Discovery of caffeic acid phenethyl ester derivatives as novel myeloid differentiation protein 2 inhibitors for treatment of acute lung injury

Chen, Lingfeng; Jin, Yiyi; Chen, Hongjin; Sun, Chao; Fu, Weitao; Zheng, Lulu; Lu, Min; Chen, Pengqin; Chen, Gaozhi; Zhang, Yali; Liu, Zhiguo; Wang, Yi; Song, Zengqiang; Liang, Guang

doi:10.1016/j.ejmech.2017.11.066

Cited by 36 publications

(9 citation statements)

References 45 publications

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“…The LPS-MD-2/TLR4 antagonist, eritoran, also failed to reduce mortality among patients with severe sepsis (64). Nevertheless, targeting MD-2 to interfere with MD-2-TLR4 signaling has been extensively explored, and the results support the concept that MD-2 is an effective target to treat inflammatory disorders such as sepsis and acute lung injury (53,(65)(66)(67)(68). We provide evidence that sMD-2 is increased in SCD, contributes to proinflammatory signaling in endothelial cells, and therefore, might be a potential therapeutic target for SCD and other hemolytic conditions.…”

Section: Discussionmentioning

confidence: 98%

Soluble MD-2 and Heme in Sickle Cell Disease Plasma Promote Pro-Inflammatory Signaling in Endothelial Cells

et al. 2021

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Recent evidence indicates that hemolysis in sickle cell disease (SCD) promotes inflammation via innate immune signaling through toll-like receptor 4 (TLR4). Free heme released by hemolyzed red blood cells can bind to myeloid differentiation factor-2 (MD-2) and activate TLR4 pro-inflammatory signaling on endothelium to promote vaso-occlusion and acute chest syndrome in murine models of SCD. MD-2 is co-expressed with TLR4 on cell membranes, but in inflammatory conditions, soluble MD-2 (sMD-2) is elevated in plasma. sMD-2 levels were significantly increased in human and murine sickle (SS) plasma as compared to normal (AA) plasma. Human umbilical vein endothelial cells (HUVEC) and human lung microvascular endothelial cells incubated with human SS plasma had significant increases in pro-inflammatory IL-8, IL-6, and soluble VCAM-1 secretion compared to endothelial cells incubated with AA plasma. The increase in HUVEC IL-8 secretion was blocked by depletion of sMD-2 from SS plasma and enhanced by the addition of sMD-2 to AA plasma. The TLR4 signaling inhibitor, TAK-242, inhibited HUVEC IL-8 secretion in response to SS plasma by 85%. Heme-agarose pull-down assays and UV/Vis spectroscopy demonstrated that heme binds to sMD-2. Hemopexin, a high affinity heme-binding protein, inhibited HUVEC IL-8 secretion induced by SS plasma or SS and AA plasma supplemented with sMD-2. These data suggest that sMD-2 bound to heme might play an important role in pro-inflammatory signaling by endothelium in SCD.

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Section: Discussionmentioning

confidence: 98%

Soluble MD-2 and Heme in Sickle Cell Disease Plasma Promote Pro-Inflammatory Signaling in Endothelial Cells

et al. 2021

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“…Notably, the adoptive transfer of peritoneal macrophages into the lungs results in the expression of certain alveolar macrophage-specific genes (43). In some studies, primary peritoneal macrophages are used to investigate the role of macrophages in lungs (19,44-46). The present study focused on the role of DHA in the LPS-challenged inflammatory response in macrophages in vitro .…”

Section: Discussionmentioning

confidence: 99%

Dihydroartemisinin attenuates lipopolysaccharide‑induced acute lung injury in mice by suppressing NF‑κB signaling in an Nrf2‑dependent manner

et al. 2019

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Acute lung injury (ALI) is a severe health issue with significant morbidity and mortality. Artemisinin is used for the treatment of fever and malaria in clinical practice. Dihydroartemisinin (DHA), the major active metabolite of artemisinin, plays a role in anti-organizational fibrosis and anti-neuronal cell death. However, whether DHA can attenuate ALI remains unclear. The current study thus examined the effects of DHA on ALI and primary macrophages. The results revealed that DHA attenuated lipopolysaccharide (LPS)-induced pulmonary pathological damage. DHA suppressed the LPS-induced infiltration of inflammatory cells, the elevation of myeloperoxidase activity, oxidative stress and the production of pro-inflammatory cytokines, including interleukin (IL)-1β, tumor necrosis factor-α, and IL-6. Furthermore, DHA reduced the LPS-induced inflammatory response by suppressing the degradation of I-κB and the nuclear translocation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)/p65 in vivo and in vitro. DHA activated the nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway, which was suppressed by LPS treatment. The Nrf2 inhibitor, ML385, diminished the protective effects of DHA against LPS-induced inflammation in macrophages. On the whole, the findings of this study demonstrate that DHA exerts therapeutic effects against LPS-induced ALI by inhibiting the Nrf2-mediated NF-κB activation in macrophages. The present study also confirmed the therapeutic effects of DHA in mice with LPS-induced ALI. Thus, these findings demonstrate that DHA exhibits anti-inflammatory activities and may be a therapeutic candidate for the treatment of ALI.

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“…Ert-butyl ( E )-(3-(4-methylthiazol-5-yl)acryloyl)tyrosinate 105 is a CAPE derivative. Similarly, this compound also inhibited LPS-induced ALI in vivo and in vitro via its anti-inflammatory activities, and the effects were induced by its high affinity with MD2 and the suppressed formation of the LPS/MD2/TLR4 complex [ 324 ].…”

Section: Natural Compounds That Exert Anti-ali Effectsmentioning

confidence: 99%

Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms

Zhou

et al. 2021

Pharmacological Research

251

121

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Discovery of caffeic acid phenethyl ester derivatives as novel myeloid differentiation protein 2 inhibitors for treatment of acute lung injury

Cited by 36 publications

References 45 publications

Soluble MD-2 and Heme in Sickle Cell Disease Plasma Promote Pro-Inflammatory Signaling in Endothelial Cells

Soluble MD-2 and Heme in Sickle Cell Disease Plasma Promote Pro-Inflammatory Signaling in Endothelial Cells

Dihydroartemisinin attenuates lipopolysaccharide‑induced acute lung injury in mice by suppressing NF‑κB signaling in an Nrf2‑dependent manner

Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms

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