Effects of K11R and G31P Mutations on the Structure and Biological Activities of CXCL8: Solution Structure of Human CXCL8(3-72)K11R/G31P

Cheng, Hsi-Tsung; Yu, Huiyuan; Gordon, John; Li, Fang; Cheng, Jya‐Wei

doi:10.3390/molecules22071229

Cited by 5 publications

(3 citation statements)

References 32 publications

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“…They mutated Arg residue at site 11 of the main binding site of human CXCL8 to Lys11 and Pro residue at site 31 of the first β-turn of human CXCL8 to Gly to generate hG31P. It has a higher affinity to CXCR1/2 and was able to inhibit downstream signal transduction and, therefore, limit neutrophil migration 42,43 . Furthermore, it was also reported that hG31P can effectively inhibit neutrophil recruitment and reduce pathology of lung in mice models 40,44 .…”

Section: Discussionmentioning

confidence: 99%

Porcine CXCR1/2 antagonist CXCL8(3–72)G31P inhibits lung inflammation in LPS-challenged mice

Wang

et al. 2020

Sci Rep

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Swine pneumonia is a great threat for pig industry around the world, which is usually accompanied with neutrophils infiltration in the airway. Although interleukin-8 (CXCL8) and its receptors, CXC chemokine receptor 1 and 2 (CXCR1/2) in human have been well documented, the expression and function of CXCR1/2 is still unknown in swine. To explore the feasibility to develop new veterinary anti-inflammatory drugs targeting porcine CXCR1/2, we detected CXCR1/2 expression in swine pneumonia through Real-Time PCR and immunohistochemistry for the first time. Two porcine CXCR1/2 antagonists, CXCL8 (3-72) N11R/G31P (pN11R) and CXCL8 (3-72) G31P (pG31P) were prepared and their anti-inflammatory effects were evaluated using cell chemotaxis assays and animal experiments. Our data showed that CXCR1/2 expression, which was closely related to neutrophil infiltration in the lung, was significantly up-regulated in swine pneumonia. The pN11R and pG31P could effectively inhibit the directional migration of neutrophils in vitro. In vivo data also indicated that both pN11R and pG31P significantly relieved LPS-induced pneumonia in mice through decreasing the expression of TNF-α, CXCL8, and IL-1β, and inhibiting neutrophil influx into the lung. pG31P was more efficient. Our study suggested that it is possible to develop new veterinary anti-inflammatory drugs targeting porcine CXCR1/2, and pG31P is a promising candidate.

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Section: Discussionmentioning

confidence: 99%

Porcine CXCR1/2 antagonist CXCL8(3–72)G31P inhibits lung inflammation in LPS-challenged mice

Wang

et al. 2020

Sci Rep

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“…CXCL8 contributes to the pathology of angiogenesis, fibrosis, infection, atherosclerosis, and tumor growth. Clinical studies have shown that elevated plasma levels of CXCL8 and other ELR-CXC chemokines can occur with acute indications such as arthritis, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, atherosclerosis, inflammatory bowel disease (IBD), psoriasis, and cancer, as well as acute indications such as reperfusion injury and acute respiratory distress syndrome (ARDS) (Cheng et al, 2017). Leukocyte recruitment is critical in many acute and chronic inflammatory diseases.…”

Section: Phaseol May Reduce Inflammatory Cell Activation and Inflamma...mentioning

confidence: 99%

Exploring the mechanism of action of licorice in the treatment of COVID-19 through bioinformatics analysis and molecular dynamics simulation

Cao

Gong²,

Wu³

et al. 2022

Front. Pharmacol.

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Purpose: The rapid worldwide spread of Corona Virus Disease 2019 (COVID-19) has become not only a global challenge, but also a lack of effective clinical treatments. Studies have shown that licorice can significantly improve clinical symptoms such as fever, dry cough and shortness of breath in COVID-19 patients with no significant adverse effects. However, there is still a lack of in-depth analysis of the specific active ingredients of licorice in the treatment of COVID-19 and its mechanism of action. Therefore, we used molecular docking and molecular dynamics to explore the mechanism of action of licorice in the treatment of COVID-19.Methods: We used bioinformatics to screen active pharmaceutical ingredients and potential targets, the disease-core gene target-drug network was established and molecular docking was used for verification. Molecular dynamics simulations were carried out to verify that active ingredients were stably combined with protein targets. The supercomputer platform was used to measure and analyze stability of protein targets at the residue level, solvent accessible surface area, number of hydrogen bonds, radius of gyration and binding free energy.Results: Licorice had 255 gene targets, COVID-19 had 4,628 gene targets, the intersection gene targets were 101. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene ontology (GO) analysis showed that licorice played an important role mainly through the signaling pathways of inflammatory factors and oxidative stress. Molecular docking showed that Glycyrol, Phaseol and Glyasperin F in licorice may playe a role in treating COVID-19 by acting on STAT3, IL2RA, MMP1, and CXCL8. Molecular dynamics were used to demonstrate and analyze the binding stability of active ingredients to protein targets.Conclusion: This study found that Phaseol in licorice may reduce inflammatory cell activation and inflammatory response by inhibiting the activation of CXCL8 and IL2RA; Glycyrol may regulate cell proliferation and survival by acting on STAT3. Glyasperin F may regulate cell growth by inhibiting the activation of MMP1, thus reducing tissue damage and cell death caused by excessive inflammatory response and promoting the growth of new tissues. Therefore, licorice is proposed as an effective candidate for the treatment of COVID-19 through STAT3, IL2RA, MMP1, and CXCL8.

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“…Previously, we have developed a novel ELR-CXC chemokine antagonist CXCL8-IP10 based on the structure of CXCL8 and IP10 20. We have demonstrated that CXCL8-IP10 markedly reduced Klebsiella -induced pulmonary inflammation, as assessed by gross pathology and histopathology, and airway neutrophil responses as well as airway and lung parenchymal myeloperoxidase, IL-1β, IL-6, IL-10, IFNγ, and TNF-α levels 21.…”

Section: Introductionmentioning

confidence: 99%

<p>A novel CXCL8 analog is effective in inhibiting the growth via cell cycle arrest and attenuating invasion of Lewis lung carcinoma</p>

Hsu

Yu²,

Lee

et al. 2019

OTT

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PurposeLung cancer and other solid tumors contain not only tumor cells but various types of stromal cells, such as fibroblasts and endothelial cells. In addition, tumors are infiltrated by inflammatory cells (neutrophils, macrophages, and lymphocytes). Tumor cells, stromal cells, and the tumor-associated leukocytes are responsible for the production of chemokines inside the tumor and the maintenance of systemic circulating chemokine levels. CXCL8 and its receptors, CXCR1 and CXCR2, were found to play important roles in tumor proliferation, migration, survival, and growth. We have developed a novel ELR-CXC chemokine antagonist CXCL8-IP10 based on the structure of CXCL8 and IP10.Patients and methodsWe assessed the anticancer efficacies of the blockade of CXCL8-CXCR1/2 axis in the Lewis lung carcinoma (LL/2) model using CXCL8-IP10.ResultsWe found that CXCL8-IP10 markedly reduced LL/2 cell anchorage-independent growth and invasion. Moreover, we demonstrated that CXCL8-IP10 could significantly suppress tumor growth and improve survival rate as well as lifespan of C57BL/6 mice inoculated with LL/2 cells.ConclusionOur results suggest that ELR-CXC chemokine antagonism would potentially be a useful therapeutic approach in patients with lung cancer.

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Effects of K11R and G31P Mutations on the Structure and Biological Activities of CXCL8: Solution Structure of Human CXCL8(3-72)K11R/G31P

Cited by 5 publications

References 32 publications

Porcine CXCR1/2 antagonist CXCL8(3–72)G31P inhibits lung inflammation in LPS-challenged mice

Porcine CXCR1/2 antagonist CXCL8(3–72)G31P inhibits lung inflammation in LPS-challenged mice

Exploring the mechanism of action of licorice in the treatment of COVID-19 through bioinformatics analysis and molecular dynamics simulation

<p>A novel CXCL8 analog is effective in inhibiting the growth via cell cycle arrest and attenuating invasion of Lewis lung carcinoma</p>

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