Table 3 Minerals alter PI3K/Akt and/or GSK3 activities

High levels in the body

 Sodium, chloride, potassium

Monkey kidney cells, HeLa cells, human or mouse melanoma, mouse renal distal convoluted tubule cells, ^aWnk4^+/+ and Wnk4^D561A/+ mice, male SD rats.

High salt foods (mainly NaCl) cause potential hyperosmotic stress, which modulates PI3K/Akt/GSK3 activities; increase or decrease phosphorylation of NaCl transporter, regulated via insulin/PI3K pathway by low salt diet or high salt diet; high salt food causes early insulin resistance, stage 0 of the kinase insensitivity (Table 1).

[24, 49–52, 108, 109]

 Calcium

Mouse osteoblast, human thyroid cancer cells, mouse neural crest cells.

Exert effects on PI3K/Akt and/or GSK3 pathway.

[47, 48, 110]

 Manganese sulfate

Mouse macrophages.

Anti-inflammation via PI3K/Akt.

[111]

 Magnesium sulfate

Rats with intestinal ischemia-reperfusion injury.

Protect injury via PI3K/Akt.

[58]

 Fucosylated chondroitin sulfate

T2D mice.

Improve insulin sensitivity via activation of PI3K/Akt.

[59]

 Heparan sulfate

Human normal astrocytes, and malignant gliomas, human breast cancer cells, human umbilical vein endothelial cells, wild type and Syndecan-1−/− mice infected by influenza.

Increase/Reduce PI3K/Akt/ERK signaling, carcinogenesis/anti-cancer and anti-inflammation.

[112–115]

 Magnesium

Brains of Wistar rats, patients with diabetes.

Required for GSK3 activation; EDTA Chelation Therapy decreases CVD events in patients with diabetes.

[116, 117]

 Trace levels in the body

Wistar rats, mouse hepatocytes.

Induce injury regulates PI3K/Akt/GSK3β pathway, whereas aged rats have less sensitivity of the regulation; iron oxide nanoparticles-mediated cytotoxicity related to PI3K/Akt pathway.

[118, 119]

 Iron

 Zinc or copper

Mouse myogenic cells, monkey kidney cells, mouse embryonic fibroblast, human hepatoma cells, human neuroblastoma cells, human prostate epithelial cells.

Stimulates PI3K/Akt signaling, leading to inhibition of GSK3β; zinc deficiency adds Akt signaling.

[120–124]

 Iodine

SD rats.

Required for synthesis of thyroid hormones that activates Akt.

[22]

 Manganese

Mouse microglial cells, human lung epithelial cells.

Induce inducible nitric oxide synthase expression via activation of both MAP kinase and PI3K/Akt pathways; increase the expression of prostaglandin-endoperoxide synthase 2 (COX-2) via p38 and PI3K/Akt.

[125, 126]

 Zinc and manganese

South Hampshire and Merino^b CLN6 sheep.

Increased in the model with reduced expression of ceroid-lipofuscinosis neuronal protein 6, accompanying with activation of Akt/GSK3 signaling (stage 1 of the kinase insensitivity (Table I)), and neurodegeneration.

[127]

 Selenium

Human prostate cancer cells.

Reduce the activities of PI3K/Akt.

[128]

 Aluminum fluoride

Mouse adipose cells.

Induce G-protein-linked PI3K signaling.

[129]

 Fluorine

SD rats.

Accumulation of it relates to increase of PI3K/Akt and p38 and tissue in bone tissue of fluorosis rats.

[130]

 Chromium

Mouse myoblast cells.

Increase expression glucose transporter and insulin receptor, resulting in enhanced glucose uptake.

[131]