LPS - Endotoxin

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

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LPS - Endotoxin
©2023 PFPC

COVID-19

Li J, Lin H, Fan T, Huang L, Zhang X, Tai Y, Fang Y, Li Q, Zhao R, Wang P, Zhou L, Wan L, Wu Y, Zhong H, Wei C, Yang X - "BPOZ-2 is a negative regulator of the NLPR3 inflammasome contributing to SARS-CoV-2-induced hyperinflammation" Front Cell Infect Microbiol 13:1134511 (2023) doi: 10.3389/fcimb.2023.1134511
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10019892/

Dorneles GP, Teixeira PC, Peres A, Rodrigues Júnior LC, da Fonseca SG, Monteiro MC, Eller S, Oliveira TF, Wendland EM, Romão PRT - "Endotoxin tolerance and low activation of TLR-4/NF-κB axis in monocytes of COVID-19 patients" J Mol Med (Berl) 101(1-2):183-195 (2023) doi: 10.1007/s00109-023-02283-x
https://link.springer.com/article/10.10 ... 23-02283-x

Liu L, Liu B, Li L, Zhou X, Li Q - "Effects of Resveratrol on Pulmonary Fibrosis via TGF-β/Smad/ERK Signaling Pathway" Am J Chin Med. 2023 Mar 9:1-26. doi: 10.1142/S0192415X23500313
https://www.worldscientific.com/doi/10. ... %200pubmed

COVID Vaccines

Seo J, Lee J, Kim S, Lee M, Yang H - "Lipid Polysaccharides have a Detrimental Effect on the Function of the Ovaries and Uterus in Mice through Increased Pro-Inflammatory Cytokines" Dev Reprod 26(4):135-144 (2022) doi: 10.12717/DR.2022.26.4.135. Epub 2022 Dec 31
https://www.ksdb.org/archive/view_artic ... r-26-4-135


Fluoride

Zhang X, Chen J, Wang G, Chen H, Cao J, Xie L, Luo Y - "Interactive effects of fluoride and seleno-l-methionine at environmental related concentrations on zebrafish (Danio rerio) liver via the gut-liver axis" Fish Shellfish Immunol 127:690-702 (2022) doi: 10.1016/j.fsi.2022.07.006
https://www.sciencedirect.com/science/a ... 4822003953

Jia B, Zong L, Lee JY, Lei J, Zhu Y, Xie H, Clemens JL, Feller MC, Na Q, Dong J, McLane MW, Jones-Beatty K, Burd I - "Maternal Supplementation of Low Dose Fluoride Alleviates Adverse Perinatal Outcomes Following Exposure to Intrauterine Inflammation" Sci Rep 9(1):2575 (2019) doi: 10.1038/s41598-018-38241-8
https://www.nature.com/articles/s41598-018-38241-8

Haught C, Xie S, Circello B, Tansky CS, Khambe D, Klukowska M, Huggins T, White DJ - "Lipopolysaccharide and Lipoteichoic Acid Virulence Deactivation by Stannous Fluoride" J Clin Dent 27(3):84-89 (2016)
https://pubmed.ncbi.nlm.nih.gov/28390203/

Ommati MM, Sabouri S, Sun Z, Zamiri MJ, Retana-Marquez S, Nategh Ahmadi H, Zuo Q, Eftekhari A, Juárez-Rojas L, Asefi Y, Lei L, Cui SG, Jadidi MH, Wang HW, Heidari R - "Inactivation of Mst/Nrf2/Keap1 signaling flexibly mitigates MAPK/NQO-HO1 activation in the reproductive axis of experimental fluorosis" Ecotoxicol Environ Saf 271:115947 (2024). doi: 10.1016/j.ecoenv.2024.115947
https://www.sciencedirect.com/science/a ... 1324000228

  • Fluorinated SSRIs:

    Izumi Y, Reiersen AM, Lenze EJ, Mennerick SJ, Zorumski CF - "SSRIs differentially modulate the effects of pro-inflammatory stimulation on hippocampal plasticity and memory via sigma 1 receptors and neurosteroids" Transl Psychiatry 13(1):39 (2023) doi: 10.1038/s41398-023-02343-3.
    https://www.nature.com/articles/s41398-023-02343-3

    Fluorinated Steroids - DEX

    Świerczek A, Jusko WJ - "Pharmacokinetic/Pharmacodynamic Modeling of Dexamethasone Anti-Inflammatory and Immunomodulatory Effects in LPS-Challenged Rats: A Model for Cytokine Release Syndrome" J Pharmacol Exp Ther 384(3):455-472 (2023)doi: 10.1124/jpet.122.001477
    https://jpet.aspetjournals.org/content/384/3/455.long

Gq/11

Wang MW, Yang Z, Chen X, Zhou SH, Huang GL, Sun JN, Jiang H, Xu WM, Lin HC, Yu X, Sun JP - "Activation of PTH1R alleviates epididymitis and orchitis through Gq and β-arrestin-1 pathways" Proc Natl Acad Sci U S A 118(45):e2107363118 (2021) doi: 10.1073/pnas.2107363118
https://www.pnas.org/doi/10.1073/pnas.2107363118

Gruenbacher G, Gander H, Dobler G, Rahm A, Klaver D, Thurnher M - "The human G protein-coupled ATP receptor P2Y11 is a target for anti-inflammatory strategies" Br J Pharmacol 178(7):1541-1555 (2021) doi: 10.1111/bph.15379
https://bpspubs.onlinelibrary.wiley.com ... /bph.15379
"During lipopolysaccharide-induced activation of TLR4, which shares the downstream signalling pathway with IL-1 receptors, P2Y11 receptors specifically prevented secretion of TNF-α."

George T, Chakraborty M, Giembycz MA, Newton R - "A bronchoprotective role for Rgs2 in a murine model of lipopolysaccharide-induced airways inflammation" Allergy Asthma Clin Immunol 14:40 (2018). doi: 10.1186/s13223-018-0266-5
https://aacijournal.biomedcentral.com/a ... 018-0266-5
"As RGS2 reduces signaling from Gq-coupled GPCRs, we have defined role(s) for this GTPase-activating protein in an acute neutrophilic model of lung inflammation."

Bernier LP, Ase AR, Boué-Grabot É, Séguéla P - "Inhibition of P2X4 function by P2Y6 UDP receptors in microglia" Glia 61(12):2038-49 m(2013) doi: 10.1002/glia.22574
https://onlinelibrary.wiley.com/doi/10.1002/glia.22574

Forte G, Sorrentino R, Montinaro A, Pinto A, Morello S - "Cl-IB-MECA enhances TNF-α release in peritoneal macrophages stimulated with LPS. Cytokine" 54(2):161-6 (2011) doi: 10.1016/j.cyto.2011.02.002
https://linkinghub.elsevier.com/retriev ... 11)00031-7

Hagiwara S, Nagata K, Kasakura K, Sakata F, Kishino S, Ogawa J, Yashiro T, Nishiyama C - "The anti-inflammatory effect of the gut lactic acid bacteria-generated metabolite 10-oxo-cis-6,trans-11-octadecadienoic acid on monocytes" Biochem Biophys Res Commun 530(1):342-347 (2020). doi: 10.1016/j.bbrc.2020.07.006
"A Gq agonist significantly suppressed LPS-induced IL-6 expression in BMMs, whereas a Gi inhibitor partially abrogated γKetoC-mediated IL-6 suppression."

Binning W, Hogan-Cann AE, Yae Sakae D, Maksoud M, Ostapchenko V, Al-Onaizi M, Matovic S, Lu WY, Prado MAM, Inoue W, Prado VF - "Chronic hM3Dq signaling in microglia ameliorates neuroinflammation in male mice" Brain Behav Immun 88:791-801 (2020) doi: 10.1016/j.bbi.2020.05.041.
https://www.sciencedirect.com/science/a ... 912030101X
"These results suggest that chronic activation of M3 muscarinic receptors (the hM3Dq progenitor) in microglia, and potentially other Gq-coupled GPCRs, can trigger an inflammatory-like response that preconditions microglia to decrease their response to further immunological challenges."

Xu M, Jiang Z, Wang C, Li N, Bo L, Zha Y, Bian J, Zhang Y, Deng X - "Acetate attenuates inflammasome activation through GPR43-mediated Ca2+-dependent NLRP3 ubiquitination" Exp Mol Med 51(7):1-13 (2019). doi: 10.1038/s12276-019-0276-5.
https://www.nature.com/articles/s12276-019-0276-5
"In vivo, acetate protects mice from NLRP3 inflammasome-dependent peritonitis and LPS-induced endotoxemia. Collectively, our research demonstrates that acetate regulates the NLRP3 inflammasome via GPR43 and Ca2+-dependent mechanisms, which reveals the mechanism of metabolite-mediated NLRP3 inflammasome attenuation and highlights acetate as a possible therapeutic strategy for NLRP3 inflammasome-related diseases.

Szeto A, Sun-Suslow N, Mendez AJ, Hernandez RI, Wagner KV, McCabe PM - "Regulation of the macrophage oxytocin receptor in response to inflammation" Am J Physiol Endocrinol Metab 312(3):E183-E189 (2017) doi: 10.1152/ajpendo.00346.2016
"OT treatment of control cells and LPS-treated cells increased ERK1/2 phosphorylation, demonstrating activation of the OXTR/Gαq/11 signaling pathway."
https://journals.physiology.org/doi/ful ... 00346.2016

Chen BC, Lin WW - "PKC- and ERK-dependent activation of I kappa B kinase by lipopolysaccharide in macrophages: enhancement by P2Y receptor-mediated CaMK activation" Br J Pharmacol 134(5):1055-65 (2001). doi: 10.1038/sj.bjp.0704334
"Taken together, we demonstration that Gq protein-coupled P2Y(6) receptor activation can potentiate LPS-stimulated IKK activity. While PKC and ERK participate in IKK activation by LPS and UTP, the phosphatidylinositide-phospholipase C-dependent activation of CaMK plays a major role in UTP potentiation of the LPS response."
  • see also: Klaver D, Gander H, Dobler G, Rahm A, Thurnher M - "The P2Y11 receptor of human M2 macrophages activates canonical and IL-1 receptor signaling to translate the extracellular danger signal ATP into anti-inflammatory and pro-angiogenic responses" Cell Mol Life Sci 79(10):519 (2022) doi: 10.1007/s00018-022-04548-z.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9476423/
Kuo PC, Schroeder RA, Bartlett ST - "Endotoxin-mediated synthesis of nitric oxide is dependent on Gq protein signal transduction" Surgery 122(2):394-402 ; discussion 402-3 (1997). doi: 10.1016/s0039-6060(97)90032-5
"Pertussis and cholera toxin did not alter NO synthesis, suggesting that the Gi and Gs classes are not involved. Inhibition of protein kinase C or upstream phospholipase C-beta activity decreased NO synthesis, implicating the Gq class of heterotrimeric G proteins."

SEE also: TLR4 -
viewtopic.php?f=68&t=4798
  • See also:

    Korhonen H, Fisslthaler B, Moers A, Wirth A, Habermehl D, Wieland T, Schütz G, Wettschureck N, Fleming I, Offermanns S - "Anaphylactic shock depends on endothelial Gq/G11" J Exp Med 206(2):411-20 (2009) doi: 10.1084/jem.20082150
    https://pubmed.ncbi.nlm.nih.gov/19171764/

    Patten M, Bünemann J, Thoma B, Krämer E, Thoenes M, Stübe S, Mittmann C, Wieland T - "Endotoxin induces desensitization of cardiac endothelin-1 receptor signaling by increased expression of RGS4 and RGS16" Cardiovasc Res 53(1):156-64 (2002) doi: 10.1016/s0008-6363(01)00443-6
    "Endotoxin (LPS)-induced acute cardiac failure during sepsis is associated with alterations in G protein mediated signal transduction."

    Coffee KA, Halushka PV, Wise WC, Cook JA - "Altered responses to modulators of guanine nucleotide binding protein activity in endotoxin tolerance" Biochim Biophys Acta 1035(2):201-5 (1990) doi: 10.1016/0304-4165(90)90117-f
    https://pubmed.ncbi.nlm.nih.gov/2118385/
Sueyoshi K, Ledderose C, Shen Y, Lee AH, Shapiro NI, Junger WG - "Lipopolysaccharide suppresses T cells by generating extracellular ATP that impairs their mitochondrial function via P2Y11 receptors" J Biol Chem 294(16):6283-6293 (2019). doi: 10.1074/jbc.RA118.007188
https://www.jbc.org/article/S0021-9258(20)36287-6/pdf
"P2Y11 receptors are ATP-selective G protein–coupled receptors that can couple to both Gq and Gs proteins that activate PLC and intracellular cAMP/PKA signaling, respectively."

Thyroid

Suzuki N, Purba FY, Nii T, Isobe N - "Effect of 6-n-propyl-2-thiouracil or dexamethasone administration on the responses of antimicrobial components in goat milk to intramammary lipopolysaccharide infusion" Anim Sci J 93(1):e13773 (2022)
https://onlinelibrary.wiley.com/doi/10.1111/asj.13773

Shcherba V, Krynytska I, Marushchak M, Korda M - "Does thyroid dysfunction influence inflammatory mediators in experimental periodontitis?" Endocr Regul 55(3):131-141 (2021) doi: 10.2478/enr-2021-0014
https://sciendo.com/article/10.2478/enr-2021-0014
"Thyroid dysfunction exacerbates cytokine imbalance and severity of inflammation in experimental LPS-induced periodontitis."

Klecha AJ, Genaro AM, Gorelik G, Barreiro Arcos ML, Silberman DM, Schuman M, Garcia SI, Pirola C, Cremaschi GA - "Integrative study of hypothalamus-pituitary-thyroid-immune system interaction: thyroid hormone-mediated modulation of lymphocyte activity through the protein kinase C signaling pathway" J Endocrinol 189(1):45-55 (2006) doi: 10.1677/joe.1.06137
https://joe.bioscientifica.com/view/jou ... 880045.xml


TSH

Corder-Ramos NLB, Flatland B, Fry MM, Sun X, Fecteau K, Giori L - "Cortisol, progesterone, 17α-hydroxyprogesterone, and TSH responses in dogs injected with low-dose lipopolysaccharide" PeerJ 7:e7468 (2019) doi: 10.7717/peerj.7468
https://peerj.com/articles/7468/

Nazar M, Nicola JP, Vélez ML, Pellizas CG, Masini-Repiso AM - "Thyroid peroxidase gene expression is induced by lipopolysaccharide involving nuclear factor (NF)-κB p65 subunit phosphorylation" Endocrinology 153(12):6114-25 (2012) doi: 10.1210/en.2012-1567
https://academic.oup.com/endo/article/1 ... 14/2424545


Deiodinase D2

Xu M, Iwasaki T, Shimokawa N, Sajdel-Sulkowska EM, Koibuchi N - "The effect of low dose lipopolysaccharide on thyroid hormone-regulated actin cytoskeleton modulation and type 2 iodothyronine deiodinase activity in astrocytes" Endocr J 60(11):1221-30 (2013). doi: 10.1507/endocrj.ej13-0294.
https://www.jstage.jst.go.jp/article/en ... 4/_article
"LPS treatment (10 ng/mL) increased D2 activity, whereas T4 (10 nM) suppressed this activity. T4 restored LPS-increased D2 activity at 10 nM."

Lamirand A, Ramaugé M, Pierre M, Courtin F - "Bacterial lipopolysaccharide induces type 2 deiodinase in cultured rat astrocytes" J Endocrinol 208(2):183-92 (2011) doi: 10.1677/JOE-10-0218
https://joe.bioscientifica.com/view/jou ... /2/183.xml

Fekete C, Gereben B, Doleschall M, Harney JW, Dora JM, Bianco AC, Sarkar S, Liposits Z, Rand W, Emerson C, Kacskovics I, Larsen PR, Lechan RM - "Lipopolysaccharide induces type 2 iodothyronine deiodinase in the mediobasal hypothalamus: implications for the nonthyroidal illness syndrome" Endocrinology 145(4):1649-55 (2004) doi: 10.1210/en.2003-1439 \
https://academic.oup.com/endo/article/1 ... 49/2878191

Fekete C, Sarkar S, Christoffolete MA, Emerson CH, Bianco AC, Lechan RM - "Bacterial lipopolysaccharide (LPS)-induced type 2 iodothyronine deiodinase (D2) activation in the mediobasal hypothalamus (MBH) is independent of the LPS-induced fall in serum thyroid hormone levels" Brain Res. 1056(1):97-9 (2005) doi: 10.1016/j.brainres.2005.07.021
https://www.sciencedirect.com/science/a ... 9305010681


SEE also:

NF-κB. viewtopic.php?f=66&t=1888

TNF-α. viewtopic.php?f=66&t=1895

ERK/MAPK. viewtopic.php?f=66&t=1914
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LPS - Endotoxin/G Protein Interaction

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GPT - The Endotoxin/G Protein Interaction

Endotoxin, also known as lipopolysaccharide (LPS), is a molecule found in the outer membrane of Gram-negative bacteria. It is a potent activator of the immune system and can induce a strong inflammatory response in the host organism. The interaction of endotoxin (LPS) with G proteins is an essential part of the signaling pathway that triggers the immune response.

G proteins are a family of intracellular signaling molecules that act as molecular switches. They play a crucial role in transmitting signals from cell surface receptors to intracellular signaling pathways. When a cell surface receptor, such as a toll-like receptor (TLR) or cluster of differentiation 14 (CD14), recognizes LPS on the bacterial cell wall, it initiates a signaling cascade that ultimately activates G proteins.

The interaction between endotoxin (LPS) and G proteins occurs through a series of steps:

1. Recognition: Endotoxin (LPS) is detected by cell surface receptors, mainly TLR4 (Toll-like receptor 4) and CD14. TLR4 is a member of the Toll-like receptor family, which recognizes various pathogen-associated molecular patterns (PAMPs), including LPS. CD14 is a co-receptor that enhances the binding of LPS to TLR4.

2. Receptor activation: Upon binding of LPS to TLR4 and CD14, a conformational change occurs in TLR4, leading to the recruitment of adapter proteins such as MyD88 (myeloid differentiation primary response 88) and TRIF (TIR domain-containing adapter-inducing interferon-beta). These adapter proteins facilitate the activation of downstream signaling pathways, including those involving G proteins.

3. G protein activation: The activated adapter proteins MyD88 and TRIF initiate a signaling cascade that leads to the activation of downstream effector molecules, including G proteins. These G proteins are trimeric, composed of three subunits - alpha (α), beta (β), and gamma (γ). In the inactive state, the α-subunit is bound to GDP (guanosine diphosphate), but when activated, it exchanges GDP for GTP (guanosine triphosphate).

4. Effector activation: The GTP-bound α-subunit dissociates from the βγ-subunit and other regulatory proteins, becoming active and capable of activating various effector molecules. These effectors can include enzymes like adenylate cyclase or phospholipase C, which in turn generate intracellular signaling molecules such as cAMP (cyclic adenosine monophosphate) and IP3 (inositol trisphosphate).

5. Immune response initiation: The activation of effector molecules sets off a series of downstream events that lead to the production and release of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6), as well as other immune mediators. These cytokines play a critical role in coordinating the immune response to the bacterial infection and help recruit immune cells to the site of infection.

In summary, the interaction of endotoxin (LPS) with G proteins is a key step in the immune response to Gram-negative bacterial infections. Through this interaction, LPS triggers a signaling cascade that leads to the activation of effector molecules and the subsequent production of pro-inflammatory cytokines, contributing to the host's defense against bacterial pathogens.
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Importance of Gq/11

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Gq/11 (Gq and G11) are specific subtypes of G proteins that play a special and important role in cell signaling. They are part of the larger family of G proteins, which are involved in transmitting signals from cell surface receptors to intracellular signaling pathways. The activation of Gq/11 leads to the stimulation of phospholipase C (PLC) and subsequent generation of two important second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).

Here's a brief overview of the role of Gq/11 in cell signaling:

Receptor activation: Gq/11 is typically coupled to a specific group of G protein-coupled receptors (GPCRs) that possess Gq/11-coupling domains. When these receptors bind to their specific ligands, they undergo a conformational change that allows them to interact with and activate Gq/11.

Activation of phospholipase C (PLC): Once Gq/11 is activated, the GTP-bound alpha (α) subunit of Gq/11 dissociates from the beta (β) and gamma (γ) subunits. The free Gαq/11 subunit then activates phospholipase C (PLC) by directly interacting with it.

Generation of second messengers: Activated PLC cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into two important second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 diffuses into the cytoplasm and binds to IP3 receptors on the endoplasmic reticulum (ER), leading to the release of calcium ions (Ca2+) from intracellular stores. On the other hand, DAG remains in the plasma membrane and activates protein kinase C (PKC), another important intracellular signaling molecule.

Cellular responses: The increased intracellular calcium levels, along with DAG-induced PKC activation, initiate a wide range of cellular responses, including smooth muscle contraction, secretion of certain hormones and neurotransmitters, regulation of ion channels, and modulation of various enzyme activities. Additionally, Gq/11-mediated signaling pathways play a crucial role in cell growth, proliferation, differentiation, and survival.

Due to its critical involvement in various cellular processes, dysregulation of Gq/11-mediated signaling has been implicated in numerous diseases, including certain types of cancers, cardiovascular diseases, and neurological disorders. Therefore, Gq/11 and its associated signaling pathways are the subject of extensive research in biomedical and pharmacological fields, with the aim of identifying potential therapeutic targets for various diseases.
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