ArticleBritish journal of pharmacology2015
MD-2 as the target of a novel small molecule, L6H21, in the attenuation of LPS-induced inflammatory response and sepsis.
Article in British journal of pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 86 citations in OpenAlex.
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- Fisetin Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Targeting Myeloid Differentiation Factor 88.Inflammation · 2026Article
- Adjuvant activity of a small molecule TLR4 agonist discovered via structure-based virtual screening.Communications biology · 2025Article
- A Novel Hybrid Peptide VLP-Aβ Efficiently Regulates Immunity by Stimulating Myeloid Differentiation Protein and Activating the NF-κB Pathway.International journal of molecular sciences · 2025Article
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- Novel Inhibitory Actions of Neuroactive Steroid [3α,5α]-3-Hydroxypregnan-20-One on Toll-like Receptor 4-Dependent Neuroimmune Signaling.Biomolecules · 2024Article
- Peptide TaY Attenuates Inflammatory Responses by Interacting with Myeloid Differentiation 2 and Inhibiting NF-κB Signaling Pathway.Molecules (Basel, Switzerland) · 2024Article
- Ginsenoside RhInternational journal of molecular sciences · 2024Article
- Inhibition of TLR4 signalling to dampen joint inflammation in osteoarthritis.Rheumatology (Oxford, England) · 2024Review
- Isoproterenol induces MD2 activation by β-AR-cAMP-PKA-ROS signalling axis in cardiomyocytes and macrophages drives inflammatory heart failure.Acta pharmacologica Sinica · 2024Article
- Chalcone-derivative L6H21 attenuates the OVA-induced asthma by targeting MD2.European journal of medical research · 2024Article
- Gastrodin Attenuates Colitis and Prevents Tumorigenesis in Mice by Interrupting TLR4/MD2/NF-κB Signaling Transduction.Anti-cancer agents in medicinal chemistry · 2024Article
- Myeloid differentiation factor 2 inhibitors exert protective effects on lipopolysaccharides-treated human dental pulp cells via suppression of toll-like receptor 4-mediated signaling.Journal of dental sciences · 2024Article
- Synthesis, Pharmacological Properties, and Potential Molecular Mechanisms of Antitumor Activity of Betulin and Its Derivatives in Gastrointestinal Cancers.Pharmaceutics · 2023Review
- Pharmacological Potential of Betulin as a Multitarget Compound.Biomolecules · 2023Review
- Inhibition of SHP2 by the Small Molecule Drug SHP099 Prevents Lipopolysaccharide-Induced Acute Lung Injury in Mice.Inflammation · 2023Article
- Immunohistochemical Localization of MD2, a Co-Receptor of TLR4, in the Adult Mouse Brain.ACS chemical neuroscience · 2023Article
- Berberine administrated with different routes attenuates inhaled LPS-induced acute respiratory distress syndrome through TLR4/NF-κB and JAK2/STAT3 inhibition.European journal of pharmacology · 2021Article
- Suppression of MD2 inhibits breast cancer in vitro and in vivo.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2021Article
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeMyeloid differentiation 2 (MD-2) recognizes LPS, which is required for TLR4 activation, and represents an attractive therapeutic target for severe inflammatory disorders. We previously found that a chalcone derivative, L6H21, could inhibit LPS-induced overexpression of TNF-α and IL-6 in macrophages. Here, we performed a series of biochemical experiments to investigate whether L6H21 specifically targets MD-2 and inhibits the interaction and signalling transduction of LPS-TLR4/MD-2. EXPERIMENTAL APPROACH: The binding affinity of L6H21 to MD-2 protein was analysed using computer docking, surface plasmon resonance analysis, elisa, fluorescence measurements and flow cytometric analysis. The effects of L6H21 on MAPK and NF-κB signalling were determined using EMSA, fluorescence staining, Western blotting and immunoprecipitation. The anti-inflammatory effects of L6H21 were confirmed using elisa and RT-qPCR in vitro. The anti-inflammatory effects of L6H21 were also evaluated in septic C57BL/6 mice. KEY
resultsCompound L6H21 inserted into the hydrophobic region of the MD-2 pocket, forming hydrogen bonds with Arg(90) and Tyr(102) in the MD-2 pocket. In vitro, L6H21 subsequently suppressed MAPK phosphorylation, NF-κB activation and cytokine expression in macrophages stimulated by LPS. In vivo, L6H21 pretreatment improved survival, prevented lung injury, decreased serum and hepatic cytokine levels in mice subjected to LPS. In addition, mice with MD-2 gene knockout were universally protected from the effects of LPS-induced septic shock. CONCLUSIONS AND IMPLICATIONS: Overall, this work demonstrated that the new chalcone derivative, L6H21, is a potential candidate for the treatment of sepsis. More importantly, the data confirmed that MD-2 is an important therapeutic target for inflammatory disorders.
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