Shikonin inhibits myeloid differentiation protein 2 to prevent LPS‐induced acute lung injury

Zhang, Yali; Xu, Tingting; Pan, Zheer; Ge, Xiangting; Sun, Chao; Lu, Chun; Chen, Hongjin; Xiao, Zhifeng; Zhang, Bing; Dai, Yuanrong; Liang, Guang

doi:10.1111/bph.14129

Cited by 65 publications

(36 citation statements)

References 71 publications

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“…NF-κB plays an important role in regulating of proinflammatory mediators in ALI ( Zhu et al, 2017 ; Zhang et al, 2018 ). NF-κB is activated by various stimuli such as cytokines, ROS, bacterial or viral products ( Zhao M.X.…”

Section: Discussionmentioning

confidence: 99%

“…Activated NF-κB translocates into the nucleus where it triggers the transcription of specific genes such as TNF-α, IL-1β, and IL-6 ( Tang et al, 2017 ). NF-κB binding sequences have also been identified in proinflammatory genes such as iNOS and COX-2 ( Zhang et al, 2018 ). The protective effects of CH on LPS-induced endotoxic shock can be attributed to attenuating inflammatory cytokines and inhibition of the expression of NF-κB ( Niu et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

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Chelerythrine Attenuates the Inflammation of Lipopolysaccharide-Induced Acute Lung Inflammation Through NF-κB Signaling Pathway Mediated by Nrf2

Fan

Liu

et al. 2018

Front. Pharmacol.

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Chelerythrine (CH), is a kind of benzo[c] phenanthridine alkaloid isolated from plants such as Chelidonium, with pharmacological activities as antitumor, antibiosis and anti-inflammation. However, few studies have demonstrated whether CH could protect against lipopolysaccharide (LPS)-induced acute lung injury (ALI), and the underlying mechanism is also uncertain. The purpose of the present study was to investigate the anti-inflammatory effects of CH on LPS-induced ALI in mice and in RAW264.7 cells. In this study, we demonstrated that treatment with CH significantly ameliorated LPS-induced pathological changes in the lung. CH also attenuated LPS-induced W/D ratio, inflammatory cell infiltration. Meanwhile, LPS-induced Tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β) production and oxidative stress were markedly suppressed by CH. Furthermore, western blot showed that CH suppressed LPS-stimulated inflammation of RAW264.7 cells through activation of nuclear factor kappa-B (NF-κB) pathway. Knocking down of nuclear factor erythroid 2-related factor 2 (Nrf2) led to the reduction of nuclear translocation of the NF-κB p65, which triggered inflammation. These experimental results provided evidence that CH could be a potential therapeutic candidate for the intervention of ALI caused by LPS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chelerythrine Attenuates the Inflammation of Lipopolysaccharide-Induced Acute Lung Inflammation Through NF-κB Signaling Pathway Mediated by Nrf2

Fan

Liu

et al. 2018

Front. Pharmacol.

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“…Notedly, the binding site of Luteolin or Diacerein to hMD‐2 was identical to that of known MD‐2 inhibitor Shikonin (Figure 3E and Figure S4C, Supporting Information). [ 21 ] Interestingly, the chemical structures of Luteolin and Shikonin were similar (Figure S2A,E, Supporting Information). Fenbufen, a compound without inhibition activity for TLR4 (Figure S1, Supporting Information), had stochastic binding sites in the interface of hMD‐2 (Figure 3F) as a negative control in this docking assay.…”

Section: Resultsmentioning

confidence: 92%

Switch Off “Parallel Circuit”: Insight of New Strategy of Simultaneously Suppressing Canonical and Noncanonical Inflammation Activation in Endotoxemic Mice

et al. 2020

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Sepsis is a life‐threatening inflammatory disease with a high mortality rate and huge implicative costs. Lipopolysaccharide (LPS) from gram‐negative bacteria activates toll‐like receptor 4 (TLR4) and may trigger septic shock. However, potent TLR4 inhibitors TAK‐242 and Eritoran have been terminated in phase III clinical trials because of inadequate efficacy. Inspired by the recently discovered intracellular, noncanonical LPS receptors, it is considered that TLR4‐mediated canonical and caspase‐mediated noncanonical inflammation can be seen as a “parallel circuit” to induce sepsis and endotoxemia. Logically, it is proposed that the dual inhibition of caspase‐4/5/11 and TLR4 can be a potential novel strategy to develop new therapeutics for sepsis. To verify the strategy, two potential compounds are found: Luteolin and Diacerein with substantial antiinflammatory activity in vitro and in vivo. The results show that the survival rate of endotoxemic mice treated by these compounds is increased remarkably. LPS‐induced organ damage is also prevented. Moreover, these compounds result in physical and mental recovery for endotoxemic mice. Notably, Luteolin exhibits better antiinflammatory activity than TAK‐242 at comparable TLR4‐inhibitory levels. These findings indicate that simultaneous inhibition of TLR4 and caspase‐4/5/11 can be an anticipative strategy defeating sepsis and endotoxemia, which can be translated into significant medical and economic benefits.

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“…Myeloid differentiation 2 (MD2), an accessory protein of toll-like receptor 4 (TLR4), is vital to mediating the lipopolysaccharide (LPS)/TLR4 acute inflammatory signaling [7,8]. Increasing evidence has shown that MD2 is associated with numerous acute and chronic inflammatory responses, and is considered a potential and meaningful therapeutic target for several inflammatory diseases [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Myeloid Differentiation Protein 2 Mediates Angiotensin II-Induced Liver Inflammation and Fibrosis in Mice

et al. 2019

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Angiotensin II (Ang II) participates in the pathogenesis of liver injury. Our previous publications reported that myeloid differentiation protein 2 (MD2) mediates Ang II-induced cardiac and kidney inflammation by directly binding to Ang II. Thus, we hypothesize that MD2 is critical to Ang II-induced liver injury. Subcutaneous injections of Ang II for 8 weeks were adopted to build the liver injury model. With a specific MD2 inhibitor L6H21 and MD2 knockout mice, we reported that MD2 inhibition and knockout significantly mitigate liver inflammation and fibrosis in mice injected with Ang II. To be more specific, the functional and pathological damages induced by Ang II were mitigated by L6H21 or MD2 knockout. MD2 knockout or L6H21 administration inhibited the Ang II-induced upregulation of fibrosis markers, inflammatory cytokines, and adhesion molecules in gene or protein levels. The activation of NF-κB and Extracellular signal-regulated kinases (ERK) induced by Ang II was also reversed by L6H21 treatment or MD2 deficiency. Note that the co-immunoprecipitation study showed that L6H21 downregulated the ANG II-induced toll-like receptor 4 (TLR4)/MD2 complex in liver tissues while having no effects on MD2 expression. Our results reported the critical role of MD2 in the progress of liver injury and suggested that MD2 is a potential therapeutic target for liver injury.

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Shikonin inhibits myeloid differentiation protein 2 to prevent LPS‐induced acute lung injury

Abstract: Our studies have uncovered the mechanism underlying the biological activity of shikonin in ALI and suggest that the targeting of MD2 may prove to be beneficial as a treatment option for this condition.

Cited by 65 publications

References 71 publications

Chelerythrine Attenuates the Inflammation of Lipopolysaccharide-Induced Acute Lung Inflammation Through NF-κB Signaling Pathway Mediated by Nrf2

Chelerythrine Attenuates the Inflammation of Lipopolysaccharide-Induced Acute Lung Inflammation Through NF-κB Signaling Pathway Mediated by Nrf2

Switch Off “Parallel Circuit”: Insight of New Strategy of Simultaneously Suppressing Canonical and Noncanonical Inflammation Activation in Endotoxemic Mice

Myeloid Differentiation Protein 2 Mediates Angiotensin II-Induced Liver Inflammation and Fibrosis in Mice

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