both mRNA and protein expression of MKP-1, the negative MAPK regulator. In addition, we observed that at 4 h, but not at 1 h, a time point coinciding with increased MAPK activity, Mn + LPS markedly increased TNF-α, IL-6 and Cox-2 mRNA, suggesting a delayed effect. The fact that all three major groups of MKKs, MKK-1/2, MKK-3/6 and MKK-4, are activated by Mn suggests that Mn-induced activation of MAPK occurs via traditional mechanisms, which perhaps involve the MAPKs furthest upstream, MKKKs (MAP3Ks). In addition, for all MKKs, Mn-induced activation was persistent at least for 4 h, indicating a long-term effect.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.