Glycolipids and Benzylammonium Lipids as Novel Antisepsis Agents: Synthesis and Biological Characterization

Piazza, Matteo; Rossini, Clara; Fiorentina, Silvia Della; Pozzi, Chiara; Comelli, Francesca; Bettoni, Isabella; Fusi, Paola; Costa, Barbara; Peri, Francesco

doi:10.1021/jm801333m

Cited by 59 publications

(59 citation statements)

References 34 publications

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“…The higher activity of compound 3 in the experimental conditions in which CD14 contributes to TLR4 activation, is a first indication that compound 3 probably interferes in both LPS/MD-2.TLR4 and LPS/CD14 interactions. This behavior is reminiscent of a first generation of positively charged monosaccharides we developed that blocked in vitro and in vivo TLR4 activation [28] by mainly displacing endotoxin from CD14 interaction. [8] The capacity of molecule 3 to stimulate CD14 internalization (Figure 3) provides further evidence of a direct interaction between the synthetic molecule and CD14.…”

Section: Resultsmentioning

confidence: 99%

Modulation of CD14 and TLR4⋅MD‐2 Activities by a Synthetic Lipid A Mimetic

et al. 2013

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Monosaccharide lipid A mimetics composed by a glucosamine core linked to two fatty acid chains and bearing one or two phosphates have been synthesized. While compounds 1 and 2, with one phosphate group, were practically inactive in inhibiting LPS-induced TLR4 signaling and cytokine production in HEK-blue™ cells and murine macrophages, compound 3 with two phosphates was found to be active in efficiently inhibiting TLR4 signal in both cell types. The direct interaction of molecule 3 with MD-2 co-receptor has been investigated by means of NMR and molecular modeling/docking analysis. This compound also interacts directly with CD14 receptor, stimulating its internalization by endocytosis. Experiments on macrophages show that the effect on CD14 reinforces the activity on MD-2.TLR4, because compound 3 activity is higher when CD14 is important for TLR4 signaling i,e, at low LPS concentration. The dual MD-2 and CD14 targeting, accompanied by good solubility in water and lack of toxicity, suggests the use of monosaccharide 3 as a lead compound to develop drugs directed against TLR4-related syndromes.

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Section: Resultsmentioning

confidence: 99%

Modulation of CD14 and TLR4⋅MD‐2 Activities by a Synthetic Lipid A Mimetic

et al. 2013

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“…A glycoconjugate preparation from Treponema spirochetes (Tm-Gp) was also reported to inhibit the interaction of LPS with CD14, acting as an antagonist of TLR4 (78); however, this preparation is chemically heterogeneous and it was not possible to determine the component responsible for the interaction. In other studies, synthetic lipids have been used to inhibit LPS-induced TLR4 activation in HEK293 cells by targeting the CD14 co-receptor (79). Benefits of suppressed TLR4 activation have been documented in several experimental models of lethal shock (44, 80), as have the benefits of using anti-CD14 (81) and anti-TLR4 (82) antibodies in humans.…”

Section: Discussionmentioning

confidence: 99%

Fasciola hepaticaFatty Acid Binding Protein Inhibits TLR4 Activation and Suppresses the Inflammatory Cytokines Induced by Lipopolysaccharide In Vitro and In Vivo

Martin

Cabán-Hernández

Figueroa-Santiago

et al. 2015

The Journal of Immunology

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Toll-like receptor 4 (TLR4), the innate immunity receptor for bacterial endotoxins, plays a pivotal role in the induction of inflammatory responses. There is a need to develop molecules that block either activation through TLR4 or the downstream signaling pathways to inhibit the storm of inflammation typically elicited by bacterial lipopolysaccharide (LPS), which is a major cause of the high mortality associated with bacterial sepsis. We report here that a single intraperitoneal injection of 15μg Fasciola hepatica fatty acid binding protein (Fh12) 1 hour before exposure to LPS suppressed significantly the expression of serum inflammatory cytokines in a model of septic shock using C57BL/6 mice. Because macrophages are good source of IL12p70 and TNFα, and critical in driving adaptive immunity, we investigated the effect of Fh12 on the function of mouse bone marrow derived macrophages (bmMΦs). Whereas Fh12 alone did not induce cytokine expression, it significantly suppressed the expression of IL12, TNFα, IL6 and IL1β cytokines as well as iNOS2 in bmMΦs, and also impaired the phagocytic capacity of bmMΦs. Fh12 had a limited effect on the expression of inflammatory cytokines induced in response to other TLR-ligands. One mechanism used by Fh12 to exert its anti-inflammatory effect is binding to the CD14 co-receptor. Moreover, it suppresses phosphorylation of ERK, p38 and JNK. The potent anti-inflammatory properties of Fh12 demonstrated here open doors to further studies directed at exploring the potential of this molecule as a new class of drug against septic shock or other inflammatory diseases.

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“…LPS binds primarily to resident macrophages or epithelial cells lining the iris and ciliary processes [39], [40]. When LPS-CD14-TLR4 cluster activation is inhibited by lipid raft-disrupting drug or lipid A mimetic antagonists, LPS-induced cellular cascading reaction is interrupted [41], [42]. We have shown in this study that GTE suppresses LPS induced elevation of CD14 and TLR-4 mRNA in the anterior uvea and the retina, suggesting that GTE treatment may alleviate ocular inflammation by suppressing formation of the LPS receptor complex.…”

Section: Discussionmentioning

confidence: 99%

Green Tea Extract Treatment Alleviates Ocular Inflammation in a Rat Model of Endotoxin-Induced Uveitis

et al. 2014

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Green tea extract (GTE) ingested by rats exerted anti-oxidative activities in various ocular tissues as shown in our previous studies. The present work investigated anti-inflammatory effects of GTE on endotoxin-induced uveitis (EIU). EIU was generated in adult rats by a footpad injection of 1 mg/kg lipopolysaccharide (LPS). Oral administration of GTE (550 mg/kg) was given one, two or four times after LPS injection. Twenty-four hours later, LPS produced severe hyperemia and edema in the iris. Immunocytochemical examinations showed an accumulation of infiltrating cells in the aqueous humor that were immunopositive for cluster of differentiation 43 (CD43) and CD68, markers for leucocytes and macrophages, respectively. Analyses of the aqueous humor showed an increase in pro-inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1). GTE treatments improved the clinical manifestations and reduced infiltrating cells and protein exudation in the aqueous humor, which were not observed under half dose of GTE (275 mg/kg). The number of CD68 positive macrophages residing in the iris and ciliary was also reduced. GTE suppressed production of TNF-α, IL-6 and MCP-1 in the aqueous humor, which was associated with a down-regulation of LPS receptor complex subunits, Toll-like receptor 4 (TLR-4) and CD14, and suppression of nuclear factor-kappa Bp65 (NF-κBp65) in the iris and ciliary body. Our findings show that GTE is a potent anti-inflammatory agent against the inflammation of EIU, and suggest a potential use in treatment of acute uveitis.

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Glycolipids and Benzylammonium Lipids as Novel Antisepsis Agents: Synthesis and Biological Characterization

Cited by 59 publications

References 34 publications

Modulation of CD14 and TLR4⋅MD‐2 Activities by a Synthetic Lipid A Mimetic

Modulation of CD14 and TLR4⋅MD‐2 Activities by a Synthetic Lipid A Mimetic

Fasciola hepaticaFatty Acid Binding Protein Inhibits TLR4 Activation and Suppresses the Inflammatory Cytokines Induced by Lipopolysaccharide In Vitro and In Vivo

Green Tea Extract Treatment Alleviates Ocular Inflammation in a Rat Model of Endotoxin-Induced Uveitis

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