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Mitogen-activated protein kinases (MAPKs) are important signal transducing enzymes that are involved in many facets of cellular regulation - gene expression, cell proliferation and programmed cell death (Chang et al, 2001).
- Chang L, Karin M - "Mammalian MAP kinase signalling cascades" Nature 410(6824):37-40 (2001)
Three major MAPK cascades are known, the extracellular signal-regulated protein kinase (ERK) cascade, c-Jun amino-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) cascade, and the p38 MAPK cascade (Strnisková et al., 2002).
- Strnisková M, Barancík M, Ravingerová T - "Mitogen-activated protein kinases and their role in regulation of cellular processes" Gen Physiol Biophys 21(3):231-55 (2002) PMID: 12537349
"The p38 MAPK pathway plays a crucial role in the release of pro-inflammatory cytokines such as IL-6 and has been implicated in acute lung injury and myocardial dysfunction. The overwhelming inflammatory response in COVID-19 infection may be caused by disproportionately upregulated p38 activities....Thus, SARS-CoV-2 may induce overwhelming inflammation by directly activating p38 and downregulating a key inhibitory pathway, while simultaneously taking advantage of p38 activity to replicate. Therapeutic inhibition of p38 could therefore attenuate COVID-19 infection. Interestingly, a prior preclinical study showed protective effects of p38 inhibition in a SARS-CoV mouse model. A number of p38 inhibitors are in the clinical stage and should be considered for clinical trials in serious COVID-19 infection."(Grimes & Grimes, 2020)
Grimes JM, Grimes KV - "p38 MAPK inhibition: A promising therapeutic approach for COVID-19" J Mol Cell Cardiol S0022-2828(20)30189-9 (2020) doi:10.1016/j.yjmcc.2020.05.007
Fung TS, Liu DX - "The ER stress sensor IRE1 and MAP kinase ERK modulate autophagy induction in cells infected with coronavirus infectious bronchitis virus" Virology 533:34-44 (2019) doi: 10.1016/j.virol.2019.05.002. Epub 2019 May 2. PMID: 31082732; PMCID: PMC7112053.
"Fluoride induces oxidative stress through the activation of mitogen activated protein kinase (MAPK) cascade which can lead to cell apoptosis." (Tian et al., 2018)
Tian Y, Xiao Y, Wang B, Sun C, Tang K, Sun F - "Vitamin E and lycopene reduce coal burning fluorosis-induced spermatogenic cell apoptosis via oxidative stress-mediated JNK and ERK signaling pathways" Biosci Rep 38(4):BSR20171003 (2018) doi: 10.1042/BSR20171003. PMID: 29273675; PMCID: PMC6066653.
Chen L, Kuang P, Liu H, Wei Q, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L - "Sodium Fluoride (NaF) Induces Inflammatory Responses Via Activating MAPKs/NF-κB Signaling Pathway and Reducing Anti-inflammatory Cytokine Expression in the Mouse Liver" Biol Trace Elem Res 189(1):157-171 (2019) doi: 10.1007/s12011-018-1458-z. Epub 2018 Jul 30. PMID: 30062462
Chen Q, Wang Z, Xiong Y, Zou X, Liu Z - "Comparative study of p38 MAPK signal transduction pathway of peripheral blood mononuclear cells from patients with coal-combustion-type fluorosis with and without high hair selenium levels" Int J Hyg Environ Health 213(5):381-6 (2010)
Yang L, Jin P, Wang X, Zhou Q, Lin X, Xi S - "Fluoride activates microglia, secretes inflammatory factors and influences synaptic neuron plasticity in the hippocampus of rats" Neurotoxicology 69:108-120 (2018) doi: 10.1016/j.neuro.2018.09.006. Epub 2018 Sep 28. PMID: 30273629
"We found that fluoride exposure activated microglia and increased the expression of DAP12 and TREM2, as well as promoted pro-inflammatory cytokines secretion via ERK/MAPK and P38/MAPK signal pathways."
Xu S, Khoo S, Dang A, Witt S, Do V, Zhen E, Schaefer EM, Cobb MH - "Differential regulation of mitogen-activated protein/ERK kinase (MEK)1 and MEK2 and activation by a Ras-independent mechanism" Mol Endocrinol 11(11):1618-25 (1997) doi: 10.1210/mend.11.11.0010. PMID: 9328344.
https://academic.oup.com/mend/article/1 ... 18/2756758
Caverzasio J, Imai T, Ammann P, Burgener D, Bonjour JP - "Aluminum potentiates the effect of fluoride on tyrosine phosphorylation and osteoblast replication in vitro and bone mass in vivo" J Bone Miner Res 11(1):46-55 (1996)
Anderson NG, Kilgour E, Sturgill TW - "Activation of mitogen-activated protein kinase in BC3H1 myocytes by fluoroaluminate" J Biol Chem 266(16):10131(1991) PMID: 1709925.
NOTE: There are many studies documenting the effects of fluoride on MAPK, including "dental fluorosis" (Zhao et al., 2021).
https://pubmed.ncbi.nlm.nih.gov/?term=f ... &sort=date
Zhao L, Su J, Liu S, Li Y, Xi T, Ruan J, Liang KX, Huang R - "MAP kinase phosphatase MKP-1 regulates p-ERK1/2 signaling pathway with fluoride treatment" Biochem Biophys Res Commun 542:65-72 (2021)
Zhao Y, Pu G, Li Y, Jiang H, Zhang Q, Chen P, Lu Q, Wang M, Yang R - "Serum Levels of CXCR4, SDF-1, MCP-1, NF-κB and ERK1/2 in Patients with Skeletal Fluorosis" Int J Environ Res Public Health 19(24):16555 (2022) doi: 10.3390/ijerph192416555
Fujiwara N, Yamashita S, Okamoto M, Cooley MA, Ozaki K, Everett ET, Suzuki M - "Perfluorooctanoic acid-induced cell death via the dual roles of ROS-MAPK/ERK signaling in ameloblast-lineage cells" Ecotoxicol Environ Saf 260:115089 (2023). doi: 10.1016/j.ecoenv.2023.115089
"Our results in this in vitro study suggest that in addition to fluoride, PFOA itself could affect enamel formation."
There are many studies showing effects of Gq/11 activation on ERK/MAPK pathways.
SEE ALSO: Gq/11. viewtopic.php?f=66&t=1879
"Gq/11 activate multiple downstream signals, including PKC, ERK1/2, Raf, tyrosine kinases, receptor tyrosine kinases (EGFR, PDGF, insulin receptor), nuclear factor κB and reactive oxygen species (ROS)."(Balakumar et al., 2014)
Balakumar P, Jagadeesh G - "A century old renin-angiotensin system still grows with endless possibilities: AT1 receptor signaling cascades in cardiovascular physiopathology" Cell Signal 26(10):2147-60 (2014) doi: 10.1016/j.cellsig.2014.06.011. Epub 2014 Jul 5. PMID: 25007996
"THs induced nongenomically the rapid translocation of protein kinase C (PKC) ζ isoform to cell membranes, extracellular-signal-regulated kinases (ERK1/2) phosphorylation and nuclear factor-κB (NF-κB) activation. The signaling cascade include sphingomyelinases acting up-stream the activation of PKCζ isoform, while ERK and NF-κB are activated downstream this PKC isoenzyme."
(Barreiro et al., 2011)
Barreiro Arcos ML, Sterle HA, Paulazo MA, Valli E, Klecha AJ, Isse B, Pellizas CG, Farias RN, Cremaschi GA - "Cooperative nongenomic and genomic actions on thyroid hormone mediated-modulation of T cell proliferation involve up-regulation of thyroid hormone receptor and inducible nitric oxide synthase expression" J Cell Physiol 226(12):3208-18 (2011) doi: 10.1002/jcp.22681. PMID: 21344381.
https://onlinelibrary.wiley.com/doi/abs ... /jcp.22681