Fluoride:
Alhusaini A, Faddaa L, Ali HM, Hassan I, El Orabi NF, Bassiouni Y - "Amelioration of the Protein Expression of Cox2, NFκB, and STAT-3 by Some Antioxidants in the Liver of Sodium Fluoride-Intoxicated Rats" Dose Response 16(3):1559325818800153 (2018). doi: 10.1177/1559325818800153.
https://pmc.ncbi.nlm.nih.gov/articles/PMC6146328/
"Sodium fluoride upregulated serum alanine and aspartate transferases activities, tumor necrosis factor α and hepatic malondialdehyde and nitric oxide levels, and the expression of cyclooxygenase 2, nuclear factor κB cell, and signal transducer and activator of transcription 3."
Ameeramja J, Perumal E - "Possible Modulatory Effect of Tamarind Seed Coat Extract on Fluoride-Induced Pulmonary Inflammation and Fibrosis in Rats" Inflammation 41(3):886-895 (2018) doi: 10.1007/s10753-018-0743-5
https://pubmed.ncbi.nlm.nih.gov/29508183/
Aslan A, Beyaz S, Gok O, Parlak G, Can MI, Agca CA, Ozercan IH, Parlak AE - "Royal jelly protects brain tissue against fluoride-induced damage by activating Bcl-2/NF-κB/caspase-3/caspase-6/Bax and Erk signaling pathways in rats" Environ Sci Pollut Res Int 30(17):49014-49025 (2023) doi: 10.1007/s11356-023-25636-y
https://link.springer.com/article/10.10 ... 23-25636-y
"The Bcl-2, NF-κB, and COX-2 protein expression levels were increased in the fluoride-treated (50 and 100 mg/kg) groups."
Dec K, Łukomska A, Skonieczna-Żydecka K, Kolasa-Wołosiuk A, Tarnowski M, Baranowska-Bosiacka I, Gutowska I - "Long-term exposure to fluoride as a factor promoting changes in the expression and activity of cyclooxygenases (COX1 and COX2) in various rat brain structures" Neurotoxicology 74:81-90 (2019) doi: 10.1016/j.neuro.2019.06.001
https://www.sciencedirect.com/science/a ... 3X19300518
Dec K, Łukomska A, Baranowska-Bosiacka I, Pilutin A, Maciejewska D, Skonieczna-Żydecka K, Derkacz R, Goschorska M, Wąsik A, Rębacz-Maron E, Gutowska I - "Pre-and postnatal exposition to fluorides induce changes in rats liver morphology by impairment of antioxidant defense mechanisms and COX induction" Chemosphere 211:112-119 (2018) doi: 10.1016/j.chemosphere.2018.07.145
https://pubmed.ncbi.nlm.nih.gov/30071422/
"The results of this study showed that F- affects antioxidant enzymes activity, COX2 protein expression and PGE2 synthesis in liver."
Goschorska M, Baranowska-Bosiacka I, Gutowska I, Tarnowski M, Piotrowska K, Metryka E, Safranow K, Chlubek D - "Effect of acetylcholinesterase inhibitors donepezil and rivastigmine on the activity and expression of cyclooxygenases in a model of the inflammatory action of fluoride on macrophages obtained from THP-1 monocytes" Toxicology 406-407:9-20 (2018) doi: 10.1016/j.tox.2018.05.007
https://www.sciencedirect.com/science/a ... 3X18300714
Gutowska I, Baranowska-Bosiacka I, Goschorska M, Kolasa A, Łukomska A, Jakubczyk K, Dec K, Chlubek D - "Fluoride as a factor initiating and potentiating inflammation in THP1 differentiated monocytes/macrophages" Toxicol In Vitro 29(7):1661-8 (2015). doi: 10.1016/j.tiv.2015.06.024
https://pubmed.ncbi.nlm.nih.gov/26119525/
"In the present work we demonstrate that fluoride increased concentration of PGE2 and TXA2 in THP1 macrophages. Following exposure to 1-10 μM NaF, COX-2 protein and COX-2 transcript increased markedly....This study indicated that even in small concentrations fluoride changes the amounts and activity of COX-1 and COX-2 enzymes taking part in the initiating and development of inflammatory process."
Huang H, Lin Y, Xin J, Sun N, Zhao Z, Wang H, Duan L, Zhou Y, Liu X, Fang J, Jing B, Pan K, Zeng Y, Zeng D, Li H, Ma H, Bai Y, Wei L, Ni X - "Fluoride exposure-induced gut microbiota alteration mediates colonic ferroptosis through N6-methyladenosine (m6A) mediated silencing of SLC7A11" Ecotoxicol Environ Saf 283:116816 (2024). doi: 10.1016/j.ecoenv.2024.116816
https://www.sciencedirect.com/science/a ... 1324008923
"RT-qPCR showed that the mRNA levels of PTGS2 and CHAC1 increased significantly after NaF exposure"
Kawase T, Oguro A, Orikasa M, Burns DM -"Characteristics of NaF-induced differentiation of HL-60 cells" J Bone Miner Res 11(11):1676-87 (1996) doi: 10.1002/jbmr.5650111111
https://academic.oup.com/jbmr/article-a ... 76/7501243
"NaF also increased cellular production of prostaglandin E2 (PGE2) and nitric oxide (NO) and induced expression of inducible nitric oxide synthase (iNOS); 1,25(OH)2D3 once again augmented these NaF-induced effects...These additional findings together with the observed slow onset (24-48 h) of NaF and 1,25(OH)2D3 interaction strongly suggest that 1,25(OH)2D3 acts as a cofactor with NaF primarily through interaction with an endogenous NaF-induced cyclo-oxygenase product(s), quite possibly PGE2 itself."
Kupnicka P, Listos J, Tarnowski M, Kolasa A, Kapczuk P, Surówka A, Kwiatkowski J, Janawa K, Chlubek D, Baranowska-Bosiacka I - "The Effect of Prenatal and Neonatal Fluoride Exposure to Morphine-Induced Neuroinflammation" Int J Mol Sci 25(2):826 (2024). doi: 10.3390/ijms25020826
https://pmc.ncbi.nlm.nih.gov/articles/PMC10815549/
"We provide evidence that both morphine administration and fluoride exposure have an impact on the inflammatory response by altering the expression of COX-1, COX-2, ionized calcium-binding adapter molecule (Iba1), and glial fibrillary acidic protein (GFAP) in brain structures involved in dependence development, such as the prefrontal cortex, striatum, hippocampus, and cerebellum. We observed that the expression of COX-1 and COX-2 in morphine-dependent rats is influenced by prior fluoride exposure, and these changes vary depending on the specific brain region."
Lund K, Refsnes M, Ramis I, Dunster C, Boe J, Schwarze PE, Skovlund E, Kelly FJ, Kongerud J - "Human exposure to hydrogen fluoride induces acute neutrophilic, eicosanoid, and antioxidant changes in nasal lavage fluid" Inhal Toxicol 14(2):119-32 (2002) doi: 10.1080/089583701753403944
https://www.tandfonline.com/doi/abs/10. ... 1753403944
"Among the eicosanoids, prostaglandin E(2), leukotriene B(4), and peptide leukotrienes were elevated after exposure."
Luo Q, Cui H, Deng H, Kuang P, Liu H, Lu Y, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L - "Sodium fluoride induces renal inflammatory responses by activating NF-κB signaling pathway and reducing anti-inflammatory cytokine expression in mice" Oncotarget 8(46):80192-80207 (2017). doi: 10.18632/oncotarget.19006
https://pmc.ncbi.nlm.nih.gov/articles/PMC5655190/
"A total of 240 ICR mice were randomly divided into four equal groups: the control group and three experimental groups (NaF was given orally at the dose of 0, 12, 24 and 48 mg/kg body weight for 42 days, respectively). The results showed that NaF in excess of 12 mg/kg induced the renal histopathological lesions, and inflammatory responses via the activation of nuclear factor-kappa B (NF-κB) signaling pathway and the reduction of anti-inflammatory cytokines expression. The activation of NF-κB signaling pathway was characterized by increasing the nitric oxide (NO) and prostaglandin E2 (PGE2) contents, inducible nitric oxide synthase (iNOS) activities and mRNA expression levels, and the mRNA and protein expression levels of cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interleukin-8 (IL-8) in three NaF-treated groups."
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
Parlak G, Aslan A, Turk G, Kuloglu T, Balgetir MK, Gok O, Beyaz S, Parlak AE, Cinkara SD - "Activation of Nrf-2 Transcription Factor and Caspase Pathway with Royal Jelly Reduces Fluoride Induced Testicular Damage and Infertility in Rats" Reprod Sci 30(10):3103-3122 (2023). doi: 10.1007/s43032-023-01265-1
https://link.springer.com/article/10.10 ... 23-01265-1
"As a result of the study, MDA level, expression level of Bcl-2, NFҡB, COX-2, TNF-α and IL1-α proteins, abnormal sperm rates were found higher in Fluoride-50 and Fluoride100 groups compared to other groups."
Reddy YP, Tiwari S, Tomar LK, Desai N, Sharma VK - "Fluoride-Induced Expression of Neuroinflammatory Markers and Neurophysiological Regulation in the Brain of Wistar Rat Model" Biol Trace Elem Res 199(7):2621-2626 (2021) doi: 10.1007/s12011-020-02362-x
https://link.springer.com/article/10.10 ... 20-02362-x
"Compared with the control group, those in the treated group showed significantly higher expression levels COX-2, VEGF, and HSP-70." NOTE: VEGF requires Gq/11
- SEE also: Li NN, Meng XS, Bao YR, Wang S, Li TJ - "Evidence for the Involvement of COX-2/VEGF and PTEN/Pl3K/AKT Pathway the Mechanism of Oroxin B Treated Liver Cancer" Pharmacogn Mag 14(54):207-213 (2018). doi: 10.4103/pm.pm_119_17
https://pubmed.ncbi.nlm.nih.gov/29720833/
https://www.sciencedirect.com/science/a ... 7409002008
"Following exposure to 5mM NaF, COX-2 protein and COX-2 transcript increased markedly...These results suggest that NaF induces COX-2 expression by transcriptional up-regulation via p38 and ERK pathways, at least in part, and that SFKs may be upstream tyrosine kinases responsible for NaF-induced COX-2 expression in A549 cells."
Shobudani M, Sakamaki Y, Karasawa A, Ojiro R, Zou X, Tang Q, Ozawa S, Jin M, Yoshida T, Shibutani M - "Metabolic shift as a compensatory response to impaired hippocampal neurogenesis after developmental exposure to sodium fluoride in rats" Acta Histochem 126(8):152204 (2024). doi: 10.1016/j.acthis.2024.152204
https://pubmed.ncbi.nlm.nih.gov/39413662/
"NaF also caused a dose-dependent increase in ARC+ granule cells, and it upregulated Ptgs2 in the DG at 100 ppm, suggesting that NaF exposure increases synaptic plasticity in granule cells."
NOTE: COX-2 is the enzyme's commonly used name. PTGS2 is the official gene name for the enzyme.
Tkachenko H, Kurhaluk N - "Oxidative Stress Biomarkers and Their Applications to Detect Excessive Fluorine" In: Patel, V.B., Preedy, V.R., Rajendram, R. (eds) Biomarkers in Toxicology. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Cham. (2002) https://doi.org/10.1007/978-3-030-87225-0_12-1
Zhang S, Jiang C, Liu H, Guan Z, Zeng Q, Zhang C, Lei R, Xia T, Gao H, Yang L, Chen Y, Wu X, Zhang X, Cui Y, Yu L, Wang Z, Wang A - "Fluoride-elicited developmental testicular toxicity in rats: roles of endoplasmic reticulum stress and inflammatory response" Toxicol Appl Pharmacol 271(2):206-15 (2013) doi: 10.1016/j.taap.2013.04.033 Tianjin Group
"Fluoride also induced testicular inflammation, as manifested by gene up-regulation of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in a nuclear factor-κB (NF-κB)-dependent manner."
Zhao P, Yuan Q, Liang C, Ma Y, Zhu X, Hao X, Li X, Shi J, Fu Q, Fan H, Wang D - "GPX4 degradation contributes to fluoride-induced neuronal ferroptosis and cognitive impairment via mtROS-chaperone-mediated autophagy" Sci Total Environ 927:172069 (2024) doi: 10.1016/j.scitotenv.2024.172069
https://www.sciencedirect.com/science/a ... 9724022125
"The mRNA level of PTGS2 in the hippocampus was greatly increased in 100 mg/L NaF-exposed mice (p < 0.05, one way ANOVA). Consistently, 100 mg/L NaF exposure significantly elevated the expression of PTGS2 (p < 0.05, one way ANOVA) and reduced the expression of GPX4."
PFAS
Huang Q, Fang C, Wu X, Fan J, Dong S - "Perfluorooctane sulfonate impairs the cardiac development of a marine medaka (Oryzias melastigma)" Aquat Toxico 105(1-2):71-7 (2011) doi: 10.1016/j.aquatox.2011.05.012
https://www.sciencedirect.com/science/a ... 5X1100141X
"The expressions of GATA4 and NKX2.5 were significantly down-regulated while COX-2, FGF8 and ATPase were significantly up-regulated at 6dpf."
Liao Y, Wang J, Huang QS, Fang C, Kiyama R, Shen H, Dong S - "Evaluation of cellular response to perfluorooctane sulfonate in human umbilical vein endothelial cells" Toxicol In Vitro 26(3):421-8 (2012) doi: 10.1016/j.tiv.2012.01.011
https://pubmed.ncbi.nlm.nih.gov/22269386/
"Moreover, the expression of IL-1β, COX-2 and NOS3 were significantly up-regulated, when cells were exposed to 100 mg/L PFOS for 24 h."
Shi L, Zheng J, Yan S, Li Y, Wang Y, Liu X, Xiao C - "Exposure to Perfluorooctanoic Acid Induces Cognitive Deficits via Altering Gut Microbiota Composition, Impairing Intestinal Barrier Integrity, and Causing Inflammation in Gut and Brain" J Agric Food Chem 68(47):13916-13928 (2020) doi: 10.1021/acs.jafc.0c05834
https://pubmed.ncbi.nlm.nih.gov/33151664/
"PFOA exposure also caused inflammation in gut and brain by increasing lipopolysaccharide, tumor necrosis factor-α, interleukin-1 beta, and cyclooxygenase-2 and decreasing interleukin-10."
Singh TS, Lee S, Kim HH, Choi JK, Kim SH - "Perfluorooctanoic acid induces mast cell-mediated allergic inflammation by the release of histamine and inflammatory mediators" Toxicol Lett 210(1):64-70 (2012) doi: 10.1016/j.toxlet.2012.01.014
https://pubmed.ncbi.nlm.nih.gov/22322153/
Wilson MW, Leung LK, Hong JT, Glauert HP - "Effect of the peroxisome proliferators ciprofibrate and perfluorodecanoic acid on eicosanoid concentrations in rat liver" Adv Exp Med Biol 400A:439-45 (1997)
https://link.springer.com/chapter/10.10 ... -5325-0_59
Yang B, Zou W, Hu Z, Liu F, Zhou L, Yang S, Kuang H, Wu L, Wei J, Wang J, Zou T, Zhang D - "Involvement of oxidative stress and inflammation in liver injury caused by perfluorooctanoic acid exposure in mice" Biomed Res Int 2014:409837 (2014)doi: 10.1155/2014/409837
https://pubmed.ncbi.nlm.nih.gov/24724082/
"Furthermore, hepatic levels of interleukin-6, cyclooxygenase-2, and C-reactive protein, markers of inflammatory response, were markedly increased by exposure to PFOA in mice."
Fluoroquinolones
El-Demerdash FM, Minjal AH, El-Sayed RA, Baghdadi HH - "Hepatoprotective Effect of Ethanolic Pomegranate Peel Extract Against Levofloxacin via Suppression of Oxidative Stress, Proinflammation, and Apoptosis in Male Rats" J Med Food 27(9) (2024) doi:10.1089/jmf.2023.0215.
https://pubmed.ncbi.nlm.nih.gov/39001843/
Mori S, Takahashi HK, Liu K, Wake H, Zhang J, Liu R, Yoshino T, Nishibori M - "Ciprofloxacin inhibits advanced glycation end products-induced adhesion molecule expression on human monocytes" Br J Pharmacol 161(1):229-40 (2010) doi: 10.1111/j.1476-5381.2010.00880.x.
https://pmc.ncbi.nlm.nih.gov/articles/PMC2962829/
"CIP induced PGE2 production in monocytes, irrespective of the presence of AGE-2 and AGE-3, by enhancing COX-2 expression; this led to an elevation of intracellular cAMP in monocytes."
Takahashi HK, Iwagaki H, Xue D, Katsuno G, Sugita S, Mizuno K, Mori S, Saito S, Yoshino T, Tanaka N, Nishibori M - "Effect of ciprofloxacin-induced prostaglandin E2 on interleukin-18-treated monocytes" Antimicrob Agents Chemother 49(8):3228-33 (2005) doi: 10.1128/AAC.49.8.3228-3233.2005.
https://pubmed.ncbi.nlm.nih.gov/16048930/
"In the present study, we found that ciprofloxacin induced the production of prostaglandin E(2) in monocytes in a concentration-dependent manner regardless of the presence of interleukin-18 by enhancing the expression of cyclooxygenase-2 protein and that this in turn led to the elevation of intercellular cyclic AMP in monocytes via the stimulation of prostaglandin receptors."
Sevoflurane
Shen X, Xiao Y, Li W, Chen K, Yu H - "Sevoflurane anesthesia during pregnancy in mice induces hearing impairment in the offspring" Drug Des Devel Ther. 12:1827-1836 (2018). doi: 10.2147/DDDT.S156040
https://www.tandfonline.com/doi/full/10 ... DT.S156040
"Caspase-3, iNOS, and COX-2 activation occurred in the fetal cochlea of the anesthesia group."
Yang ZY, Yuan CX. IL-17A promotes the neuroinflammation and cognitive function in sevoflurane anesthetized aged rats via activation of NF-κB signaling pathway. BMC Anesthesiol. 2018 Oct 20;18(1):147. doi: 10.1186/s12871-018-0607-4. PMID: 30342469; PMCID: PMC6195755.
https://pubmed.ncbi.nlm.nih.gov/30342469/
"In addition, increased levels in hippocampal expression of malondialdehyde (MDA), IL-17A, NF-κB p65, inducible nitric oxide synthase (iNOS) and COX-2, as well as a reduced level of superoxide dismutase (SOD) were also observed in these animals"
Zhang Q, Li Y, Yin C, Gao M, Yu J, Guo J, Xian X, Hou Z, Wang Q. IL-17A deletion reduces sevoflurane-induced neurocognitive impairment in neonatal mice by inhibiting NF-κB signaling pathway. Bioengineered. 2022 Jun;13(6):14562-14577. doi: 10.1080/21655979.2022.2090608. PMID: 35758051; PMCID: PMC9342424.
https://www.tandfonline.com/doi/full/10 ... 8#abstract
"In addition, the increased levels of NF-κB p65, iNOS, COX-2, IL-17A, IL-6 and IL-1β, reduced neuronal numbers and neuropathological changes were ameliorated in neonatal mice in the IL-17A−/− + Sev group compared with neonatal mice in Sev group."
Fluoxetine
Simplicio JA, Resstel LB, Tirapelli DP, D'Orléans-Juste P, Tirapelli CR - "Contribution of oxidative stress and prostanoids in endothelial dysfunction induced by chronic fluoxetine treatment" Vascul Pharmacol 73:124-37 (2015) doi: 10.1016/j.vph.2015.06.015
https://www.sciencedirect.com/science/a ... 9115001469
Voriconazole
Ikeya S, Sakabe JI, Yamada T, Naito T, Tokura Y - "Voriconazole-induced photocarcinogenesis is promoted by aryl hydrocarbon receptor-dependent COX-2 upregulation" Sci Rep 8: 5050 (2018)
https://doi.org/10.1038/s41598-018-23439-7
"Since COX-2 is critical enzyme for UV-induced skin cancer promotion, this signaling pathway possibly leads to skin tumor promotion as in breast cancer cells."
Gq/11
Evans J, Catalano RD, Morgan K, Critchley HO, Millar RP, Jabbour HN - "Prokineticin 1 signaling and gene regulation in early human pregnancy" Endocrinology 149(6):2877-87 (2008) doi: 10.1210/en.2007-1633. Epub 2008 Mar 13. PMID: 18339712; PMCID: PMC2696030.
https://pubmed.ncbi.nlm.nih.gov/18339712/
"COX-2 mRNA and protein expression, and prostaglandin synthesis, were elevated in response to treatment with PROK1. Moreover, expression of COX-2 by PROK1 was dependent on activation of the Gq-phospholipase C-beta-cSrc-epidermal growth factor receptor-MAPK/ERK kinase pathway. "
Pham H, Vincenti R, Slice LW - "COX-2 promoter activation by AT1R-Gq-PAK-p38beta signaling in intestinal epithelial cells" Biochim Biophys Acta 1779(6-7):408-13 (2008). doi: 10.1016/j.bbagrm.2008.05.004
https://pubmed.ncbi.nlm.nih.gov/18515110/
"These data demonstrate that in IEC-18 cells, Ang II-dependent activation of the COX-2 promoter is mediated primarily through Gq/11 signaling via a PAK/MKK6/p38beta/CREB signaling cascade."
Wei D, Birla H, Dou Y, Mei Y, Huo X, Whitehead V, Osei-Owusu P, Feske S, Patafio G, Tao Y, Hu H - "PGE2 Potentiates Orai1-Mediated Calcium Entry Contributing to Peripheral Sensitization" J Neurosci 44(1):e0329232023 (2024). doi: 10.1523/JNEUROSCI.0329-23.2023
https://pubmed.ncbi.nlm.nih.gov/37952941/
"Inhibition of Gq/11, PKC, or ERK abolished PGE2-induced SOCE increase, indicating PGE2-induced SOCE enhancement is mediated by EP1-mediated downstream cascade." (Freund's adjuvant)