PI3K - Research
Posted: Wed Jan 01, 2025 9:20 am
PFPC Research compiled by W.S. - In Progress
WHAT IS THE PI3K/AKT PATHWAY?
https://www.youtube.com/watch?v=WDVjRU8Ko4A
Neurotoxicity of developmental hypothyroxinemia and hypothyroidism in rats is mediated by the PI3K pathway (Wang et al., 2013).
The PI3K pathway is also a central regulator of mast cell activation.
FLUORIDE:
Ding X, Lai L, Jia Y, Liu X, Hu J, Chen W - "Effects of chronic fluorosis on the expression of VEGF/PI3K/AKT/eNOS in the gingival tissue of rats with orthodontic tooth movement" Exp Ther Med 27(3):121 (2024). doi: 10.3892/etm.2024.12409
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10867716/
"With the extension of the application of orthodontic stress, the mRNA and protein expression levels of VEGF, PI3K, AKT and eNOS in the gingiva of the O and FO groups showed a trend of increasing at first and subsequently decreasing, which corresponds with the tooth movement cycle."
Fan B, Yu Y, Zhang Y - "PI3K-Akt1 expression and its significance in liver tissues with chronic fluorosis" Int J Clin Exp Pathol 8(2):1226-36 (2015)
https://pmc.ncbi.nlm.nih.gov/articles/PMC4396260/
"The expression of PI3K and Akt1 mRNA and proteins was significantly increased in fluorosis hepatocytes...The apoptosis and the intracellular calcium concentration were increased. Therefore, we conclude that PI3K-Akt signaling pathway may be one of the signaling pathways in the pathogenesis of liver injury caused by fluorosis."
Guo L, Yang B, Chen F, Yuan X, Cheng J, Chen X, Zhou Y, Yang X, Li Y, Liu Y, Tang D, Wang F - "Disruption of the SIRT1/PI3K/AKT Signaling Axis Mediates Fluoride-Induced Cardiotoxicity: Evidence from in Vitro and Zebrafish Models" Biol Trace Elem Res (2025) doi: 10.1007/s12011-025-04828-2.
https://pubmed.ncbi.nlm.nih.gov/40963040/
"F induces cardiotoxicity by disrupting the SIRT1/PI3K/AKT signaling pathway, leading to increased oxidative stress, inflammation, and apoptosis."
Jiang X, Zhang L, He Y, Zhang R, Shang X, Xie Y, He M, Zhang Y - "Effect of sodium fluoride on expression of PI3K/Akt signal molecules and apoptosis in human osteosarcoma Saos-2 cells" J Anat (CAS) S01:157 (2021)
http://218.28.6.71:81/Qikan/Article/Det ... 7105193768
"The changes of PI3K-Akt signaling pathway and mitochondrial apoptotic pathway-related molecule FoxO1 were detected after 24 h and 48 h."
Korkmaz R, Yüksek V, Dede S - "The Effects of Sodium Fluoride (NaF) Treatment on the PI3K/Akt Signal Pathway in NRK-52E Cells" Biol Trace Elem Res. 200(7):3294-3302 (2022) doi: 10.1007/s12011-021-02927-4
https://link.springer.com/article/10.10 ... 21-02927-4
"According to the results obtained in the study, the low NaF concentration increased the expression levels of the ERBB2, PI3K, and Akt genes, while the higher concentrations did not significantly affect these levels. The expression of mTOR decreased at all given concentrations. The expression of the TP53 gene did not change at the low concentration, while it increased at the high concentrations."
Kuang P, Deng H, Liu H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L - "Sodium fluoride induces splenocyte autophagy via the mammalian targets of rapamycin (mTOR) signaling pathway in growing mice" Aging (Albany NY) 10(7):1649-1665 (2018). doi: 10.18632/aging.101499
https://pmc.ncbi.nlm.nih.gov/articles/PMC6075432/
"NaF caused inhibition of mTOR activity, which was characterized by down-regulation of PI3K, Akt and mTOR mRNA and protein expression levels."
Li Y, Wang Z, Li J, Yu Y, Wang Y, Jin X, Dong Y, Liu Q, Duan X, Yan N - "Sodium Butyrate Ameliorates Fluorosis-Induced Neurotoxicity by Regulating Hippocampal Glycolysis In Vivo" Biol Trace Elem Res 201(11):5230-5241 (2023) doi: 10.1007/s12011-023-03583-6
https://pubmed.ncbi.nlm.nih.gov/36710293/
"Results suggested that SB [Sodium Butyrate] could ameliorate fluorosis-induced neurotoxicity, which might be linked with its function in regulating glycolysis as well as inhibition of the PI3K/AKT/HIF-1α pathway."
Linghu Y, Deng CN, He L, Wu Q, Xu L, Yu YN - "Fluoride induces osteoblast autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway in vivo and in vitro" Exp Biol Med (Maywood) 248(13):1159-1172 (2023)doi: 10.1177/15353702231191117
https://pmc.ncbi.nlm.nih.gov/articles/PMC10583752/
"These results demonstrate that fluoride induces autophagy in osteoblasts by inhibiting the PI3K/AKT/mTOR signaling pathway, which deepens our understanding of the molecular mechanisms underlying fluoride-induced bone damage and provides a theoretical basis for the prevention and treatment of skeletal fluorosis."
Ma L, Zhang R, Li D, Qiao T, Guo X - "Fluoride regulates chondrocyte proliferation and autophagy via PI3K/AKT/mTOR signaling pathway" Chem Biol Interact 349:109659 (2021)
https://pubmed.ncbi.nlm.nih.gov/34536393/
Ohsaka Y, Nomura Y - "Rat white adipocytes activate p85/p110 PI3K and induce PM GLUT4 in response to adrenoceptor agonists or aluminum fluoride" Physiol Int 103(1):35-48 (2016) doi: 10.1556/036.103.2016.1.4.
https://akjournals.com/view/journals/03 ... le-p35.xml
Parada-Cruz B, Aztatzi-Aguilar OG, Ramírez-Martínez G, Jacobo-Estrada TL, Cárdenas-González M, Escamilla-Rivera V, Martínez-Olivas MA, Narváez-Morales J, Ávila-Rojas SH, Álvarez-Salas LM, Barbier O - "Inflammation- and cancer-related microRNAs in rat renal cortex after subchronic exposure to fluoride" Chem Biol Interact 379:110519 (2023) doi: 10.1016/j.cbi.2023.110519
https://www.sciencedirect.com/science/a ... 9723001862
Pei J, Xu J, Gao Y, Sun H, Lv C, Jiang Y, Sun W, Jiang W, Qu L, Jiang L, Sun D - "Identification of pathogenesis-related microRNA profiles in skeletal fluorosis" Fluoride 52(1):29-41 (2019)
https://www.fluorideresearch.org/epub/files/008.pdf
"Pathway analysis of miRNAs by KEGG revealed the MAPK signaling pathway, pathways in cancer, the PI3K-Akt signaling pathway, proteoglycans in cancer, and the endocytosis pathway to be regulated by the differentially expressed miRNAs."
Qin Z, Yang X, Wang B, Zhang T, Huang Y, Zhang J, Jin Z, Hong F - "Effects of combined fluoride and arsenic exposure on BMP-2, RANK, PI3K, and Akt1 gene transcription levels in rat tooth tissue" Chinese Journal of Industrial Hygiene and Occupational Diseases 35(8):702-708 (2018) Chinese. doi: 10.13213/j.cnki.jeom.2018.18228
"Dental fluorosis was negatively correlated with RANK and PI3K mRNA expression in dental tissue (r=-0.283, -0.273, bothP<0.05)."
Shenoy SP, Sen U, Kapoor S, Ranade AV, Chowdhury CR, Bose B - "Sodium fluoride induced skeletal muscle changes: Degradation of proteins and signaling mechanism" Environ Pollut 242(Pt B):1078-1086 (2018) doi:10.1016/j.envpol.2018.10.03.
https://www.sciencedirect.com/science/a ... 9118325673
"Sodium fluoride at low concentrations causes hypertrophy of the differentiating C2C12 myoblasts and activates PI3K/AKT signaling pathway."
Song C, Zhao J, Fu B, Li D, Mao T, Peng W, Wu H, Zhang Y - "Melatonin-mediated upregulation of Sirt3 attenuates sodium fluoride-induced hepatotoxicity by activating the MT1-PI3K/AKT-PGC-1α signaling pathway" Free Radic Biol Med 112:616-630 (2017) doi: 10.1016/j.freeradbiomed.2017.09.005
https://pubmed.ncbi.nlm.nih.gov/28912098/
Varışlı B, Darendelioğlu E, Caglayan C, Kandemir FM, Ayna A, Genç A, Kandemir Ö - "Hesperidin Attenuates Oxidative Stress, Inflammation, Apoptosis, and Cardiac Dysfunction in Sodium Fluoride-Induced Cardiotoxicity in Rats" Cardiovasc Toxicol 22(8):727-735 (2022). doi: 10.1007/s12012-022-09751-9.
https://pubmed.ncbi.nlm.nih.gov/35606666/
Wang F, Chen F, Song W, Li Y, Wu H, Tian T, Tian M, Tang D, Liu Y - "Sodium Fluoride Exposure Induces Developmental Toxicity and Cardiotoxicity in Zebrafish Embryos" Biol Trace Elem Res. 2024 Sep 17. doi: 10.1007/s12011-024-04381-4
https://pubmed.ncbi.nlm.nih.gov/39287768/
"Gene ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the DEGs showed that cardiac-related pathways, such as actin cytoskeleton regulation, Jak-Stat, PI3k-Akt, and Ras, were activated in the NaF-exposed group."
Wang J , Xu H , Cheng X , Yang J , Yan Z , Ma H , Zhao Y , Ommati MM , Manthari RK , Wang J - "Calcium relieves fluoride-induced bone damage through the PI3K/AKT pathway" Food Funct 11(1):1155-1164 (2020)
https://pubmed.ncbi.nlm.nih.gov/31872845/
Wang F, Liu Y, Li Y, Yang X, Zhao J, Yang B, Tang D, Zhang C, He Z, Ming D, Zhu X - "Combining Network Pharmacology and Experimental Verification to Ascertain the Mechanism of Action of Asparagus officinalis Against the Brain Damage Caused by Fluorosis" Environ Toxicol (2024)10.1002/tox.24382.
https://onlinelibrary.wiley.com/doi/10.1002/tox.24382
"Enrichment analyses showed that 'mitogen-activated protein kinase' (MAPK), 'phosphoinositide 3-kinase/protein kinase B' (PI3K-Akt), 'nuclear factor-kappa B' (NF-κB), and the 'neurotrophin signaling pathway' were the most enriched biological processes and signaling pathways...Upon ASP treatment, expression of silent information regulator (SIRT)1, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), MAPK, NF-κB, PI3K, Akt, and B-cell lymphoma-2 in rat brain tissue increased gradually, whereas that of Bax, caspase-3, and p53 decreased gradually."
Wang F, Li C, Qin Y, Han X, Gao J, Zhang A, Luo P, Pan X - "Analysis of the microRNA Profile of Coal-Burning Endemic Fluorosis Using Deep Sequencing and Bioinformatic Approaches" Bull Environ Contam Toxicol 103(1):56-63 (2019) doi: 10.1007/s00128-019-02660-8
https://link.springer.com/article/10.10 ... 19-02660-8
"KEGG pathway enrichment analyses of downregulated genes revealed that they were mainly enriched in the Ras signaling pathway, the phosphatidylinositol 3-kinase-protein kinase B (PI3K/AKT) signaling pathway, pathways in cancer, endocytosis, the Rap1 signaling pathway, and the mitogen-activated protein kinase (MAPK) signaling pathway."
Wang J, Hu H, Yan Z, Yang J, Zhu Y, Cheng X, Wang J - "Separation and identification of differential protein in rat's bone with fluorosis and calcium supplementation intervention" Chinese Journal of Biotechnology 35(6):1097-1108 (2019) doi: 10.13345/j.cjb.180497
https://www.chndoi.org/Resolution/Handl ... cjb.180497
"These differential proteins are enriched in 38 bone metabolic pathways such as focal adhesion, PI3K-Akt signaling pathway, and AMPK signaling pathway. And the functions of these proteins are mainly related to cytoskeleton, energy metabolism, substance transport, ion channel, and apoptosis. Therefore, it is speculated that calcium may alleviate the fluoride-induced bone damage by regulating the focal adhesion, PI3K-Akt, AMPK and other signaling pathway..."
Yang B, Wang F, Yang X, Yuan X, Yang Y, Chen X, Tian T, Chen F, Tang D, He Z, Liu Y, Li Y - "The Role of SIRT1-BDNF Signaling Pathway in Fluoride-Induced Toxicity for Glial BV-2 Cells" Biol Trace Elem Res (2025) doi: 10.1007/s12011-024-04503-y
https://link.springer.com/article/10.10 ... 24-04503-y
"The fluoride-exposed groups had reduced SIRT1, BDNF, TrkB, PI3K, AKT, and MAPK protein expression levels, and increased FOXO1A protein expression. SRT1720 mitigated the harmful effects of NaF, stimulated cell proliferation and cell cycle progression, decreased apoptosis, reduced oxidative stress and inflammatory factors, elevated SIRT1, BDNF, TrkB, PI3K, AKT, and MAPK protein levels, and suppressed FOXO1A protein expression. The results indicate that NaF potentially harms glial cells by suppressing SIRT1 activation, and SIRT1 significantly mitigated the damage."
Yao SR, Weng QQ, Zhu YY, Liu J, Zhang Y - "Exploring Molecular Mechanisms of Fluoride's Impact on Ameloblasts Based on Transcriptome Sequencing" Journal of Oral Science Research 41(5):420-425 (2025)
https://doi.org/10.13701/j.cnki.kqyxyj.2025.05.011
LS8 ameloblast cells exposed to 1.5 mmol/L NaF for 24 h showed 104 DEGs (34 up, 70 down), with KEGG enrichment implicating PI3K/Akt and MAPK. RT-qPCR and Western blot both indicated decreased PI3K/Akt and ERK (p44/p42 MAPK) signaling activity, supporting these pathways as part of fluoride’s cytotoxic mechanism in ameloblasts.
Yıldız MO, Çelik H, Caglayan C, Kandemir FM, Gür C, Bayav İ, Genç A, Kandemir Ö - "Neuromodulatory effects of hesperidin against sodium fluoride-induced neurotoxicity in rats: Involvement of neuroinflammation, endoplasmic reticulum stress, apoptosis and autophagy" Neurotoxicology 90:197-204 (2022). doi: 10.1016/j.neuro.2022.04.002
https://pubmed.ncbi.nlm.nih.gov/35413380/
"Hesperidin was able to down-regulate the mRNA transcript levels of apoptosis and endoplasmic reticulum stress markers such as caspase-3, Bax, Bcl-2, PERK, IRE1, ATF6, and GRP78 in NaF-induced neurotoxicity. Hesperidin also reduced the adverse effects caused by NaF by modulating the PI3K/Akt/mTOR signaling pathway."
Yu X, Xia L, Zhang S, Zhou G, Li Y, Liu H, Hou C, Zhao Q, Dong L, Cui Y, Zeng Q, Wang A, Liu L - "Fluoride exposure and children's intelligence: Gene-environment interaction based on SNP-set, gene and pathway analysis, using a case-control design based on a cross-sectional study" Environ Int 155:10668 (2021). doi: 10.1016/j.envint.2021.106681
https://www.sciencedirect.com/science/a ... 2021003068
"In pathway level, Alzheimer disease pathway, metabolic pathway, signal transduction pathway, sphingolipid signaling pathway and PI3K-AKT signaling pathway interacted with fluoride on intelligence in men."
Xu S, Xie X, Li C, Liu Z, Zuo D - "Micromolar sodium fluoride promotes osteo/odontogenic differentiation in dental pulp stem cells by inhibiting PI3K/AKT pathway" Arch Oral Biol 131:105265 (2021). doi: 10.1016/j.archoralbio.2021.105265doi: 10.1016/j.archoralbio.2021.105341
https://www.sciencedirect.com/science/a ... 6921002284
"Micromolar NaF can promote the osteo/odontogenic differentiation of DPSCs [dental pulp stem cells] by inhibiting the PI3K/AKT pathway."
Zhang J, Zhu Y, Shi Y, Han Y, Liang C, Feng Z, Zheng H, Eng M, Wang J - "Fluoride-Induced Autophagy via the Regulation of Phosphorylation of Mammalian Targets of Rapamycin in Mice Leydig Cells" J Agric Food Chem 65(40):8966-8976 (2017) doi: 10.1021/acs.jafc.7b03822
https://pubs.acs.org/doi/10.1021/acs.jafc.7b03822
"Fluoride inhibited the phosphorylation of mammalian targets of rapamycin and 4EBP1, which in turn resulted in a decrease in the levels of AKT and PI3K mRNA expression, as well as an elevation of the level of AMPK expression in both testes and primary Leydig cells."
Zhao C - "Effects of chronic fluoride exposure on spatial learning and memory and hippocampal PI3K/Akt/mTOR signaling pathway in second offspring rats" China Med Abstr (Intern Med) 1:20-21 (2024). PFPC Library
http://218.28.6.71:81/Qikan/Article/Det ... 7112355978
"Except for mTOR mRNA in the low-fluoride group, the mRNA and protein expression levels of PI3K, Akt, and mTOR in the hippocampus of rats in all other exposure groups were significantly lower than those in the control group (P < 0.05)...chronic fluoride
exposure can lead to spatial learning and memory impairment in F2 generation rats, and its mechanism of action may be related to the inhibition of the PI3K/Akt/mTOR signaling pathway in the hippocampus."
Zhao T, Lv J, Peng M, Mi J, Zhang S, Liu J, Chen T, Sun Z, Niu R - "Fecal microbiota transplantation and short-chain fatty acids improve learning and memory in fluorosis mice by BDNF-PI3K/AKT pathway" Chem Biol Interact 110786 (2023). doi: 10.1016/j.cbi.2023.110786
https://pubmed.ncbi.nlm.nih.gov/39491142/
"Moreover, the expressions of mRNA in hippocampal BDNF, PDK1, AKT, Bcl-2, and Bcl-xL were downregulated in mice exposed to fluoride, but the levels of PI3K, Bax, Bak, and Caspase-7 mRNA were upregulated. NaF treatment had an increase in PI3K and Caspase-3 protein levels and reduced the expressions of these four proteins, including BDNF, p-PI3K, AKT and p-AKT."
Zhou BH, Tan PP, Jia LS, Zhao WP, Wang JC, Wang HW - "PI3K/AKT signaling pathway involvement in fluoride-induced apoptosis in C2C12 cells" Chemosphere 199:297-302 (2018)
https://pubmed.ncbi.nlm.nih.gov/29448197/
"Fluoride-induced apoptosis in C2C12 cells is related to the PI3K/AKT signaling pathway."
Żwierełło W, Maruszewska A, Skórka-Majewicz M, Wszołek A, Gutowska I - "Is Fluoride Blameless?-The Influence of Fluorine Compounds on the Invasiveness of the Human Glioma-like Cell Line U-87" Int J Mol Sci 25(23):12773 (2024) doi: 10.3390/ijms252312773
https://pmc.ncbi.nlm.nih.gov/articles/PMC11641017/
"For AKT kinase, a substantial 6- to 7-fold increase in the level of phosphorylated AKT protein (pS473) was observed at all tested NaF concentrations compared to the control."
PFAS
Chen Z, Chen Z, Gao S, Shi J, Li X, Sun F - "PFOS exposure destroys the integrity of the blood-testis barrier (BTB) through PI3K/AKT/mTOR-mediated autophagy" Reprod Biol 24(1):100846 (2023) doi: 10.1016/j.repbio.2023.100846 doi: 10.1016/j.repbio.2024.100892
https://www.sciencedirect.com/science/a ... 1X23001183
"Our results demonstrated that exposure to PFOS induced BTB injury and autophagy, as evidenced by increased expression of autophagy-related proteins, accumulation of autophagosomes, observed through representative electron micrographs, and decreased activity of the PI3K/AKT/mTOR pathway. Moreover, treatment with chloroquine, an autophagy inhibitor, alleviated the effects of PFOS on the integrity of TM4 cells in the BTB and the PI3K/AKT/mTOR pathway."
Chen X, Nie X, Mao J, Zhang Y, Yin K, Sun P, Luo J, Liu Y, Jiang S, Sun L - "Perfluorooctane sulfonate mediates secretion of IL-1β through PI3K/AKT NF-кB pathway in astrocytes" Neurotoxicol Teratol 67:65-75 (2018) doi: 10.1016/j.ntt.2018.03.004
https://www.sciencedirect.com/science/a ... 6217302064
Fangninou FF, Yu Z, Li W, Xue L, Yin D - "Metastatic effects of perfluorooctanoic acid (PFOA) on Drosophila melanogaster with metabolic reprogramming and dysrhythmia in a multigenerational exposure scenario" Sci Total Environ 912:169305 (2024) doi: 10.1016/j.scitotenv.2023.169305.
https://pubmed.ncbi.nlm.nih.gov/38103603/
"As one legacy PFAS, perfluorooctanoic acid (PFOA) exposure correlated with various cancers and their mortality...PFOA exposure generated provoked oxidative stress via H2O2 and stimulated antioxidants including glutathione (GSH), catalase (CAT), melatonin, serotonin and cortisol, with downregulations on PI3K/AKT pathways and upregulations on MAPK ones...The present study performed PFOA exposure for 3 consecutive generations. Results showed that the metastasis by PFOA increased over generations, and it was further deteriorated by dysrhythmia."
Gao M, Shen H, Li Q, Gu X, Jia T, Wang Y - "Perfluorooctane sulfonate (PFOS) induces apoptosis and autophagy by inhibition of PI3K/AKT/mTOR pathway in human granulosa cell line KGN" Environ Pollut 344:123333 (2024) doi: 10.1016/j.envpol.2024.123333
https://www.sciencedirect.com/science/a ... 9124000472
"Molecular docking investigations, in conjunction with Western blot experiments, substantiated PFOS's significant inhibition of the PI3K/AKT/mTOR signaling pathway."
Hong J, Du K, Jin H, Chen Y, Jiang Y, Zhang W, Chen D, Zheng S, Cao L - "Evidence of promoting effects of 6:2 Cl-PFESA on hepatocellular carcinoma proliferation in humans: An ideal alternative for PFOS in terms of environmental health?" Environ Int 186:108582 (2024). doi: 10.1016/j.envint.2024.108582
https://www.sciencedirect.com/science/a ... 2024001685
"Both PFOS and 6:2 Cl-PFES) have been shown to activate the PI3K/AKT/mTOR signaling pathway and inhibit necroptosis. This action consequently enhances the proliferation of HCC cells. Our phenotypic assay findings suggest that the tumorigenic potential of 6:2 Cl-PFESA surpasses that of PFOS; in a subcutaneous tumor model using nude mice, the mean tumor weight for the 6:2 Cl-PFESA-treated cohort was 2.33 times that observed in the PFOS cohort (p < 0.01). Despite 6:2 Cl-PFESA being considered a safer substitute for PFOS, the pronounced effects of this chemical on HCC cell growth warrant a thorough assessment of hepatotoxicity risks linked to its usage."
Hong J, Wang X, Jin H, Chen Y, Jiang Y, Du K, Chen D, Zheng S, Cao L - "Environment relevant exposure of perfluorooctanoic acid accelerates the growth of hepatocellular carcinoma cells through mammalian target of rapamycin (mTOR) signal pathway" Environ Pollut 341:122910 (2024) doi: 10.1016/j.envpol.2023.122910
https://www.sciencedirect.com/science/a ... 9123019127
"We systematically evaluated the effects of PFOA on HCC cells and found that PFOA's exposure can selectively activate the PI3K/AKT/mTOR/4E-BP1 signaling pathway...Our work illuminates the obscured domain of PFOA-induced hepatoxicity, shedding light on its ties to hepatocellular carcinoma progression."
Li F, Chen L, Shi S, Hong WJ, Li M, Guo LH - "Perfluorobutanoic acid: A short-chain perfluoroalkyl substance exhibiting estrogenic effects through the estrogen-related receptor γ pathways" J Hazard Mater 485:136947 (2024) doi: 10.1016/j.jhazmat.2024.136947
https://linkinghub.elsevier.com/retriev ... 9424035283
"Furthermore, PFBA up-regulated the proliferation-related factors downstream of ERRγ and inhibited by PI3K/Akt inhibitor LY294002, which also suppressed the cell proliferation induced by PFBA."
Liu Q, Liu Y, Li X, Wang D, Zhang A, Pang J, He J, Chen X, Tang NJ - "Perfluoroalkyl substances promote breast cancer progression via ERα and GPER mediated PI3K/Akt and MAPK/Erk signaling pathways" Ecotoxicol Environ Saf 258:114980 (2023) . doi: 10.1016/j.ecoenv.2023.114980
https://www.sciencedirect.com/science/a ... 1323004840
"Two estrogen receptors (ER), ERα and G protein-coupled estrogen receptor (GPER), mediated the promoting effects of PFOA by activating MAPK/Erk and PI3K/Akt signaling pathways. These pathways were regulated by ERα and GPER in MCF-7 cells or independently by GPER in MDA-MB-231 cells. Overall, our study provides a better overview of the mechanisms associated with PFASs-induced breast cancer development and progression."
Lu YT, Guo ZY, Guo L, He YH, Liu LM, Jiao X, Li YH - "Mitigation PFHxA-induced neurotoxicity in Carassius auratus brain cells by selenium-enriched Bacillus subtilis via the BDNF/PI3K/AKT/GSK-3β pathway" Ecotoxicol Environ Saf 290:117567 (2024). doi: 10.1016/j.ecoenv.2024.117567
https://www.sciencedirect.com/science/a ... 1324016439
"LY294002 and LiCl confirm the crucial role of the PI3K/AKT/GSK-3β in neuroprotection."
Mei J, Jiang J, Li Z, Pan Y, Xu K, Gao X, Yuan J, Li L, Wang Y, Wang L, Zhao A, Jiang S, Wang X, Yi S, Li S, Xue Y, Ma Y, Liu Y, Wang Y, Li J, Chen C, Liu Y - "Increased perfluorooctanoic acid accumulation facilitates the migration and invasion of lung cancer cells via remodeling cell mechanics" Proc Natl Acad Sci U S A 121(51):e2408575121 (2024) doi: 10.1073/pnas.2408575121
https://www.pnas.org/doi/10.1073/pnas.2408575121
"Mechanistically, the interaction between PFOA and transmembrane integrins in cancer cells triggers changes in cellular mechanical properties, leading to the reorganization of the cytoskeleton, and activation of the intracellular FAK-PI3K-Akt signaling pathway. Our findings demonstrate that in individuals with lung adenocarcinoma, PFOA can increase the risk of cancer metastasis even at daily exposure levels."
Oh JH, Kim EY, Choi YH, Nam TJ - "Negative regulation of ERK1/2 by PI3K is required for the protective effects of Pyropia yezoensis peptide against perfluorooctane sulfonate-induced endoplasmic reticulum stress" Mol Med Rep 15(5):2583-2587 (2017). doi: 10.3892/mmr.2017.6285
"These findings indicate that negative regulation of ERK1/2 by PI3K is essential for the protective effects of PYP against PFOS-induced cell death."
Wang X, Li B, Zhao WD, Liu YJ, Shang DS, Fang WG, Chen YH - "Perfluorooctane sulfonate triggers tight junction 'opening' in brain endothelial cells via phosphatidylinositol 3-kinase" Biochem Biophys Res Commun 410(2):258-63 (2011) doi: 10.1016/j.bbrc.2011.05.128
https://www.sciencedirect.com/science/a ... 1X1100903X
"Results demonstrated that PFOS promoted the activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in HBMEC. We found that overexpression of PI3K dominant-negative mutant in HBMEC abolished the PFOS-induced TJ disassembly. These data demonstrated that PFOS can trigger the 'opening' of tight junction in brain endothelial cells through PI3K signaling pathway."
Wu Y, Huang J, Deng M, Jin Y, Yang H, Liu Y, Cao Q, Mennigen JA, Tu W - "Acute exposure to environmentally relevant concentrations of Chinese PFOS alternative F-53B induces oxidative stress in early developing zebrafish" Chemosphere 235:945-951 (2019) doi: 10.1016/j.chemosphere.2019.07.016.
https://linkinghub.elsevier.com/retriev ... 3519314961
"The contents of malondialdehyde (MDA) and reduced glutathione (GSH), as well as the activities, mRNA and protein levels of most of antioxidant enzyme genes involved in the phosphatidylinositol 3-kinase (PI3K)/Akt/Nrf2-ARE pathway were significantly reduced. Further in silico study indicated that F-53B binds tightly to PI3K, which may be related to the inhibition of Nrf2-regulated antioxidant functions by F-53B as a PI3K inhibitor."
Xin Y, Wan B, Yang Y, Cui XJ, Xie YC, Guo LH - "Perfluoroalkyl acid exposure induces protective mitochondrial and endoplasmic reticulum autophagy in lung cells" Arch Toxicol 92(10):3131-3147 (2018) doi: 10.1007/s00204-018-2266-0
https://link.springer.com/article/10.10 ... 018-2266-0
"Analysis on the signaling pathways showed that PFAAs activated the MAPK pathways and inhibited the PI3K/Akt pathway, with potencies following the order of PFDA > PFNA > PFOA. "
Yan S, Zhang H, Zheng F, Sheng N, Guo X, Dai J - "Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice" Sci Rep 5:11029 (2015) doi: 10.1038/srep11029
https://pmc.ncbi.nlm.nih.gov/articles/PMC4464286/
"We report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver."
Zhang QY, Zhong MT, Gi M, Chen YK, Lai MQ, Liu JY, Liu YM, Wang Q, Xie XL - "Inulin alleviates perfluorooctanoic acid-induced intestinal injury in mice by modulating the PI3K/AKT/mTOR signaling pathway" Environ Pollut 342:123090 (2024) doi: 10.1016/j.envpol.2023.123090
https://linkinghub.elsevier.com/retriev ... 23)02092-4
"Inulin restored the intestinal injury by activating the PI3K/AKT/mTOR pathway."
Zhang Q, Wang J, Chen C, Kong Y, Yan H, Duan J, Wang C, Sha Y, Wen X, Wang C - "Perfluorooctanoic acid induces migration and invasion and inhibits apoptosis through the PI3K/AKT signaling pathway in human rhabdomyosarcoma cells" Oncol Rep 42(4):1558-1568 (2019) doi: 10.3892/or.2019.7265.
"The results obtained show that the PI3K/AKT signaling pathway is implicated in mediating the pro‑neoplastic effects of PFOA. The data suggests that PFOA is a carcinogen capable of promoting RD cell migration and invasion and inhibiting apoptosis through the PI3K/AKT signaling pathway."
HYPOTHYROIDISM/PTU
Dong S, Liu Q, Jiang M, Ma Q, Huang Q, Liu T, Li Y, Ni L, Shi Y - "Xiao-Luo-Wan treats propylthiouracil-induced goiter with hypothyroidism in rats through the PI3K-AKT/RAS pathways based on UPLC/MS and network pharmacology" J Ethnopharmacol 289:115045 (2022). doi: 10.1016/j.jep.2022.115045.
https://pubmed.ncbi.nlm.nih.gov/35101570/
Yao Y, Chang X, Wang D, Ma H, Wang H, Zhang H, Li C, Wang J - "Roles of ERK1/2 and PI3K/AKT signaling pathways in mitochondria-mediated apoptosis in testes of hypothyroid rats" Toxicol Res (Camb) 7(6):1214-1224 (2018)
https://pubmed.ncbi.nlm.nih.gov/30542605/
"These results suggested that ERK1/2 and PI3K/AKT signaling pathways could be suppressed by hypothyroidism via inhibiting the expressions of ERs [estrogen receptors] and could finally induce apoptosis in testes."
Wang Y, Wei W, Wang Y, Dong J, Song B, Min H, Teng W, Chen J - "Neurotoxicity of developmental hypothyroxinemia and hypothyroidism in rats: Impairments of long-term potentiation are mediated by phosphatidylinositol 3-kinase signaling pathway" Toxicol Appl Pharmacol 271(2):257-65 (2013). doi: 10.1016/j.taap.2013.04.034
https://www.sciencedirect.com/science/a ... 8X13002184
"Decreased activation of the PI3K signaling pathway was also observed in rats subjected to developmental hypothyroxinemia or hypothyroidism. Our results may support the hypothesis that neurotoxicity of both developmental hypothyroxinemia and hypothyroidism causes damages to learning and memory. Our results also suggest that decreased activation of the PI3K signaling pathway may contribute to impairments of LTP caused by neurotoxicity of both developmental hypothyroxinemia and hypothyroidism."
Zhan Y, Lang L, Wang F, Wu X, Zhang H, Dong Y, Yang H, Zhu D - "Hypothyroidism promotes microglia M1 polarization by inhibiting BDNF-promoted PI3K-Akt signaling pathway" Neuroendocrinology 1-19 (2024) doi: 10.1159/000542858
https://karger.com/nen/article/doi/10.1 ... larization
"Our study demonstrated a sound conclusion that hypothyroidism promotes microglia M1 polarization by inhibiting BDNF-activated PI3K-Akt signaling pathway in brain, which could serve as a promising therapeutic target for microglia-induced neurodegenerative or emotional disorders in future."
TSHr
Voutsadakis IA - "The TSH/Thyroid Hormones Axis and Breast Cancer" J Clin Med. 11(3):687 (2022). doi: 10.3390/jcm11030687
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836919/
"The activation of TSHR in the plasma cell membrane transmits signals through G proteins Gas and Gaq, and downstream through the cAMP/PKA/CREB pathway and the phospholipase C/PI3K/AKT/mTOR pathway. The role of TSHR is established in well-differentiated thyroid cancers, where treatment with T4 to suppress TSH secretion from the hypophysis, in order to prevent TSHR activation, is the mainstay of treatment [69]. TSHR is also expressed in other cancers, such as ovarian carcinomas, hepatomas and melanomas [68,70,71,72]. The expression of TSHR is increased in breast cancer tissues compared to adjacent normal mammary tissues [73]."
Liu C, Li L, Ha M, Qi S, Duan P, Yang K - "The PI3K/Akt and ERK pathways elevate thyroid hormone receptor β1 and TRH receptor to decrease thyroid hormones after exposure to PCB153 and p,p'-DDE" Chemosphere 118:229-38 (2015)
https://pubmed.ncbi.nlm.nih.gov/25278044/
"Taken together, after exposure to PCB153 and p,p'-DDE, activated PI3K/Akt and ERK pathways disrupt the hypothalamic-pituitary-thyroid (HPT) axis via TRβ1 and TRHr and then decrease TH levels, and that would be a potential mechanism by which PCBs and DDT disturb TH homeostasis."
Yao Y, Chang X, Wang D, Ma H, Wang H, Zhang H, Li C, Wang J - "Roles of ERK1/2 and PI3K/AKT signaling pathways in mitochondria-mediated apoptosis in testes of hypothyroid rats" Toxicol Res (Camb) 7(6):1214-1224 (2018)
https://pubmed.ncbi.nlm.nih.gov/30542605/
Chen J, Shi M, Wang N, Yi P, Sun L, Meng Q - "TSH inhibits eNOS expression in HMEC-1 cells through the TSHR/PI3K/AKT signaling pathway" Ann Endocrinol (Paris) 80(5-6):273-279 (2019)
https://pubmed.ncbi.nlm.nih.gov/31606200/
Li B, Smith TJ - "PI3K/AKT pathway mediates induction of IL-1RA by TSH in fibrocytes: modulation by PTEN" J Clin Endocrinol Metab 99(9):3363-72 (2014)
https://pubmed.ncbi.nlm.nih.gov/24840811/
Woeller CF, Roztocil E, Hammond C, Feldon SE - "TSHR Signaling Stimulates Proliferation Through PI3K/Akt and Induction of miR-146a and miR-155 in Thyroid Eye Disease Orbital Fibroblasts" Invest Ophthalmol Vis Sci 60(13):4336-4345 (2019)
https://pubmed.ncbi.nlm.nih.gov/31622470/
García-Jiménez C, Santisteban P - "TSH signalling and cancer" Arq Bras Endocrinol Metabol 51(5):654-71(2007)
https://digital.csic.es/bitstream/10261/2171/1/tsh.pdf
"Oncogenes relevant to thyroid carcinogenesis are normally engaged in proliferation and/or survival pathways, the paradigms are RET/Ras/B-Raf, PTEN/Akt and Ecadherin/β-catenin representing the MAPK, PI3K and Wnt pathways respectively. These pathways are integrated in the thyrocyte signalling network among them and with the cAMP/PKA pathway and altering their crosstalk may lead to carcinogenesis."
Suh JM, Song JH, Kim DW, Kim H, Chung HK, Hwang JH, Kim JM, Hwang ES, Chung J, Han JH, Cho BY, Ro HK, Shong M - "Regulation of the phosphatidylinositol 3-kinase, Akt/protein kinase B, FRAP/mammalian target of rapamycin, and ribosomal S6 kinase 1 signaling pathways by thyroid-stimulating hormone (TSH) and stimulating type TSH receptor antibodies in the thyroid gland" J Biol Chem 278(24):21960-71 (2003). doi: 10.1074/jbc.M300805200
https://linkinghub.elsevier.com/retriev ... 20)68606-9
"TSH and cAMP increased the tyrosine phosphorylation of TSHR and the association between TSHR and the p85alpha regulatory subunit of PI3K. TSH induced a redistribution of PDK1 from the cytoplasm to the plasma membrane in the cells in a PI3K- and protein kinase A-dependent manner."
T3
Chang X, Zhang B, Lihua L, Feng Z - "T3 inhibits the calcification of vascular smooth muscle cells and the potential mechanism" Am J Transl Res 8(11):4694-4704 (2016)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126314/
"T3 may act on PI3K/Akt signaling pathway to inhibit the phenotype transformation of VSMC, which then suppresses the calcium/phosphate induced calcification of rat VSMCs. Thus, T3 is an endogenous molecule that can protect the blood vessels against calcification."
Carrillo-Sepúlveda MA, Ceravolo GS, Fortes ZB, Carvalho MH, Tostes RC, Laurindo FR, Webb RC, Barreto-Chaves ML - "Thyroid hormone stimulates NO production via activation of the PI3K/Akt pathway in vascular myocytes" Cardiovasc Res 85(3):560-70 (2010) doi: 10.1093/cvr/cvp304
https://pmc.ncbi.nlm.nih.gov/articles/PMC3031311/
"These findings show for the first time that the PI3K/Akt signalling pathway is involved in T3-induced NO production by VSMCs, which occurs with expressive participation of inducible and neuronal NOS."
Brown AR, Simmen RC, Simmen FA - "The role of thyroid hormone signaling in the prevention of digestive system cancers" Int J Mol Sci 14(8):16240-57 (2013). doi: 10.3390/ijms140816240
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759909/
"In addition to the intracellular TRs, the integrin αVβ3 has more recently been identified as a cell surface receptor for TH [16]. Two separate binding sites for TH have been identified on the extracellular domain of this integrin. One site binds T3 to stimulate the PI3K pathway, leading to the translocation of TRα to the nucleus for transcription of HIF-1α; the other site binds primarily to T4 to activate ERK1/2 leading to nuclear localization of TRβ1 [17].
Diniz GP, Carneiro-Ramos MS, Barreto-Chaves ML - "Angiotensin type 1 receptor mediates thyroid hormone-induced cardiomyocyte hypertrophy through the Akt/GSK-3beta/mTOR signaling pathway" Basic Res Cardiol 104(6):653-67 (2009) doi: 10.1007/s00395-009-0043-1
https://link.springer.com/article/10.10 ... 009-0043-1
"The cardiomyocytes treated with T3 demonstrated a rapid activation of Akt/GSK-3beta/mTOR signaling pathway, which was completely inhibited by the use of PI3K inhibitors (LY294002, 10 microM and Wortmannin, 200 nM)."
Lei J, Ingbar DH - "Src kinase integrates PI3K/Akt and MAPK/ERK1/2 pathways in T3-induced Na-K-ATPase activity in adult rat alveolar cells" Am J Physiol Lung Cell Mol Physiol 301(5):L765-71 (2011) doi: 10.1152/ajplung.00151.2011
https://journals.physiology.org/doi/ful ... 00151.2011
"Adult rat AECs [alveolar cells] T3-stimulated Src kinase activity can activate both PI3K/Akt and MAPK/ERK1/2, and activation of Akt is necessary for T3-induced Na-K-ATPase activity."
Lin HY, Sun M, Tang HY, Lin C, Luidens MK, Mousa SA, Incerpi S, Drusano GL, Davis FB, Davis PJ - "L-Thyroxine vs. 3,5,3'-triiodo-L-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase" Am J Physiol Cell Physio 296(5):C980-91 (2009) doi: 10.1152/ajpcell.00305.2008
https://journals.physiology.org/doi/ful ... 00305.2008
"We find that both T4 and T3 activate ERK1/2 and cause cell proliferation, indicated by accumulation of proliferating cell nuclear antigen (PCNA) and radiolabeled thymidine incorporation, in a human glioma (U-87 MG) cell line that has been studied extensively by others (4, 21, 34, 42). However, only T3 causes tyrosine phosphorylation (activation) of PI3-kinase. This latter cell surface action of T3, however, does not contribute to cell proliferation; instead, its consequences include translocation of the nuclear hormone receptor, TRα, from cytoplasm to the nucleus of hormone-treated cells and increased expression of the hypoxia-inducible factor (HIF)-1α gene."
T4
Xian H, Wang F, Teng W, Yang D, Zhang M - "Thyroid hormone induce a p53-dependent DNA damage through PI3K/Akt activation in sperm" Gene 615:1-7 (2017) doi: 10.1016/j.gene.2017.03.014
https://pubmed.ncbi.nlm.nih.gov/28322991/
"Our results highlight that inhibition of PI3K/Akt pathway or p53 degradation is important in maintaining sperm motility in a thyroxine receptor (TR)-dependent manner."
Aoki T, Tsunekawa K, Araki O, Ogiwara T, Nara M, Sumino H, Kimura T, Murakami M - "Type 2 Iodothyronine Deiodinase Activity Is Required for Rapid Stimulation of PI3K by Thyroxine in Human Umbilical Vein Endothelial Cells" Endocrinology 156(11):4312-24 (2015) doi: 10.1210/en.2014-1988
https://pmc.ncbi.nlm.nih.gov/articles/PMC4606755/
"These findings suggest that conversion of T4 to T3 by D2 is required for TRα1/PI3K-mediated nongenomic actions of T4 in HUVECs, including stimulation of Akt phosphorylation and Rac activation, which result in cell migration."
Li Z, Xu T, Fan X, Chen K, Wan C, Li X, Yin H, Li S - "Bisphenol A aggravate selenium deficiency-induced apoptosis via miR-215-3p/Dio1 to activate ROS/PI3K/AKT pathway in chicken arterial" J Cell Physiol 238(6):1256-1274 (2023). doi: 10.1002/jcp.31007
https://onlinelibrary.wiley.com/doi/10.1002/jcp.31007
"These results suggest that BPA exposure aggravates the apoptosis of Se deficient arterial endothelial cells in chickens by regulating the ROS/PI3K/AKT pathway activated by miR-215-3p/Dio1."
RHEUMATOID ARTHITIS - Gq/11
Wang Y, Li Y, He Y, Sun Y, Sun W, Xie Q, Yin G, Du Y, Wang L, Shi G - "Expression of G protein αq Subunit is Decreased in Lymphocytes from Patients with Rheumatoid Arthritis and is Correlated with Disease Activity" Scand J Immunol 75(2):203-9 (2012) doi: 10.1111/j.1365-3083.2011.02635.x. PMID: 21923740.
https://onlinelibrary.wiley.com/doi/10. ... 11.02635.x
"Gαq, the alpha subunit of Gq, a member of the Gq/11 sub-family, was reported to inhibit phosphatidylinositol-3-Kinase (PI3K) activation and prevent the activation of Akt. Previous studies demonstrated that mice losing Gαq in their immune system could spontaneously develop inflammatory arthritis. In this study, we showed that the Gαq expressions at mRNA and protein levels in the peripheral blood lymphocytes (PBLs) from patients with rheumatoid arthritis (RA) were significantly decreased in comparison of which in healthy individuals. The expression levels of Gαq mRNA in PBLs from patients with RA were correlated with RA disease activity (DAS28), anti-cyclic citrullinated protein antibodies, C-reactive protein and rheumatoid factor. We also demonstrated that Gαq controlled the apoptosis of RA PBLs through regulating the activity of Mcl-1 and caspase-3. These data suggested that Gαq might be involved in the pathogenesis of RA by regulating PBLs apoptosis."
Gq/11
Dugourd C, Gervais M, Corvol P, Monnot C - "Akt is a major downstream target of PI3-kinase involved in angiotensin II-induced proliferation" Hypertension 41(4):882-90 (2003)
https://pubmed.ncbi.nlm.nih.gov/12623864/
Kong KC, Billington CK, Gandhi U, Panettieri RA Jr, Penn RB - "Cooperative mitogenic signaling by G protein-coupled receptors and growth factors is dependent on G(q/11)" FASEB J 20(9):1558-60 (2006)
https://pubmed.ncbi.nlm.nih.gov/16723377/
Taboubi S, Garrouste F, Parat F, Pommier G, Faure E, Monferran S, Kovacic H, Lehmann M - " Gq-coupled purinergic receptors inhibit insulin-like growth factor-I/phosphoinositide 3-kinase pathway-dependent keratinocyte migration" Mol Biol Cell 21(6):946-55 (2011)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836975/
"These findings provide new insight into the signaling cross-talk between receptor tyrosine kinase and Gα(q/11)-coupled receptors, which mediate opposite effects on p110α-PI3K activity and keratinocyte migration."
Ueda H, Morishita R, Narumiya S, Kato K, Asano T - "Galphaq/11 signaling induces apoptosis through two pathways involving reduction of Akt phosphorylation and activation of RhoA in HeLa cells" Exp Cell Res 298(1):207-17 (2004). doi: 10.1016/j.yexcr.2004.04.015
https://pubmed.ncbi.nlm.nih.gov/15242775/
Wang Y, Li Y, He Y, Sun Y, Sun W, Xie Q, Yin G, Du Y, Wang L, Shi G - "Expression of G protein αq Subunit is Decreased in Lymphocytes from Patients with Rheumatoid Arthritis and is Correlated with Disease Activity" Scand J Immunol 75(2):203-9 (2012). doi: 10.1111/j.1365-3083.2011.02635.x.
https://pubmed.ncbi.nlm.nih.gov/21923740/
"Gαq, the alpha subunit of Gq, a member of the Gq/11 sub-family, was reported to inhibit phosphatidylinositol-3-Kinase (PI3K) activation and prevent the activation of Akt."
Wu EH, Tam BH, Wong YH - "Constitutively active alpha subunits of G(q/11) and G(12/13) families inhibit activation of the pro-survival Akt signaling cascade" FEBS J 273(11):2388-98 (2006). doi: 10.1111/j.1742-4658.2006.05245.x.
https://febs.onlinelibrary.wiley.com/do ... 06.05245.x
COVID-19/MERS
Purcaru OS, Artene SA, Barcan E, Silosi CA, Stanciu I, Danoiu S, Tudorache S, Tataranu LG, Dricu A - "The Interference between SARS-CoV-2 and Tyrosine Kinase Receptor Signaling in Cancer" Int J Mol Sci 22(9):4830 (2021) doi: 10.3390/ijms22094830
https://pmc.ncbi.nlm.nih.gov/articles/PMC8124491/
"MAPK/ERK and PI3K/AKT/mTOR signaling responses have been shown to be relevant in MERS-CoV infection through bioinformatics analysis in vivo. Therefore, by suppressing these pathways, the replication was substantially inhibited in vitro."
https://pubmed.ncbi.nlm.nih.gov/33081581/
IODINE (EXCESS)
Serrano-Nascimento C, Nicola JP, Teixeira Sda S, Poyares LL, Lellis-Santos C, Bordin S, Masini-Repiso AM, Nunes MT - "Excess iodide downregulates Na(+)/I(-) symporter gene transcription through activation of PI3K/Akt pathway" Mol Cell Endocrinol 426:73-90 (2016)
https://pubmed.ncbi.nlm.nih.gov/26872612
Serrano-Nascimento C, da Silva Teixeira S, Nicola JP, Nachbar RT, Masini-Repiso AM, Nunes MT - "The acute inhibitory effect of iodide excess on sodium/iodide symporter expression and activity involves the PI3K/Akt signaling pathway" Endocrinology 155(3):1145-56 (2014)
https://pubmed.ncbi.nlm.nih.gov/24424051/
"Overall, our data demonstrated the involvement of the PI3K/Akt signaling pathway as a novel mediator of the I(-)-induced thyroid autoregulation, linking the role of thyroid oxidative state to the Wolff-Chaikoff effect."
Liu S, Ding P, Yu X, Xing Z, Cui Y, Liu H - "Excess iodine promotes papillary thyroid carcinoma through the AKT/mTOR pathway" Preprint (2024) doi:10.21203/rs.3.rs-5395582/v1.
https://assets-eu.researchsquare.com/fi ... 1734310013
NOTE: This study is by the Tianjin group (Cui, Liu et al.)
ALZHEIMER'S
Gabbouj S, Ryhänen S, Marttinen M, Wittrahm R, Takalo M, Kemppainen S, Martiskainen H, Tanila H, Haapasalo A, Hiltunen M, Natunen T - "Altered Insulin Signaling in Alzheimer's Disease Brain - Special Emphasis on PI3K-Akt Pathway" Front Neurosci 13:629 (2019)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591470/
Naringin & Thyroid
Abd-Elmawla MA, Essam RM, Ahmed KA, Abdelmonem M - "Implication of Wnt/GSK-3β/β-Catenin Signaling in the Pathogenesis of Mood Disturbances Associated with Hyperthyroidism in Rats: Potential Therapeutic Effect of Naringin" ACS Chem Neurosci 14(11):2035-2048 (2023). doi: 10.1021/acschemneuro.3c00013
https://pubs.acs.org/doi/abs/10.1021/ac ... ro.3c00013
Pistollato F, Masias M, Agudo P, Giampieri F, Battino M - "Effects of phytochemicals on thyroid function and their possible role in thyroid disease" Ann N Y Acad Sci 1443(1):3-19 (2019). doi: 10.1111/nyas.13980
https://pubmed.ncbi.nlm.nih.gov/30381840/
Shashank Shakyawal, Gayatri Rai, Payal Mahobiya - "Biochemical, Histopathological, and Immunohistochemical Study of Repeated Environmental Toxicant Ultraviolet B Radiation-Induced Hyperthyroidism: Alleviation of Oxidative Stress and Prevention by Naringin in Male Swiss Albino Mice" Authorea, June 6, 2023.
https://www.authorea.com/doi/full/10.22 ... 4.40013842
"Naringin was utilised as an antioxidant in our analysis. Additionally, compared to the UVB-irradiated group, the administration of naringin resulted in a substantial drop in T3, T4, FT3, and FT4 levels and a large increase in TSH levels."
Naringin & PI3K/AKT
Naringin is a flavonoid, a type of plant compound with antioxidant properties, found primarily in citrus fruits like grapefruits and oranges. It is responsible for the bitter taste in grapefruits.
Zhou J, Xia L, Zhang Y - "Naringin inhibits thyroid cancer cell proliferation and induces cell apoptosis through repressing PI3K/AKT pathway" Pathol Res Pract 215(12):152707 (2019). doi: 10.1016/j.prp.2019.152707
https://www.sciencedirect.com/science/a ... via%3Dihub
Du Y, Wang G, Liu B, Guo M, Yan X, Dou M, Yu F, Ba Y, Zhou G - "Naringin alleviates fluoride-induced neurological impairment: A focus on the regulation of energy metabolism mediated by mitochondrial permeability transition pore" Sci Total Environ 177073 (2024). doi: 10.1016/j.scitotenv.2024.177073
https://pubmed.ncbi.nlm.nih.gov/39447898/
AEBSF
Hosoi T, Hyoda K, Okuma Y, Nomura Y, Ozawa K - "Inhibitory effect of 4-(2-aminoethyl)-benzenesulfonyl fluoride, a serine protease inhibitor, on PI3K inhibitor-induced CHOP expression" Eur J Pharmacol 554(1):8-11 (2007). doi: 10.1016/j.ejphar.2006.09.063
https://www.sciencedirect.com/science/a ... 9906011058
"We found that AEBSF completely inhibited PI3K inhibitor-induced CHOP expression at both mRNA and protein levels."
Fluorinated Candidates as PI3K Inhibitors
Tantawy AH, El-Behairy MF, Abd-Allah WH, Jiang H, Wang MQ, Marzouk AA - "Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Fluorinated Candidates as PI3K Inhibitors: Targeting Fluorophilic Binding Sites" J Med Chem 64(23):17468-17485 (2021) doi: 10.1021/acs.jmedchem.1c01674
https://pubs.acs.org/doi/abs/10.1021/ac ... em.1c01674
PM2.5
Tang S, Li D, Ding H, Jiang M, Zhao Y, Yu D, Zhang R, Chen W, Chen R, Zheng Y, Piao J - "GLIS3 mediated by the Rap1/PI3K/AKT signal pathway facilitates real-ambient PM2.5 exposure disturbed thyroid hormone homeostasis regulation" Ecotoxicol Environ Saf 232:113248 (2022) doi: 10.1016/j.ecoenv.2022.113248
https://www.sciencedirect.com/science/a ... 1322000884
"PM2.5 exposure induces histological changes in the thyroid gland and thyroid dysfunction in mice. The exposure activates GLIS3 through the Rap1/PI3K/AKT pathway to promote the expression of proteins related to thyroid hormone synthesis, leading to increased dysregulating TH homeostasis."
Cypermethrin
Ha M, Huang X, Li L, Lu D, Liu C - "PKCα mediated by the PI3K/Akt-FOXA1 cascade facilitates cypermethrin-induced hyperthyroidism" Sci Total Environ 757:143727 (2021) doi: 10.1016/j.scitotenv.2020.143727
https://pubmed.ncbi.nlm.nih.gov/33250241/
"Further studies found that β-CYP induced PKCα translation by the miR-330-3p-targeted PI3K/Akt-FOXA1 cascade and then PKCα positively regulated TTF-1 to promote TPO and Tg expressions, which in turn facilitated TH biosynthesis."
miRNA-125a
Chen D, Huang X, Lu S, Deng H, Gan H, Huang R, Zhang B - "miRNA-125a modulates autophagy of thyroiditis through PI3K/Akt/mTOR signaling pathway" Exp Ther Med 17(4):2465-2472 (2019) doi: 10.3892/etm.2019.7256
https://www.spandidos-publications.com/etm/17/4/2465
"PI3K inhibition enhanced the ability of miR‑125a to increase the inflammatory response in vitro via regulation of the PI3K/Akt/mTOR signaling pathway. These results suggest miR‑125a inhibited autophagy in a model of thyroiditis through the PI3K/Akt/mTOR signaling pathway."
miR-155
Fu Q, Zhu X, Fang Q, Han H, Wang Z, Xie J, Qian D, Wu X, Wu Y, Chen K - "miR-155 enhances apoptosis of macrophage through suppressing PI3K-AKT activation in Pseudomonas aeruginosa keratitis" Heliyon 10(17):e36585 (2024). doi: 10.1016/j.heliyon.2024.e36585
https://pubmed.ncbi.nlm.nih.gov/39263048/
Phorbol esters
Weiss RH, Yabes AP - "Mitogenic inhibition by phorbol esters is associated with decreased phosphatidylinositol-3 kinase activation" Am J Physiol 270(2 Pt 1):C619-27 (1996) doi: 10.1152/ajpcell.1996.270.2.C619
https://journals.physiology.org/doi/abs ... 270.2.C619
"These data suggest that the site of growth inhibition by PMA in VSM cells lies upstream of signal transfer particle aggregation and that such growth arrest may be mediated through inhibition of activation of PI3K."
Voriconazole
Martín-Segura A, Ahmed T, Casadomé-Perales Á, Palomares-Perez I, Palomer E, Kerstens A, Munck S, Balschun D, Dotti CG - "Age-associated cholesterol reduction triggers brain insulin resistance by facilitating ligand-independent receptor activation and pathway desensitization" Aging Cell. 18(3):e12932 (2019). doi: 10.1111/acel.12932
"Biochemically, hippocampal fractions from the treated mice showed significantly reduced levels of PI3K/Akt and the downstream effector p70S6K compared to untreated old mice."
Fluoroquinolones
Aranda A, Mayorga C, Ariza A, Doña I, Rosado A, Blanca-Lopez N, Andreu I, Torres MJ - "In vitro evaluation of IgE-mediated hypersensitivity reactions to quinolones" Allergy 66(2):247-54 (2011) doi: 10.1111/j.1398-9995.2010.02460.x.
https://pubmed.ncbi.nlm.nih.gov/20722637/
WHAT IS THE PI3K/AKT PATHWAY?
https://www.youtube.com/watch?v=WDVjRU8Ko4A
- CANCER: Hyperactivation of the PI3K pathway is common in many cancers, leading to uncontrolled growth and survival.
- IMMUNE DISORDERS: Aberrant PI3K signaling in immune cells can contribute to inflammatory diseases, allergies, and autoimmune disorders.
- METABOLIC DISORDERS: Dysregulation of PI3K-Akt signaling is implicated in insulin resistance and type 2 diabetes.
- AUTISM: In ASD, this pathway is often hyperactive. PI3K–Akt–mTOR is now considered one of the key molecular axes linking cell signalling to autism phenotypes.
Neurotoxicity of developmental hypothyroxinemia and hypothyroidism in rats is mediated by the PI3K pathway (Wang et al., 2013).
The PI3K pathway is also a central regulator of mast cell activation.
FLUORIDE:
Ding X, Lai L, Jia Y, Liu X, Hu J, Chen W - "Effects of chronic fluorosis on the expression of VEGF/PI3K/AKT/eNOS in the gingival tissue of rats with orthodontic tooth movement" Exp Ther Med 27(3):121 (2024). doi: 10.3892/etm.2024.12409
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10867716/
"With the extension of the application of orthodontic stress, the mRNA and protein expression levels of VEGF, PI3K, AKT and eNOS in the gingiva of the O and FO groups showed a trend of increasing at first and subsequently decreasing, which corresponds with the tooth movement cycle."
Fan B, Yu Y, Zhang Y - "PI3K-Akt1 expression and its significance in liver tissues with chronic fluorosis" Int J Clin Exp Pathol 8(2):1226-36 (2015)
https://pmc.ncbi.nlm.nih.gov/articles/PMC4396260/
"The expression of PI3K and Akt1 mRNA and proteins was significantly increased in fluorosis hepatocytes...The apoptosis and the intracellular calcium concentration were increased. Therefore, we conclude that PI3K-Akt signaling pathway may be one of the signaling pathways in the pathogenesis of liver injury caused by fluorosis."
Guo L, Yang B, Chen F, Yuan X, Cheng J, Chen X, Zhou Y, Yang X, Li Y, Liu Y, Tang D, Wang F - "Disruption of the SIRT1/PI3K/AKT Signaling Axis Mediates Fluoride-Induced Cardiotoxicity: Evidence from in Vitro and Zebrafish Models" Biol Trace Elem Res (2025) doi: 10.1007/s12011-025-04828-2.
https://pubmed.ncbi.nlm.nih.gov/40963040/
"F induces cardiotoxicity by disrupting the SIRT1/PI3K/AKT signaling pathway, leading to increased oxidative stress, inflammation, and apoptosis."
Jiang X, Zhang L, He Y, Zhang R, Shang X, Xie Y, He M, Zhang Y - "Effect of sodium fluoride on expression of PI3K/Akt signal molecules and apoptosis in human osteosarcoma Saos-2 cells" J Anat (CAS) S01:157 (2021)
http://218.28.6.71:81/Qikan/Article/Det ... 7105193768
"The changes of PI3K-Akt signaling pathway and mitochondrial apoptotic pathway-related molecule FoxO1 were detected after 24 h and 48 h."
Korkmaz R, Yüksek V, Dede S - "The Effects of Sodium Fluoride (NaF) Treatment on the PI3K/Akt Signal Pathway in NRK-52E Cells" Biol Trace Elem Res. 200(7):3294-3302 (2022) doi: 10.1007/s12011-021-02927-4
https://link.springer.com/article/10.10 ... 21-02927-4
"According to the results obtained in the study, the low NaF concentration increased the expression levels of the ERBB2, PI3K, and Akt genes, while the higher concentrations did not significantly affect these levels. The expression of mTOR decreased at all given concentrations. The expression of the TP53 gene did not change at the low concentration, while it increased at the high concentrations."
Kuang P, Deng H, Liu H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L - "Sodium fluoride induces splenocyte autophagy via the mammalian targets of rapamycin (mTOR) signaling pathway in growing mice" Aging (Albany NY) 10(7):1649-1665 (2018). doi: 10.18632/aging.101499
https://pmc.ncbi.nlm.nih.gov/articles/PMC6075432/
"NaF caused inhibition of mTOR activity, which was characterized by down-regulation of PI3K, Akt and mTOR mRNA and protein expression levels."
Li Y, Wang Z, Li J, Yu Y, Wang Y, Jin X, Dong Y, Liu Q, Duan X, Yan N - "Sodium Butyrate Ameliorates Fluorosis-Induced Neurotoxicity by Regulating Hippocampal Glycolysis In Vivo" Biol Trace Elem Res 201(11):5230-5241 (2023) doi: 10.1007/s12011-023-03583-6
https://pubmed.ncbi.nlm.nih.gov/36710293/
"Results suggested that SB [Sodium Butyrate] could ameliorate fluorosis-induced neurotoxicity, which might be linked with its function in regulating glycolysis as well as inhibition of the PI3K/AKT/HIF-1α pathway."
Linghu Y, Deng CN, He L, Wu Q, Xu L, Yu YN - "Fluoride induces osteoblast autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway in vivo and in vitro" Exp Biol Med (Maywood) 248(13):1159-1172 (2023)doi: 10.1177/15353702231191117
https://pmc.ncbi.nlm.nih.gov/articles/PMC10583752/
"These results demonstrate that fluoride induces autophagy in osteoblasts by inhibiting the PI3K/AKT/mTOR signaling pathway, which deepens our understanding of the molecular mechanisms underlying fluoride-induced bone damage and provides a theoretical basis for the prevention and treatment of skeletal fluorosis."
Ma L, Zhang R, Li D, Qiao T, Guo X - "Fluoride regulates chondrocyte proliferation and autophagy via PI3K/AKT/mTOR signaling pathway" Chem Biol Interact 349:109659 (2021)
https://pubmed.ncbi.nlm.nih.gov/34536393/
Ohsaka Y, Nomura Y - "Rat white adipocytes activate p85/p110 PI3K and induce PM GLUT4 in response to adrenoceptor agonists or aluminum fluoride" Physiol Int 103(1):35-48 (2016) doi: 10.1556/036.103.2016.1.4.
https://akjournals.com/view/journals/03 ... le-p35.xml
Parada-Cruz B, Aztatzi-Aguilar OG, Ramírez-Martínez G, Jacobo-Estrada TL, Cárdenas-González M, Escamilla-Rivera V, Martínez-Olivas MA, Narváez-Morales J, Ávila-Rojas SH, Álvarez-Salas LM, Barbier O - "Inflammation- and cancer-related microRNAs in rat renal cortex after subchronic exposure to fluoride" Chem Biol Interact 379:110519 (2023) doi: 10.1016/j.cbi.2023.110519
https://www.sciencedirect.com/science/a ... 9723001862
Pei J, Xu J, Gao Y, Sun H, Lv C, Jiang Y, Sun W, Jiang W, Qu L, Jiang L, Sun D - "Identification of pathogenesis-related microRNA profiles in skeletal fluorosis" Fluoride 52(1):29-41 (2019)
https://www.fluorideresearch.org/epub/files/008.pdf
"Pathway analysis of miRNAs by KEGG revealed the MAPK signaling pathway, pathways in cancer, the PI3K-Akt signaling pathway, proteoglycans in cancer, and the endocytosis pathway to be regulated by the differentially expressed miRNAs."
Qin Z, Yang X, Wang B, Zhang T, Huang Y, Zhang J, Jin Z, Hong F - "Effects of combined fluoride and arsenic exposure on BMP-2, RANK, PI3K, and Akt1 gene transcription levels in rat tooth tissue" Chinese Journal of Industrial Hygiene and Occupational Diseases 35(8):702-708 (2018) Chinese. doi: 10.13213/j.cnki.jeom.2018.18228
"Dental fluorosis was negatively correlated with RANK and PI3K mRNA expression in dental tissue (r=-0.283, -0.273, bothP<0.05)."
Shenoy SP, Sen U, Kapoor S, Ranade AV, Chowdhury CR, Bose B - "Sodium fluoride induced skeletal muscle changes: Degradation of proteins and signaling mechanism" Environ Pollut 242(Pt B):1078-1086 (2018) doi:10.1016/j.envpol.2018.10.03.
https://www.sciencedirect.com/science/a ... 9118325673
"Sodium fluoride at low concentrations causes hypertrophy of the differentiating C2C12 myoblasts and activates PI3K/AKT signaling pathway."
Song C, Zhao J, Fu B, Li D, Mao T, Peng W, Wu H, Zhang Y - "Melatonin-mediated upregulation of Sirt3 attenuates sodium fluoride-induced hepatotoxicity by activating the MT1-PI3K/AKT-PGC-1α signaling pathway" Free Radic Biol Med 112:616-630 (2017) doi: 10.1016/j.freeradbiomed.2017.09.005
https://pubmed.ncbi.nlm.nih.gov/28912098/
Varışlı B, Darendelioğlu E, Caglayan C, Kandemir FM, Ayna A, Genç A, Kandemir Ö - "Hesperidin Attenuates Oxidative Stress, Inflammation, Apoptosis, and Cardiac Dysfunction in Sodium Fluoride-Induced Cardiotoxicity in Rats" Cardiovasc Toxicol 22(8):727-735 (2022). doi: 10.1007/s12012-022-09751-9.
https://pubmed.ncbi.nlm.nih.gov/35606666/
Wang F, Chen F, Song W, Li Y, Wu H, Tian T, Tian M, Tang D, Liu Y - "Sodium Fluoride Exposure Induces Developmental Toxicity and Cardiotoxicity in Zebrafish Embryos" Biol Trace Elem Res. 2024 Sep 17. doi: 10.1007/s12011-024-04381-4
https://pubmed.ncbi.nlm.nih.gov/39287768/
"Gene ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the DEGs showed that cardiac-related pathways, such as actin cytoskeleton regulation, Jak-Stat, PI3k-Akt, and Ras, were activated in the NaF-exposed group."
Wang J , Xu H , Cheng X , Yang J , Yan Z , Ma H , Zhao Y , Ommati MM , Manthari RK , Wang J - "Calcium relieves fluoride-induced bone damage through the PI3K/AKT pathway" Food Funct 11(1):1155-1164 (2020)
https://pubmed.ncbi.nlm.nih.gov/31872845/
Wang F, Liu Y, Li Y, Yang X, Zhao J, Yang B, Tang D, Zhang C, He Z, Ming D, Zhu X - "Combining Network Pharmacology and Experimental Verification to Ascertain the Mechanism of Action of Asparagus officinalis Against the Brain Damage Caused by Fluorosis" Environ Toxicol (2024)10.1002/tox.24382.
https://onlinelibrary.wiley.com/doi/10.1002/tox.24382
"Enrichment analyses showed that 'mitogen-activated protein kinase' (MAPK), 'phosphoinositide 3-kinase/protein kinase B' (PI3K-Akt), 'nuclear factor-kappa B' (NF-κB), and the 'neurotrophin signaling pathway' were the most enriched biological processes and signaling pathways...Upon ASP treatment, expression of silent information regulator (SIRT)1, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), MAPK, NF-κB, PI3K, Akt, and B-cell lymphoma-2 in rat brain tissue increased gradually, whereas that of Bax, caspase-3, and p53 decreased gradually."
Wang F, Li C, Qin Y, Han X, Gao J, Zhang A, Luo P, Pan X - "Analysis of the microRNA Profile of Coal-Burning Endemic Fluorosis Using Deep Sequencing and Bioinformatic Approaches" Bull Environ Contam Toxicol 103(1):56-63 (2019) doi: 10.1007/s00128-019-02660-8
https://link.springer.com/article/10.10 ... 19-02660-8
"KEGG pathway enrichment analyses of downregulated genes revealed that they were mainly enriched in the Ras signaling pathway, the phosphatidylinositol 3-kinase-protein kinase B (PI3K/AKT) signaling pathway, pathways in cancer, endocytosis, the Rap1 signaling pathway, and the mitogen-activated protein kinase (MAPK) signaling pathway."
Wang J, Hu H, Yan Z, Yang J, Zhu Y, Cheng X, Wang J - "Separation and identification of differential protein in rat's bone with fluorosis and calcium supplementation intervention" Chinese Journal of Biotechnology 35(6):1097-1108 (2019) doi: 10.13345/j.cjb.180497
https://www.chndoi.org/Resolution/Handl ... cjb.180497
"These differential proteins are enriched in 38 bone metabolic pathways such as focal adhesion, PI3K-Akt signaling pathway, and AMPK signaling pathway. And the functions of these proteins are mainly related to cytoskeleton, energy metabolism, substance transport, ion channel, and apoptosis. Therefore, it is speculated that calcium may alleviate the fluoride-induced bone damage by regulating the focal adhesion, PI3K-Akt, AMPK and other signaling pathway..."
Yang B, Wang F, Yang X, Yuan X, Yang Y, Chen X, Tian T, Chen F, Tang D, He Z, Liu Y, Li Y - "The Role of SIRT1-BDNF Signaling Pathway in Fluoride-Induced Toxicity for Glial BV-2 Cells" Biol Trace Elem Res (2025) doi: 10.1007/s12011-024-04503-y
https://link.springer.com/article/10.10 ... 24-04503-y
"The fluoride-exposed groups had reduced SIRT1, BDNF, TrkB, PI3K, AKT, and MAPK protein expression levels, and increased FOXO1A protein expression. SRT1720 mitigated the harmful effects of NaF, stimulated cell proliferation and cell cycle progression, decreased apoptosis, reduced oxidative stress and inflammatory factors, elevated SIRT1, BDNF, TrkB, PI3K, AKT, and MAPK protein levels, and suppressed FOXO1A protein expression. The results indicate that NaF potentially harms glial cells by suppressing SIRT1 activation, and SIRT1 significantly mitigated the damage."
Yao SR, Weng QQ, Zhu YY, Liu J, Zhang Y - "Exploring Molecular Mechanisms of Fluoride's Impact on Ameloblasts Based on Transcriptome Sequencing" Journal of Oral Science Research 41(5):420-425 (2025)
https://doi.org/10.13701/j.cnki.kqyxyj.2025.05.011
LS8 ameloblast cells exposed to 1.5 mmol/L NaF for 24 h showed 104 DEGs (34 up, 70 down), with KEGG enrichment implicating PI3K/Akt and MAPK. RT-qPCR and Western blot both indicated decreased PI3K/Akt and ERK (p44/p42 MAPK) signaling activity, supporting these pathways as part of fluoride’s cytotoxic mechanism in ameloblasts.
Yıldız MO, Çelik H, Caglayan C, Kandemir FM, Gür C, Bayav İ, Genç A, Kandemir Ö - "Neuromodulatory effects of hesperidin against sodium fluoride-induced neurotoxicity in rats: Involvement of neuroinflammation, endoplasmic reticulum stress, apoptosis and autophagy" Neurotoxicology 90:197-204 (2022). doi: 10.1016/j.neuro.2022.04.002
https://pubmed.ncbi.nlm.nih.gov/35413380/
"Hesperidin was able to down-regulate the mRNA transcript levels of apoptosis and endoplasmic reticulum stress markers such as caspase-3, Bax, Bcl-2, PERK, IRE1, ATF6, and GRP78 in NaF-induced neurotoxicity. Hesperidin also reduced the adverse effects caused by NaF by modulating the PI3K/Akt/mTOR signaling pathway."
Yu X, Xia L, Zhang S, Zhou G, Li Y, Liu H, Hou C, Zhao Q, Dong L, Cui Y, Zeng Q, Wang A, Liu L - "Fluoride exposure and children's intelligence: Gene-environment interaction based on SNP-set, gene and pathway analysis, using a case-control design based on a cross-sectional study" Environ Int 155:10668 (2021). doi: 10.1016/j.envint.2021.106681
https://www.sciencedirect.com/science/a ... 2021003068
"In pathway level, Alzheimer disease pathway, metabolic pathway, signal transduction pathway, sphingolipid signaling pathway and PI3K-AKT signaling pathway interacted with fluoride on intelligence in men."
Xu S, Xie X, Li C, Liu Z, Zuo D - "Micromolar sodium fluoride promotes osteo/odontogenic differentiation in dental pulp stem cells by inhibiting PI3K/AKT pathway" Arch Oral Biol 131:105265 (2021). doi: 10.1016/j.archoralbio.2021.105265doi: 10.1016/j.archoralbio.2021.105341
https://www.sciencedirect.com/science/a ... 6921002284
"Micromolar NaF can promote the osteo/odontogenic differentiation of DPSCs [dental pulp stem cells] by inhibiting the PI3K/AKT pathway."
Zhang J, Zhu Y, Shi Y, Han Y, Liang C, Feng Z, Zheng H, Eng M, Wang J - "Fluoride-Induced Autophagy via the Regulation of Phosphorylation of Mammalian Targets of Rapamycin in Mice Leydig Cells" J Agric Food Chem 65(40):8966-8976 (2017) doi: 10.1021/acs.jafc.7b03822
https://pubs.acs.org/doi/10.1021/acs.jafc.7b03822
"Fluoride inhibited the phosphorylation of mammalian targets of rapamycin and 4EBP1, which in turn resulted in a decrease in the levels of AKT and PI3K mRNA expression, as well as an elevation of the level of AMPK expression in both testes and primary Leydig cells."
Zhao C - "Effects of chronic fluoride exposure on spatial learning and memory and hippocampal PI3K/Akt/mTOR signaling pathway in second offspring rats" China Med Abstr (Intern Med) 1:20-21 (2024). PFPC Library
http://218.28.6.71:81/Qikan/Article/Det ... 7112355978
"Except for mTOR mRNA in the low-fluoride group, the mRNA and protein expression levels of PI3K, Akt, and mTOR in the hippocampus of rats in all other exposure groups were significantly lower than those in the control group (P < 0.05)...chronic fluoride
exposure can lead to spatial learning and memory impairment in F2 generation rats, and its mechanism of action may be related to the inhibition of the PI3K/Akt/mTOR signaling pathway in the hippocampus."
Zhao T, Lv J, Peng M, Mi J, Zhang S, Liu J, Chen T, Sun Z, Niu R - "Fecal microbiota transplantation and short-chain fatty acids improve learning and memory in fluorosis mice by BDNF-PI3K/AKT pathway" Chem Biol Interact 110786 (2023). doi: 10.1016/j.cbi.2023.110786
https://pubmed.ncbi.nlm.nih.gov/39491142/
"Moreover, the expressions of mRNA in hippocampal BDNF, PDK1, AKT, Bcl-2, and Bcl-xL were downregulated in mice exposed to fluoride, but the levels of PI3K, Bax, Bak, and Caspase-7 mRNA were upregulated. NaF treatment had an increase in PI3K and Caspase-3 protein levels and reduced the expressions of these four proteins, including BDNF, p-PI3K, AKT and p-AKT."
Zhou BH, Tan PP, Jia LS, Zhao WP, Wang JC, Wang HW - "PI3K/AKT signaling pathway involvement in fluoride-induced apoptosis in C2C12 cells" Chemosphere 199:297-302 (2018)
https://pubmed.ncbi.nlm.nih.gov/29448197/
"Fluoride-induced apoptosis in C2C12 cells is related to the PI3K/AKT signaling pathway."
Żwierełło W, Maruszewska A, Skórka-Majewicz M, Wszołek A, Gutowska I - "Is Fluoride Blameless?-The Influence of Fluorine Compounds on the Invasiveness of the Human Glioma-like Cell Line U-87" Int J Mol Sci 25(23):12773 (2024) doi: 10.3390/ijms252312773
https://pmc.ncbi.nlm.nih.gov/articles/PMC11641017/
"For AKT kinase, a substantial 6- to 7-fold increase in the level of phosphorylated AKT protein (pS473) was observed at all tested NaF concentrations compared to the control."
PFAS
Chen Z, Chen Z, Gao S, Shi J, Li X, Sun F - "PFOS exposure destroys the integrity of the blood-testis barrier (BTB) through PI3K/AKT/mTOR-mediated autophagy" Reprod Biol 24(1):100846 (2023) doi: 10.1016/j.repbio.2023.100846 doi: 10.1016/j.repbio.2024.100892
https://www.sciencedirect.com/science/a ... 1X23001183
"Our results demonstrated that exposure to PFOS induced BTB injury and autophagy, as evidenced by increased expression of autophagy-related proteins, accumulation of autophagosomes, observed through representative electron micrographs, and decreased activity of the PI3K/AKT/mTOR pathway. Moreover, treatment with chloroquine, an autophagy inhibitor, alleviated the effects of PFOS on the integrity of TM4 cells in the BTB and the PI3K/AKT/mTOR pathway."
Chen X, Nie X, Mao J, Zhang Y, Yin K, Sun P, Luo J, Liu Y, Jiang S, Sun L - "Perfluorooctane sulfonate mediates secretion of IL-1β through PI3K/AKT NF-кB pathway in astrocytes" Neurotoxicol Teratol 67:65-75 (2018) doi: 10.1016/j.ntt.2018.03.004
https://www.sciencedirect.com/science/a ... 6217302064
Fangninou FF, Yu Z, Li W, Xue L, Yin D - "Metastatic effects of perfluorooctanoic acid (PFOA) on Drosophila melanogaster with metabolic reprogramming and dysrhythmia in a multigenerational exposure scenario" Sci Total Environ 912:169305 (2024) doi: 10.1016/j.scitotenv.2023.169305.
https://pubmed.ncbi.nlm.nih.gov/38103603/
"As one legacy PFAS, perfluorooctanoic acid (PFOA) exposure correlated with various cancers and their mortality...PFOA exposure generated provoked oxidative stress via H2O2 and stimulated antioxidants including glutathione (GSH), catalase (CAT), melatonin, serotonin and cortisol, with downregulations on PI3K/AKT pathways and upregulations on MAPK ones...The present study performed PFOA exposure for 3 consecutive generations. Results showed that the metastasis by PFOA increased over generations, and it was further deteriorated by dysrhythmia."
Gao M, Shen H, Li Q, Gu X, Jia T, Wang Y - "Perfluorooctane sulfonate (PFOS) induces apoptosis and autophagy by inhibition of PI3K/AKT/mTOR pathway in human granulosa cell line KGN" Environ Pollut 344:123333 (2024) doi: 10.1016/j.envpol.2024.123333
https://www.sciencedirect.com/science/a ... 9124000472
"Molecular docking investigations, in conjunction with Western blot experiments, substantiated PFOS's significant inhibition of the PI3K/AKT/mTOR signaling pathway."
Hong J, Du K, Jin H, Chen Y, Jiang Y, Zhang W, Chen D, Zheng S, Cao L - "Evidence of promoting effects of 6:2 Cl-PFESA on hepatocellular carcinoma proliferation in humans: An ideal alternative for PFOS in terms of environmental health?" Environ Int 186:108582 (2024). doi: 10.1016/j.envint.2024.108582
https://www.sciencedirect.com/science/a ... 2024001685
"Both PFOS and 6:2 Cl-PFES) have been shown to activate the PI3K/AKT/mTOR signaling pathway and inhibit necroptosis. This action consequently enhances the proliferation of HCC cells. Our phenotypic assay findings suggest that the tumorigenic potential of 6:2 Cl-PFESA surpasses that of PFOS; in a subcutaneous tumor model using nude mice, the mean tumor weight for the 6:2 Cl-PFESA-treated cohort was 2.33 times that observed in the PFOS cohort (p < 0.01). Despite 6:2 Cl-PFESA being considered a safer substitute for PFOS, the pronounced effects of this chemical on HCC cell growth warrant a thorough assessment of hepatotoxicity risks linked to its usage."
Hong J, Wang X, Jin H, Chen Y, Jiang Y, Du K, Chen D, Zheng S, Cao L - "Environment relevant exposure of perfluorooctanoic acid accelerates the growth of hepatocellular carcinoma cells through mammalian target of rapamycin (mTOR) signal pathway" Environ Pollut 341:122910 (2024) doi: 10.1016/j.envpol.2023.122910
https://www.sciencedirect.com/science/a ... 9123019127
"We systematically evaluated the effects of PFOA on HCC cells and found that PFOA's exposure can selectively activate the PI3K/AKT/mTOR/4E-BP1 signaling pathway...Our work illuminates the obscured domain of PFOA-induced hepatoxicity, shedding light on its ties to hepatocellular carcinoma progression."
Li F, Chen L, Shi S, Hong WJ, Li M, Guo LH - "Perfluorobutanoic acid: A short-chain perfluoroalkyl substance exhibiting estrogenic effects through the estrogen-related receptor γ pathways" J Hazard Mater 485:136947 (2024) doi: 10.1016/j.jhazmat.2024.136947
https://linkinghub.elsevier.com/retriev ... 9424035283
"Furthermore, PFBA up-regulated the proliferation-related factors downstream of ERRγ and inhibited by PI3K/Akt inhibitor LY294002, which also suppressed the cell proliferation induced by PFBA."
Liu Q, Liu Y, Li X, Wang D, Zhang A, Pang J, He J, Chen X, Tang NJ - "Perfluoroalkyl substances promote breast cancer progression via ERα and GPER mediated PI3K/Akt and MAPK/Erk signaling pathways" Ecotoxicol Environ Saf 258:114980 (2023) . doi: 10.1016/j.ecoenv.2023.114980
https://www.sciencedirect.com/science/a ... 1323004840
"Two estrogen receptors (ER), ERα and G protein-coupled estrogen receptor (GPER), mediated the promoting effects of PFOA by activating MAPK/Erk and PI3K/Akt signaling pathways. These pathways were regulated by ERα and GPER in MCF-7 cells or independently by GPER in MDA-MB-231 cells. Overall, our study provides a better overview of the mechanisms associated with PFASs-induced breast cancer development and progression."
Lu YT, Guo ZY, Guo L, He YH, Liu LM, Jiao X, Li YH - "Mitigation PFHxA-induced neurotoxicity in Carassius auratus brain cells by selenium-enriched Bacillus subtilis via the BDNF/PI3K/AKT/GSK-3β pathway" Ecotoxicol Environ Saf 290:117567 (2024). doi: 10.1016/j.ecoenv.2024.117567
https://www.sciencedirect.com/science/a ... 1324016439
"LY294002 and LiCl confirm the crucial role of the PI3K/AKT/GSK-3β in neuroprotection."
Mei J, Jiang J, Li Z, Pan Y, Xu K, Gao X, Yuan J, Li L, Wang Y, Wang L, Zhao A, Jiang S, Wang X, Yi S, Li S, Xue Y, Ma Y, Liu Y, Wang Y, Li J, Chen C, Liu Y - "Increased perfluorooctanoic acid accumulation facilitates the migration and invasion of lung cancer cells via remodeling cell mechanics" Proc Natl Acad Sci U S A 121(51):e2408575121 (2024) doi: 10.1073/pnas.2408575121
https://www.pnas.org/doi/10.1073/pnas.2408575121
"Mechanistically, the interaction between PFOA and transmembrane integrins in cancer cells triggers changes in cellular mechanical properties, leading to the reorganization of the cytoskeleton, and activation of the intracellular FAK-PI3K-Akt signaling pathway. Our findings demonstrate that in individuals with lung adenocarcinoma, PFOA can increase the risk of cancer metastasis even at daily exposure levels."
Oh JH, Kim EY, Choi YH, Nam TJ - "Negative regulation of ERK1/2 by PI3K is required for the protective effects of Pyropia yezoensis peptide against perfluorooctane sulfonate-induced endoplasmic reticulum stress" Mol Med Rep 15(5):2583-2587 (2017). doi: 10.3892/mmr.2017.6285
"These findings indicate that negative regulation of ERK1/2 by PI3K is essential for the protective effects of PYP against PFOS-induced cell death."
Wang X, Li B, Zhao WD, Liu YJ, Shang DS, Fang WG, Chen YH - "Perfluorooctane sulfonate triggers tight junction 'opening' in brain endothelial cells via phosphatidylinositol 3-kinase" Biochem Biophys Res Commun 410(2):258-63 (2011) doi: 10.1016/j.bbrc.2011.05.128
https://www.sciencedirect.com/science/a ... 1X1100903X
"Results demonstrated that PFOS promoted the activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in HBMEC. We found that overexpression of PI3K dominant-negative mutant in HBMEC abolished the PFOS-induced TJ disassembly. These data demonstrated that PFOS can trigger the 'opening' of tight junction in brain endothelial cells through PI3K signaling pathway."
Wu Y, Huang J, Deng M, Jin Y, Yang H, Liu Y, Cao Q, Mennigen JA, Tu W - "Acute exposure to environmentally relevant concentrations of Chinese PFOS alternative F-53B induces oxidative stress in early developing zebrafish" Chemosphere 235:945-951 (2019) doi: 10.1016/j.chemosphere.2019.07.016.
https://linkinghub.elsevier.com/retriev ... 3519314961
"The contents of malondialdehyde (MDA) and reduced glutathione (GSH), as well as the activities, mRNA and protein levels of most of antioxidant enzyme genes involved in the phosphatidylinositol 3-kinase (PI3K)/Akt/Nrf2-ARE pathway were significantly reduced. Further in silico study indicated that F-53B binds tightly to PI3K, which may be related to the inhibition of Nrf2-regulated antioxidant functions by F-53B as a PI3K inhibitor."
Xin Y, Wan B, Yang Y, Cui XJ, Xie YC, Guo LH - "Perfluoroalkyl acid exposure induces protective mitochondrial and endoplasmic reticulum autophagy in lung cells" Arch Toxicol 92(10):3131-3147 (2018) doi: 10.1007/s00204-018-2266-0
https://link.springer.com/article/10.10 ... 018-2266-0
"Analysis on the signaling pathways showed that PFAAs activated the MAPK pathways and inhibited the PI3K/Akt pathway, with potencies following the order of PFDA > PFNA > PFOA. "
Yan S, Zhang H, Zheng F, Sheng N, Guo X, Dai J - "Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice" Sci Rep 5:11029 (2015) doi: 10.1038/srep11029
https://pmc.ncbi.nlm.nih.gov/articles/PMC4464286/
"We report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver."
Zhang QY, Zhong MT, Gi M, Chen YK, Lai MQ, Liu JY, Liu YM, Wang Q, Xie XL - "Inulin alleviates perfluorooctanoic acid-induced intestinal injury in mice by modulating the PI3K/AKT/mTOR signaling pathway" Environ Pollut 342:123090 (2024) doi: 10.1016/j.envpol.2023.123090
https://linkinghub.elsevier.com/retriev ... 23)02092-4
"Inulin restored the intestinal injury by activating the PI3K/AKT/mTOR pathway."
Zhang Q, Wang J, Chen C, Kong Y, Yan H, Duan J, Wang C, Sha Y, Wen X, Wang C - "Perfluorooctanoic acid induces migration and invasion and inhibits apoptosis through the PI3K/AKT signaling pathway in human rhabdomyosarcoma cells" Oncol Rep 42(4):1558-1568 (2019) doi: 10.3892/or.2019.7265.
"The results obtained show that the PI3K/AKT signaling pathway is implicated in mediating the pro‑neoplastic effects of PFOA. The data suggests that PFOA is a carcinogen capable of promoting RD cell migration and invasion and inhibiting apoptosis through the PI3K/AKT signaling pathway."
HYPOTHYROIDISM/PTU
Dong S, Liu Q, Jiang M, Ma Q, Huang Q, Liu T, Li Y, Ni L, Shi Y - "Xiao-Luo-Wan treats propylthiouracil-induced goiter with hypothyroidism in rats through the PI3K-AKT/RAS pathways based on UPLC/MS and network pharmacology" J Ethnopharmacol 289:115045 (2022). doi: 10.1016/j.jep.2022.115045.
https://pubmed.ncbi.nlm.nih.gov/35101570/
Yao Y, Chang X, Wang D, Ma H, Wang H, Zhang H, Li C, Wang J - "Roles of ERK1/2 and PI3K/AKT signaling pathways in mitochondria-mediated apoptosis in testes of hypothyroid rats" Toxicol Res (Camb) 7(6):1214-1224 (2018)
https://pubmed.ncbi.nlm.nih.gov/30542605/
"These results suggested that ERK1/2 and PI3K/AKT signaling pathways could be suppressed by hypothyroidism via inhibiting the expressions of ERs [estrogen receptors] and could finally induce apoptosis in testes."
Wang Y, Wei W, Wang Y, Dong J, Song B, Min H, Teng W, Chen J - "Neurotoxicity of developmental hypothyroxinemia and hypothyroidism in rats: Impairments of long-term potentiation are mediated by phosphatidylinositol 3-kinase signaling pathway" Toxicol Appl Pharmacol 271(2):257-65 (2013). doi: 10.1016/j.taap.2013.04.034
https://www.sciencedirect.com/science/a ... 8X13002184
"Decreased activation of the PI3K signaling pathway was also observed in rats subjected to developmental hypothyroxinemia or hypothyroidism. Our results may support the hypothesis that neurotoxicity of both developmental hypothyroxinemia and hypothyroidism causes damages to learning and memory. Our results also suggest that decreased activation of the PI3K signaling pathway may contribute to impairments of LTP caused by neurotoxicity of both developmental hypothyroxinemia and hypothyroidism."
Zhan Y, Lang L, Wang F, Wu X, Zhang H, Dong Y, Yang H, Zhu D - "Hypothyroidism promotes microglia M1 polarization by inhibiting BDNF-promoted PI3K-Akt signaling pathway" Neuroendocrinology 1-19 (2024) doi: 10.1159/000542858
https://karger.com/nen/article/doi/10.1 ... larization
"Our study demonstrated a sound conclusion that hypothyroidism promotes microglia M1 polarization by inhibiting BDNF-activated PI3K-Akt signaling pathway in brain, which could serve as a promising therapeutic target for microglia-induced neurodegenerative or emotional disorders in future."
TSHr
Voutsadakis IA - "The TSH/Thyroid Hormones Axis and Breast Cancer" J Clin Med. 11(3):687 (2022). doi: 10.3390/jcm11030687
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836919/
"The activation of TSHR in the plasma cell membrane transmits signals through G proteins Gas and Gaq, and downstream through the cAMP/PKA/CREB pathway and the phospholipase C/PI3K/AKT/mTOR pathway. The role of TSHR is established in well-differentiated thyroid cancers, where treatment with T4 to suppress TSH secretion from the hypophysis, in order to prevent TSHR activation, is the mainstay of treatment [69]. TSHR is also expressed in other cancers, such as ovarian carcinomas, hepatomas and melanomas [68,70,71,72]. The expression of TSHR is increased in breast cancer tissues compared to adjacent normal mammary tissues [73]."
Liu C, Li L, Ha M, Qi S, Duan P, Yang K - "The PI3K/Akt and ERK pathways elevate thyroid hormone receptor β1 and TRH receptor to decrease thyroid hormones after exposure to PCB153 and p,p'-DDE" Chemosphere 118:229-38 (2015)
https://pubmed.ncbi.nlm.nih.gov/25278044/
"Taken together, after exposure to PCB153 and p,p'-DDE, activated PI3K/Akt and ERK pathways disrupt the hypothalamic-pituitary-thyroid (HPT) axis via TRβ1 and TRHr and then decrease TH levels, and that would be a potential mechanism by which PCBs and DDT disturb TH homeostasis."
Yao Y, Chang X, Wang D, Ma H, Wang H, Zhang H, Li C, Wang J - "Roles of ERK1/2 and PI3K/AKT signaling pathways in mitochondria-mediated apoptosis in testes of hypothyroid rats" Toxicol Res (Camb) 7(6):1214-1224 (2018)
https://pubmed.ncbi.nlm.nih.gov/30542605/
Chen J, Shi M, Wang N, Yi P, Sun L, Meng Q - "TSH inhibits eNOS expression in HMEC-1 cells through the TSHR/PI3K/AKT signaling pathway" Ann Endocrinol (Paris) 80(5-6):273-279 (2019)
https://pubmed.ncbi.nlm.nih.gov/31606200/
Li B, Smith TJ - "PI3K/AKT pathway mediates induction of IL-1RA by TSH in fibrocytes: modulation by PTEN" J Clin Endocrinol Metab 99(9):3363-72 (2014)
https://pubmed.ncbi.nlm.nih.gov/24840811/
Woeller CF, Roztocil E, Hammond C, Feldon SE - "TSHR Signaling Stimulates Proliferation Through PI3K/Akt and Induction of miR-146a and miR-155 in Thyroid Eye Disease Orbital Fibroblasts" Invest Ophthalmol Vis Sci 60(13):4336-4345 (2019)
https://pubmed.ncbi.nlm.nih.gov/31622470/
García-Jiménez C, Santisteban P - "TSH signalling and cancer" Arq Bras Endocrinol Metabol 51(5):654-71(2007)
https://digital.csic.es/bitstream/10261/2171/1/tsh.pdf
"Oncogenes relevant to thyroid carcinogenesis are normally engaged in proliferation and/or survival pathways, the paradigms are RET/Ras/B-Raf, PTEN/Akt and Ecadherin/β-catenin representing the MAPK, PI3K and Wnt pathways respectively. These pathways are integrated in the thyrocyte signalling network among them and with the cAMP/PKA pathway and altering their crosstalk may lead to carcinogenesis."
Suh JM, Song JH, Kim DW, Kim H, Chung HK, Hwang JH, Kim JM, Hwang ES, Chung J, Han JH, Cho BY, Ro HK, Shong M - "Regulation of the phosphatidylinositol 3-kinase, Akt/protein kinase B, FRAP/mammalian target of rapamycin, and ribosomal S6 kinase 1 signaling pathways by thyroid-stimulating hormone (TSH) and stimulating type TSH receptor antibodies in the thyroid gland" J Biol Chem 278(24):21960-71 (2003). doi: 10.1074/jbc.M300805200
https://linkinghub.elsevier.com/retriev ... 20)68606-9
"TSH and cAMP increased the tyrosine phosphorylation of TSHR and the association between TSHR and the p85alpha regulatory subunit of PI3K. TSH induced a redistribution of PDK1 from the cytoplasm to the plasma membrane in the cells in a PI3K- and protein kinase A-dependent manner."
T3
Chang X, Zhang B, Lihua L, Feng Z - "T3 inhibits the calcification of vascular smooth muscle cells and the potential mechanism" Am J Transl Res 8(11):4694-4704 (2016)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126314/
"T3 may act on PI3K/Akt signaling pathway to inhibit the phenotype transformation of VSMC, which then suppresses the calcium/phosphate induced calcification of rat VSMCs. Thus, T3 is an endogenous molecule that can protect the blood vessels against calcification."
Carrillo-Sepúlveda MA, Ceravolo GS, Fortes ZB, Carvalho MH, Tostes RC, Laurindo FR, Webb RC, Barreto-Chaves ML - "Thyroid hormone stimulates NO production via activation of the PI3K/Akt pathway in vascular myocytes" Cardiovasc Res 85(3):560-70 (2010) doi: 10.1093/cvr/cvp304
https://pmc.ncbi.nlm.nih.gov/articles/PMC3031311/
"These findings show for the first time that the PI3K/Akt signalling pathway is involved in T3-induced NO production by VSMCs, which occurs with expressive participation of inducible and neuronal NOS."
Brown AR, Simmen RC, Simmen FA - "The role of thyroid hormone signaling in the prevention of digestive system cancers" Int J Mol Sci 14(8):16240-57 (2013). doi: 10.3390/ijms140816240
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759909/
"In addition to the intracellular TRs, the integrin αVβ3 has more recently been identified as a cell surface receptor for TH [16]. Two separate binding sites for TH have been identified on the extracellular domain of this integrin. One site binds T3 to stimulate the PI3K pathway, leading to the translocation of TRα to the nucleus for transcription of HIF-1α; the other site binds primarily to T4 to activate ERK1/2 leading to nuclear localization of TRβ1 [17].
Diniz GP, Carneiro-Ramos MS, Barreto-Chaves ML - "Angiotensin type 1 receptor mediates thyroid hormone-induced cardiomyocyte hypertrophy through the Akt/GSK-3beta/mTOR signaling pathway" Basic Res Cardiol 104(6):653-67 (2009) doi: 10.1007/s00395-009-0043-1
https://link.springer.com/article/10.10 ... 009-0043-1
"The cardiomyocytes treated with T3 demonstrated a rapid activation of Akt/GSK-3beta/mTOR signaling pathway, which was completely inhibited by the use of PI3K inhibitors (LY294002, 10 microM and Wortmannin, 200 nM)."
Lei J, Ingbar DH - "Src kinase integrates PI3K/Akt and MAPK/ERK1/2 pathways in T3-induced Na-K-ATPase activity in adult rat alveolar cells" Am J Physiol Lung Cell Mol Physiol 301(5):L765-71 (2011) doi: 10.1152/ajplung.00151.2011
https://journals.physiology.org/doi/ful ... 00151.2011
"Adult rat AECs [alveolar cells] T3-stimulated Src kinase activity can activate both PI3K/Akt and MAPK/ERK1/2, and activation of Akt is necessary for T3-induced Na-K-ATPase activity."
Lin HY, Sun M, Tang HY, Lin C, Luidens MK, Mousa SA, Incerpi S, Drusano GL, Davis FB, Davis PJ - "L-Thyroxine vs. 3,5,3'-triiodo-L-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase" Am J Physiol Cell Physio 296(5):C980-91 (2009) doi: 10.1152/ajpcell.00305.2008
https://journals.physiology.org/doi/ful ... 00305.2008
"We find that both T4 and T3 activate ERK1/2 and cause cell proliferation, indicated by accumulation of proliferating cell nuclear antigen (PCNA) and radiolabeled thymidine incorporation, in a human glioma (U-87 MG) cell line that has been studied extensively by others (4, 21, 34, 42). However, only T3 causes tyrosine phosphorylation (activation) of PI3-kinase. This latter cell surface action of T3, however, does not contribute to cell proliferation; instead, its consequences include translocation of the nuclear hormone receptor, TRα, from cytoplasm to the nucleus of hormone-treated cells and increased expression of the hypoxia-inducible factor (HIF)-1α gene."
T4
Xian H, Wang F, Teng W, Yang D, Zhang M - "Thyroid hormone induce a p53-dependent DNA damage through PI3K/Akt activation in sperm" Gene 615:1-7 (2017) doi: 10.1016/j.gene.2017.03.014
https://pubmed.ncbi.nlm.nih.gov/28322991/
"Our results highlight that inhibition of PI3K/Akt pathway or p53 degradation is important in maintaining sperm motility in a thyroxine receptor (TR)-dependent manner."
- Re: Hypoxia -> HIF-1a
Hypoxia - excessive iodine triggers hypoxia pathway -> which triggers D3 (Russo, Bianco et al., 2021)
- Zhang L, Sun X, Liu L, Wang P, Qian L - "Excessive iodine induces thyroid follicular epithelial cells apoptosis by activating HIF-1α-mediated hypoxia pathway in Hashimoto thyroiditis" Mol Biol Rep 50(4):3633-3640 (2023) doi: 10.1007/s11033-023-08273-z.
https://link.springer.com/article/10.10 ... 23-08273-z
Caspase 3 increases with increasing iodine --> induces hypoxia factor
- Russo SC, Salas-Lucia F, Bianco AC - "Deiodinases and the Metabolic Code for Thyroid Hormone Action" Endocrinology 162(8):bqab059 (2021)
https://pubmed.ncbi.nlm.nih.gov/33720335/
D3 expression is induced by hypoxia-inducible factor 1α (HIF-1a), dampening T3 signaling and the metabolic rate. The coordinated expression of these enzymes adjusts TH signaling in a time- and tissue-specific fashion, affecting metabolic pathways in health and disease states.
- Zhang L, Sun X, Liu L, Wang P, Qian L - "Excessive iodine induces thyroid follicular epithelial cells apoptosis by activating HIF-1α-mediated hypoxia pathway in Hashimoto thyroiditis" Mol Biol Rep 50(4):3633-3640 (2023) doi: 10.1007/s11033-023-08273-z.
Aoki T, Tsunekawa K, Araki O, Ogiwara T, Nara M, Sumino H, Kimura T, Murakami M - "Type 2 Iodothyronine Deiodinase Activity Is Required for Rapid Stimulation of PI3K by Thyroxine in Human Umbilical Vein Endothelial Cells" Endocrinology 156(11):4312-24 (2015) doi: 10.1210/en.2014-1988
https://pmc.ncbi.nlm.nih.gov/articles/PMC4606755/
"These findings suggest that conversion of T4 to T3 by D2 is required for TRα1/PI3K-mediated nongenomic actions of T4 in HUVECs, including stimulation of Akt phosphorylation and Rac activation, which result in cell migration."
Li Z, Xu T, Fan X, Chen K, Wan C, Li X, Yin H, Li S - "Bisphenol A aggravate selenium deficiency-induced apoptosis via miR-215-3p/Dio1 to activate ROS/PI3K/AKT pathway in chicken arterial" J Cell Physiol 238(6):1256-1274 (2023). doi: 10.1002/jcp.31007
https://onlinelibrary.wiley.com/doi/10.1002/jcp.31007
"These results suggest that BPA exposure aggravates the apoptosis of Se deficient arterial endothelial cells in chickens by regulating the ROS/PI3K/AKT pathway activated by miR-215-3p/Dio1."
RHEUMATOID ARTHITIS - Gq/11
Wang Y, Li Y, He Y, Sun Y, Sun W, Xie Q, Yin G, Du Y, Wang L, Shi G - "Expression of G protein αq Subunit is Decreased in Lymphocytes from Patients with Rheumatoid Arthritis and is Correlated with Disease Activity" Scand J Immunol 75(2):203-9 (2012) doi: 10.1111/j.1365-3083.2011.02635.x. PMID: 21923740.
https://onlinelibrary.wiley.com/doi/10. ... 11.02635.x
"Gαq, the alpha subunit of Gq, a member of the Gq/11 sub-family, was reported to inhibit phosphatidylinositol-3-Kinase (PI3K) activation and prevent the activation of Akt. Previous studies demonstrated that mice losing Gαq in their immune system could spontaneously develop inflammatory arthritis. In this study, we showed that the Gαq expressions at mRNA and protein levels in the peripheral blood lymphocytes (PBLs) from patients with rheumatoid arthritis (RA) were significantly decreased in comparison of which in healthy individuals. The expression levels of Gαq mRNA in PBLs from patients with RA were correlated with RA disease activity (DAS28), anti-cyclic citrullinated protein antibodies, C-reactive protein and rheumatoid factor. We also demonstrated that Gαq controlled the apoptosis of RA PBLs through regulating the activity of Mcl-1 and caspase-3. These data suggested that Gαq might be involved in the pathogenesis of RA by regulating PBLs apoptosis."
Gq/11
Dugourd C, Gervais M, Corvol P, Monnot C - "Akt is a major downstream target of PI3-kinase involved in angiotensin II-induced proliferation" Hypertension 41(4):882-90 (2003)
https://pubmed.ncbi.nlm.nih.gov/12623864/
Kong KC, Billington CK, Gandhi U, Panettieri RA Jr, Penn RB - "Cooperative mitogenic signaling by G protein-coupled receptors and growth factors is dependent on G(q/11)" FASEB J 20(9):1558-60 (2006)
https://pubmed.ncbi.nlm.nih.gov/16723377/
Taboubi S, Garrouste F, Parat F, Pommier G, Faure E, Monferran S, Kovacic H, Lehmann M - " Gq-coupled purinergic receptors inhibit insulin-like growth factor-I/phosphoinositide 3-kinase pathway-dependent keratinocyte migration" Mol Biol Cell 21(6):946-55 (2011)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836975/
"These findings provide new insight into the signaling cross-talk between receptor tyrosine kinase and Gα(q/11)-coupled receptors, which mediate opposite effects on p110α-PI3K activity and keratinocyte migration."
Ueda H, Morishita R, Narumiya S, Kato K, Asano T - "Galphaq/11 signaling induces apoptosis through two pathways involving reduction of Akt phosphorylation and activation of RhoA in HeLa cells" Exp Cell Res 298(1):207-17 (2004). doi: 10.1016/j.yexcr.2004.04.015
https://pubmed.ncbi.nlm.nih.gov/15242775/
Wang Y, Li Y, He Y, Sun Y, Sun W, Xie Q, Yin G, Du Y, Wang L, Shi G - "Expression of G protein αq Subunit is Decreased in Lymphocytes from Patients with Rheumatoid Arthritis and is Correlated with Disease Activity" Scand J Immunol 75(2):203-9 (2012). doi: 10.1111/j.1365-3083.2011.02635.x.
https://pubmed.ncbi.nlm.nih.gov/21923740/
"Gαq, the alpha subunit of Gq, a member of the Gq/11 sub-family, was reported to inhibit phosphatidylinositol-3-Kinase (PI3K) activation and prevent the activation of Akt."
Wu EH, Tam BH, Wong YH - "Constitutively active alpha subunits of G(q/11) and G(12/13) families inhibit activation of the pro-survival Akt signaling cascade" FEBS J 273(11):2388-98 (2006). doi: 10.1111/j.1742-4658.2006.05245.x.
https://febs.onlinelibrary.wiley.com/do ... 06.05245.x
- GNA14 (Gq/11)
NOTE: Gq/11 family consists of Gna11, Gna14, Gnaq and Gna15.
GNA14 specifically is a member of the Gq/11 family of G proteins, which are involved in activating phospholipase C beta (PLCβ). This activation leads to the production of DAG and subsequent activation of PKC. PKC, in turn, can activate PI3K, leading to the activation of the AKT pathway.
Xu C, Li YM, Sun B, Zhong FJ, Yang LY - "GNA14's interaction with RACK1 inhibits hepatocellular carcinoma progression through reducing MAPK/JNK and PI3K/AKT signaling pathway" Carcinogenesis 42(11):1357-1369 (2021). doi: 10.1093/carcin/bgab098
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598382/
COVID-19/MERS
Purcaru OS, Artene SA, Barcan E, Silosi CA, Stanciu I, Danoiu S, Tudorache S, Tataranu LG, Dricu A - "The Interference between SARS-CoV-2 and Tyrosine Kinase Receptor Signaling in Cancer" Int J Mol Sci 22(9):4830 (2021) doi: 10.3390/ijms22094830
https://pmc.ncbi.nlm.nih.gov/articles/PMC8124491/
"MAPK/ERK and PI3K/AKT/mTOR signaling responses have been shown to be relevant in MERS-CoV infection through bioinformatics analysis in vivo. Therefore, by suppressing these pathways, the replication was substantially inhibited in vitro."
- SEE: Kindrachuk J, Ork B, Hart BJ, Mazur S, Holbrook MR, Frieman MB, Traynor D, Johnson RF, Dyall J, Kuhn JH, Olinger GG, Hensley LE, Jahrling PB - "Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis" Antimicrob Agents Chemother 59(2):1088-99 (2015). doi: 10.1128/AAC.03659-14
https://pubmed.ncbi.nlm.nih.gov/25487801/
https://pubmed.ncbi.nlm.nih.gov/33081581/
- SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2
Li SL, Chen X, Wu T, Zhang XW, Li H, Zhang Y, Ji ZZ - "Knockdown of TMPRSS3 inhibits gastric cancer cell proliferation, invasion and EMT via regulation of the ERK1/2 and PI3K/Akt pathways" Biomed Pharmacother 107:841-848 (2018). doi: 10.1016/j.biopha.2018.08.023
https://pubmed.ncbi.nlm.nih.gov/30142546/
IODINE (EXCESS)
Serrano-Nascimento C, Nicola JP, Teixeira Sda S, Poyares LL, Lellis-Santos C, Bordin S, Masini-Repiso AM, Nunes MT - "Excess iodide downregulates Na(+)/I(-) symporter gene transcription through activation of PI3K/Akt pathway" Mol Cell Endocrinol 426:73-90 (2016)
https://pubmed.ncbi.nlm.nih.gov/26872612
Serrano-Nascimento C, da Silva Teixeira S, Nicola JP, Nachbar RT, Masini-Repiso AM, Nunes MT - "The acute inhibitory effect of iodide excess on sodium/iodide symporter expression and activity involves the PI3K/Akt signaling pathway" Endocrinology 155(3):1145-56 (2014)
https://pubmed.ncbi.nlm.nih.gov/24424051/
"Overall, our data demonstrated the involvement of the PI3K/Akt signaling pathway as a novel mediator of the I(-)-induced thyroid autoregulation, linking the role of thyroid oxidative state to the Wolff-Chaikoff effect."
Liu S, Ding P, Yu X, Xing Z, Cui Y, Liu H - "Excess iodine promotes papillary thyroid carcinoma through the AKT/mTOR pathway" Preprint (2024) doi:10.21203/rs.3.rs-5395582/v1.
https://assets-eu.researchsquare.com/fi ... 1734310013
NOTE: This study is by the Tianjin group (Cui, Liu et al.)
ALZHEIMER'S
Gabbouj S, Ryhänen S, Marttinen M, Wittrahm R, Takalo M, Kemppainen S, Martiskainen H, Tanila H, Haapasalo A, Hiltunen M, Natunen T - "Altered Insulin Signaling in Alzheimer's Disease Brain - Special Emphasis on PI3K-Akt Pathway" Front Neurosci 13:629 (2019)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591470/
Naringin & Thyroid
Abd-Elmawla MA, Essam RM, Ahmed KA, Abdelmonem M - "Implication of Wnt/GSK-3β/β-Catenin Signaling in the Pathogenesis of Mood Disturbances Associated with Hyperthyroidism in Rats: Potential Therapeutic Effect of Naringin" ACS Chem Neurosci 14(11):2035-2048 (2023). doi: 10.1021/acschemneuro.3c00013
https://pubs.acs.org/doi/abs/10.1021/ac ... ro.3c00013
Pistollato F, Masias M, Agudo P, Giampieri F, Battino M - "Effects of phytochemicals on thyroid function and their possible role in thyroid disease" Ann N Y Acad Sci 1443(1):3-19 (2019). doi: 10.1111/nyas.13980
https://pubmed.ncbi.nlm.nih.gov/30381840/
Shashank Shakyawal, Gayatri Rai, Payal Mahobiya - "Biochemical, Histopathological, and Immunohistochemical Study of Repeated Environmental Toxicant Ultraviolet B Radiation-Induced Hyperthyroidism: Alleviation of Oxidative Stress and Prevention by Naringin in Male Swiss Albino Mice" Authorea, June 6, 2023.
https://www.authorea.com/doi/full/10.22 ... 4.40013842
"Naringin was utilised as an antioxidant in our analysis. Additionally, compared to the UVB-irradiated group, the administration of naringin resulted in a substantial drop in T3, T4, FT3, and FT4 levels and a large increase in TSH levels."
Naringin & PI3K/AKT
Naringin is a flavonoid, a type of plant compound with antioxidant properties, found primarily in citrus fruits like grapefruits and oranges. It is responsible for the bitter taste in grapefruits.
Zhou J, Xia L, Zhang Y - "Naringin inhibits thyroid cancer cell proliferation and induces cell apoptosis through repressing PI3K/AKT pathway" Pathol Res Pract 215(12):152707 (2019). doi: 10.1016/j.prp.2019.152707
https://www.sciencedirect.com/science/a ... via%3Dihub
Du Y, Wang G, Liu B, Guo M, Yan X, Dou M, Yu F, Ba Y, Zhou G - "Naringin alleviates fluoride-induced neurological impairment: A focus on the regulation of energy metabolism mediated by mitochondrial permeability transition pore" Sci Total Environ 177073 (2024). doi: 10.1016/j.scitotenv.2024.177073
https://pubmed.ncbi.nlm.nih.gov/39447898/
AEBSF
Hosoi T, Hyoda K, Okuma Y, Nomura Y, Ozawa K - "Inhibitory effect of 4-(2-aminoethyl)-benzenesulfonyl fluoride, a serine protease inhibitor, on PI3K inhibitor-induced CHOP expression" Eur J Pharmacol 554(1):8-11 (2007). doi: 10.1016/j.ejphar.2006.09.063
https://www.sciencedirect.com/science/a ... 9906011058
"We found that AEBSF completely inhibited PI3K inhibitor-induced CHOP expression at both mRNA and protein levels."
Fluorinated Candidates as PI3K Inhibitors
Tantawy AH, El-Behairy MF, Abd-Allah WH, Jiang H, Wang MQ, Marzouk AA - "Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Fluorinated Candidates as PI3K Inhibitors: Targeting Fluorophilic Binding Sites" J Med Chem 64(23):17468-17485 (2021) doi: 10.1021/acs.jmedchem.1c01674
https://pubs.acs.org/doi/abs/10.1021/ac ... em.1c01674
PM2.5
Tang S, Li D, Ding H, Jiang M, Zhao Y, Yu D, Zhang R, Chen W, Chen R, Zheng Y, Piao J - "GLIS3 mediated by the Rap1/PI3K/AKT signal pathway facilitates real-ambient PM2.5 exposure disturbed thyroid hormone homeostasis regulation" Ecotoxicol Environ Saf 232:113248 (2022) doi: 10.1016/j.ecoenv.2022.113248
https://www.sciencedirect.com/science/a ... 1322000884
"PM2.5 exposure induces histological changes in the thyroid gland and thyroid dysfunction in mice. The exposure activates GLIS3 through the Rap1/PI3K/AKT pathway to promote the expression of proteins related to thyroid hormone synthesis, leading to increased dysregulating TH homeostasis."
Cypermethrin
Ha M, Huang X, Li L, Lu D, Liu C - "PKCα mediated by the PI3K/Akt-FOXA1 cascade facilitates cypermethrin-induced hyperthyroidism" Sci Total Environ 757:143727 (2021) doi: 10.1016/j.scitotenv.2020.143727
https://pubmed.ncbi.nlm.nih.gov/33250241/
"Further studies found that β-CYP induced PKCα translation by the miR-330-3p-targeted PI3K/Akt-FOXA1 cascade and then PKCα positively regulated TTF-1 to promote TPO and Tg expressions, which in turn facilitated TH biosynthesis."
miRNA-125a
Chen D, Huang X, Lu S, Deng H, Gan H, Huang R, Zhang B - "miRNA-125a modulates autophagy of thyroiditis through PI3K/Akt/mTOR signaling pathway" Exp Ther Med 17(4):2465-2472 (2019) doi: 10.3892/etm.2019.7256
https://www.spandidos-publications.com/etm/17/4/2465
"PI3K inhibition enhanced the ability of miR‑125a to increase the inflammatory response in vitro via regulation of the PI3K/Akt/mTOR signaling pathway. These results suggest miR‑125a inhibited autophagy in a model of thyroiditis through the PI3K/Akt/mTOR signaling pathway."
miR-155
Fu Q, Zhu X, Fang Q, Han H, Wang Z, Xie J, Qian D, Wu X, Wu Y, Chen K - "miR-155 enhances apoptosis of macrophage through suppressing PI3K-AKT activation in Pseudomonas aeruginosa keratitis" Heliyon 10(17):e36585 (2024). doi: 10.1016/j.heliyon.2024.e36585
https://pubmed.ncbi.nlm.nih.gov/39263048/
Phorbol esters
Weiss RH, Yabes AP - "Mitogenic inhibition by phorbol esters is associated with decreased phosphatidylinositol-3 kinase activation" Am J Physiol 270(2 Pt 1):C619-27 (1996) doi: 10.1152/ajpcell.1996.270.2.C619
https://journals.physiology.org/doi/abs ... 270.2.C619
"These data suggest that the site of growth inhibition by PMA in VSM cells lies upstream of signal transfer particle aggregation and that such growth arrest may be mediated through inhibition of activation of PI3K."
Voriconazole
Martín-Segura A, Ahmed T, Casadomé-Perales Á, Palomares-Perez I, Palomer E, Kerstens A, Munck S, Balschun D, Dotti CG - "Age-associated cholesterol reduction triggers brain insulin resistance by facilitating ligand-independent receptor activation and pathway desensitization" Aging Cell. 18(3):e12932 (2019). doi: 10.1111/acel.12932
"Biochemically, hippocampal fractions from the treated mice showed significantly reduced levels of PI3K/Akt and the downstream effector p70S6K compared to untreated old mice."
Fluoroquinolones
Aranda A, Mayorga C, Ariza A, Doña I, Rosado A, Blanca-Lopez N, Andreu I, Torres MJ - "In vitro evaluation of IgE-mediated hypersensitivity reactions to quinolones" Allergy 66(2):247-54 (2011) doi: 10.1111/j.1398-9995.2010.02460.x.
https://pubmed.ncbi.nlm.nih.gov/20722637/