ERK/MAPK

A forum investigating the similarities between COVID-19 and fluoride poisoning, thyroid dysfunction and Gq/11 pathways.
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ERK/MAPK

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ERK/MAPK
© 2020 PFPC

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).
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
    https://pubmed.ncbi.nlm.nih.gov/12537349/
COVID-19
"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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112053/

Fluoride:

"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.
https://www.ncbi.nlm.nih.gov/pmc/articles/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
https://pubmed.ncbi.nlm.nih.gov/30062462/

"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."


(Yang et al., 2018)

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
https://pubmed.ncbi.nlm.nih.gov/30273629/

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.
https://www.jbc.org/content/266/16/10131.long

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)
https://pubmed.ncbi.nlm.nih.gov/33493990/

Gq/11

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
https://pubmed.ncbi.nlm.nih.gov/25007996

Thyroid

"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
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ERK/MAPK - TSH

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TSH:

"In vitro experiments further revealed that TSH activated MAPKs (ERK1/2, p38α, and JNK) and IκB/p65 pathways in macrophages and increased inflammatory cytokine production and their recruitment of monocytes."

Yang C, Lu M, Chen W, He Z, Hou X, Feng M, Zhang H, Bo T, Zhou X, Yu Y, Zhang H, Zhao M, Wang L, Yu C, Gao L, Jiang W, Zhang Q, Zhao J - "Thyrotropin aggravates atherosclerosis by promoting macrophage inflammation in plaques" J Exp Med 216(5):1182-1198 (2019) doi: 10.1084/jem.20181473. Epub 2019 Apr 2. PMID: 30940720; PMCID: PMC6504213
https://pubmed.ncbi.nlm.nih.gov/30940720/

TSH level was found to be independently correlated with both carotid plaque prevalence and intima-media thickness.

"However, increased risk of hypercholesterolemia and cardiovascular diseases including atherosclerosis are also found among subclinical hypothyroidism (SH) patients, whose thyroid hormone levels remain normal and only thyroid-stimulating hormone (TSH) levels are increased (Hak et al., 2000; Rodondi et al., 2010; Collet et al., 2014). This suggests that TSH may also play roles in atherosclerosis independent from its influence on thyroid hormones."

"In this study, TSH was found to activate NF-κB and MAPK (ERK1/2, p38, and JNK) pathways in the macrophages. As NF-κB (Kanters et al., 2003, 2004; Goossens et al., 2011; Park et al., 2012) and MAPKs (Ricci et al., 2004; Devries-Seimon et al., 2005; Schneider et al., 2006; Kim et al., 2012; Lou et al., 2013) in macrophages are deeply intertwined in atherosclerosis, they are likely to interact extensively for the atherogenic effect of TSH. As numerous research has revealed critical roles of NF-κB and MAPKs in regulating chemokine expression (Ali et al., 2000; Shahrara et al., 2010; Carmo et al., 2014), it is very likely that MAPKs and NF-κB have cooperated to induce the expression of chemokines in the macrophages, leading to increased monocyte recruitment driven by TSH."
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Dental fluorosis and MAPK

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Note: ERK1/2 is activated via Gq/11.

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)
https://pubmed.ncbi.nlm.nih.gov/33493990/

Abstract

Dental fluorosis is characterized by hypomineralization of tooth enamel caused by ingestion of excessive fluoride during enamel formation. Excess fluoride could have effects on the ERK signaling, which is essential for the ameloblasts differentiation and tooth development. MAP kinase phosphatase-1 (MKP-1) plays a critical role in regulating ERK related kinases. However, the role of MKP-1 in ameloblast and the mechanisms of MKP-1/ERK signaling in the pathogenesis of dental fluorosis are incompletely understood. Here, we adopted an in vitro fluorosis cell model using murine ameloblasts-like LS8 cells by employing sodium fluoride (NaF) as inducer. Using this system, we demonstrated that fluoride exposure led to an inhibition of p-MEK and p-ERK1/2 with a subsequent increase in MKP-1 expression in a dose-dependent manner. We further identified, under high dose fluoride, MKP-1 acted as a negative regulator of the fluoride-induced p-ERK1/2 signaling, leading to downregulation of CREB, c-myc, and Elk-1. Our results identify a novel MKP-1/ERK signaling mechanism that regulates dental fluorosis and provide a framework for studying the molecular mechanisms of intervention and fluorosis remodeling under normal and pathological conditions. MKP-1 inhibitors may prove to be a benefit therapeutic strategy for dental fluorosis treatment.

see also:

"In this study, after exposing mice to NaF, ERK1/2 expression increased significantly, suggesting that fluoride mediates apoptosis in thyroid follicular epithelial cells through the sustained activation of ERK1/2. The daily administration of 50 mg/kg GABA over 14 days significantly inhibited ERK1/2, demonstrating that GABA mitigates fluoride-induced apoptosis by inhibiting the activation of ERK1/2."

Yang H, Xing R, Liu S, Yu H, Li P - "Analysis of the protective effects of γ-aminobutyric acid during fluoride-induced hypothyroidism in male Kunming mice" Pharm Biol 57(1):29-37 (2019)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346718/

SEE ALSO:
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