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Cyanobacterial toxins
Published in Ingrid Chorus, Martin Welker, Toxic Cyanobacteria in Water, 2021
In particular, LPS is known to bind to one type of so-called toll-like receptors, namely, TLR4 (Bryant et al., 2010), triggering a cascade of cellular reactions that involve the regulation of the expression of a large number of genes (Akira & Takeda, 2004). In healthy individuals, the recognition of LPS by TLR4 triggers innate and adaptive immune responses as part of the normal defence against invasive microbes (Takeda et al., 2003), and only a massive reaction in response to LPS in the bloodstream leads to a critical health status. The strength of the binding of LPS to TLR4 is dependent on the structure of lipid A, explaining varying strength of reactions in patients but also in bioassays. The cascading host response to LPS rather than the toxic properties of LPS itself therefore accounts for the potentially lethal consequences (Opal, 2010). For this reason, LPS (or endotoxin) has been discussed to be classified rather as an (exogenous) hormone than as a toxin in a strict sense (Marshall, 2005). Arguably, LPS is not a secondary metabolite like the known cyanotoxins but a highly variable fraction of a cellular constituent rather than a defined structure.
Clinical Effects of Pollution
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 5, 2017
William J. Rea, Kalpana D. Patel
To define the degree of systemic inflammation, substances measured are inflammatory mediators such as C-reactive protein, prostaglandin E metabolite, and heat shock protein 60; IL-10 was the selected TH2 anti-inflammatory cytokine. Given that controlled ozone exposures are associated with upregulation of mCD14 on airway macrophages and monocytes, and that a synergistic action on the CD14 effect has been suggested between PM-LPS and ozone,37 they selected mCD14, sCD14, and LPS-binding protein (LBP)38,39 to characterize the LPS-recognition complex components. LPS forms a complex with an acute-phase protein called LBP responsible for the binding and transport of LPS in the circulation.39 A major response to LPS is mediated by its interaction with CD14, a 55-kDa myeloid differentiation antigen that allows endotoxin to interact with the TLR4.39 Finally, TLR4 specifically recognizes LPS and is part of the endotoxin signaling receptor complex that initiates proinflammatory signaling. Since missense mutations such as Asp299Gly are associated with a blunted response to inhaled LPS, it was determined the allelic frequencies of Asp299Gly TLR4 polymorphism in both cohorts and included only children fully capable of responding to LPS.40 Certainly, the chemically sensitive can go down this pathway eventually causing permanent brain damage.
Immune Responses
Published in Ronald Fayer, Lihua Xiao, Cryptosporidium and Cryptosporidiosis, 2007
Epithelial cells express Toll-like receptors (TLRs), a group of innate molecular sensors of infection that ligate with conserved antigenic structures such as bacterial lipopolysaccharide (TLR4), bacterial cell wall components (TLR2), or DNA (TLR9) (Abreu et al., 2005). Cell signaling via an adaptor molecular that associates with TLRs, MyD88, leads to activation and migration to the cell nucleus of NF-?B, a key transcription factor for a variety of inflammatory molecules. NF-?B has been shown to be activated during C. parvum infection, and a key function for this molecule appears to be to prevent the infected cell undergoing apoptosis (Chen et al., 2001). It was shown that activation of a bile duct epithelial cell line via TLR2 and TLR4 occurs during C. parvum infection. Transfection of the cells with dominantnegative TLR2, TLR4, or MyD88 mutants or treatment of cells with interference RNA to the TLRs inhibited NF-?B activation by the parasite (Chen et al., 2005). MyD88 deficiency in these epithelial cells also increased parasite replication and in another study MyD881 mice had enhanced susceptibility to C. parvum infection (note that the MyD88 deficiency of these animals is not confined to epithelial cells) (Rogers et al., 2006). Treatment of neonatal mice with an oligodeoxynucleotide that is a ligand for TLR9 induced resistance to parasite reproduction (Barrier et al., 2006). Clearly, therefore, TLRs play a role in innate immunity, but the parasite molecules that act as ligands have yet to be identified.
Association of genetic polymorphisms with mercapturic acids in the urine of young healthy subjects before and after exposure to outdoor air pollution
Published in International Journal of Environmental Health Research, 2023
Wenping Song, Lingjie Bian, Mengran Xiong, Yuanyuan Duan, Yi Wang, Xia Zhang, Biao Li, Yulong Dai, Jiawei Lu, Meng Li, Zhiguo Liu, Shigang Liu, Li Zhang, Hongjuan Yao, Rongguang Shao, Guangxi Li, Liang Li
Toll-like receptor 4 (TLR4) was the first discovered human homolog of the Dorsophila Toll protein, which is responsible for selective recognition of the endotoxin LPS (Shetab Boushehri and Lamprecht 2018). The TLR4 signaling pathway is involved in cancer progression and inflammatory response. Previous studies have emphasized that active TLR4 can increase IL-8, IL-6 and nitric oxide production and the expression of VEGF and TGF-β1. The release of various inflammatory mediators, cytokines and chemokines by active TLR4 could contribute to cancer progression (Chen et al. 2018). We found that SNPs in TLR4 were closely related to Po1/C- or Pu1/Po1-fold changes in urinary SPMA, HPMA or HEMA. These findings further confirmed that TLR4 polymorphisms had impacts on the changes in the level of MAs in urine after exposure to polluted air, which were considered carcinogenic biomarkers in humans.
Circulating markers of intestinal barrier injury and inflammation following exertion in hypobaric hypoxia
Published in European Journal of Sport Science, 2023
Zachary J. McKenna, Bryanne N. Bellovary, Jeremy B. Ducharme, Michael R. Deyhle, Andrew D. Wells, Zachary J. Fennel, Jonathan W. Specht, Jonathan M. Houck, Trevor J. Mayschak, Christine M. Mermier
Under normal physiological conditions the intestinal epithelium operates in a state of “physiologic hypoxia”, often characterized as a steep oxygen gradient from the submucosa to the intestinal lumen (Konjar et al., 2021; Singhal & Shah, 2020; Zheng et al., 2015). Indeed, this physiologic hypoxia allows for several intracellular adaptations that collectively promote intestinal barrier homeostasis via hypoxia inducible factors (Konjar et al., 2021; Singhal & Shah, 2020; Zheng et al., 2015). However, in some scenarios this hypoxia can become pathological resulting in intestinal injury and inflammation (Singhal & Shah, 2020). High altitude exposures can reduce splanchnic perfusion (Loshbaugh et al., 2006) and lower blood oxygen levels causing local hypoxic and oxidative stress in the gut (Dosek et al., 2007). These stressors can injure the intestinal barrier leading to increased intestinal permeability and bacterial endotoxin translocation (Lian et al., 2021; McKenna et al., 2022b). The translocation of Gram-negative bacteria which harbor lipopolysaccharides (LPS) on their outer membrane can activate innate immune cells via Toll like receptor-4 (TLR-4) to initiate local and systemic inflammatory responses (Ducharme et al., 2022). Indeed, residence at high altitude has been shown to damage the intestinal barrier and increase intestinal permeability (Karl et al., 2018). Subsequent LPS-mediated increases in pro-inflammatory cytokines could cross the blood brain barrier and contribute to central nervous system dysfunction which may be a contributing factor to development of AMS (Banks et al., 1995).
Evaluation of the proinflammatory effects of contaminated bathing water
Published in Journal of Toxicology and Environmental Health, Part A, 2019
Anas A. Sattar, Wondwossen Abate, Gyorgy Fejer, Graham Bradley, Simon K. Jackson
When LPS enters the bloodstream, even picogram amounts are capable of inducing a potent immunological reaction (Mayeux 1997; Rice et al. 2003; Velloso, Folli, and Saad 2015). In cells of the innate immune system, including monocytes and macrophages, LPS signals through the receptor TLR4 (Alexander and Rietschel 2001; Velloso, Folli, and Saad 2015) that initiates a signaling cascade leading to the release of various cellular mediators such as proinflammatory cytokines. Cytokines are small cell-signaling proteins that are released by various cells and they play a pivotal role in inflammation and the level of proinflammatory cytokines is generally elevated during inflammation (Lee and Lawrence 2018). Released cytokines act as messengers playing a key role in regulating and initiating inflammatory responses to LPS which is augmented by attracting more immune cells to the affected site (Groves and Jiang 1995; Lee and Lawrence 2018; Masi et al. 2017). In extreme cases, excessive induction of proinflammatory cytokines by LPS results in septic shock, organ failure and death (Shapira et al. 1996). In the lung, alveolar macrophages also respond to LPS via TLR4 recognition which was linked to asthma-like conditions and lung injury (Helyes and Hajna 2012).