Cissus subtetragona Planch. Ameliorates Inflammatory Responses in LPS-induced Macrophages, HCl/EtOH-induced Gastritis, and LPS-induced Lung Injury via Attenuation of Src and TAK1.

Laily Rahmawati,Ji Hwa Jung,Nur Aziz,Jieun Oh,Taewoo Kim,Phetlasy Souladeth,Mohammad Amjad Hossain,Jae Youl Cho,Jong-Hoon Kim,Philaxay Manilack,Jinwhoa Yum,Yong Deog Hong,Yo Han Hong,Mi Jeong Jeon,Byoung Young Woo,Woo Shin Lee

doi:10.3390/molecules26196073

Abstract

Several Cissus species have been used and reported to possess medicinal benefits. However, the anti-inflammatory mechanisms of Cissus subtetragona have not been described. In this study, we examined the potential anti-inflammatory effects of C. subtetragona ethanol extract (Cs-EE) in vitro and in vivo, and investigated its molecular mechanism as well as its flavonoid content. Lipopolysaccharide (LPS)-induced macrophage-like RAW264.7 cells and primary macrophages as well as LPS-induced acute lung injury (ALI) and HCl/EtOH-induced acute gastritis mouse models were utilized. Luciferase assays, immunoblotting analyses, overexpression strategies, and cellular thermal shift assay (CETSA) were performed to identify the molecular mechanisms and targets of Cs-EE. Cs-EE concentration-dependently reduced the secretion of NO and PGE2, inhibited the expression of inflammation-related cytokines in LPS-induced RAW264.7 cells, and decreased NF-κB- and AP-1-luciferase activity. Subsequently, we determined that Cs-EE decreased the phosphorylation events of NF-κB and AP-1 pathways. Cs-EE treatment also significantly ameliorated the inflammatory symptoms of HCl/EtOH-induced acute gastritis and LPS-induced ALI mouse models. Overexpression of HA-Src and HA-TAK1 along with CETSA experiments validated that inhibited inflammatory responses are the outcome of attenuation of Src and TAK1 activation. Taken together, these findings suggest that Cs-EE could be utilized as an anti-inflammatory remedy especially targeting against gastritis and acute lung injury by attenuating the activities of Src and TAK1.

Highlights

The essential role of inflammation as part of the innate immune response has been widely reported
Since we previously found that pre-treatment of LPS-treated decrease mediators, nitric oxide (NO)
Cs-EE(pusing another inflammaNext, we evaluated the anti-inflammatory efficacy of using another treatment together with a standard drug, dexamethasone, relieved the pulmonary tory model, the LPS-induced acute lung injury (ALI) mouse model, which was created by nasal inhalation, inflammatory model, the mouse model, which of was created by by nasal (Figurein7b)

Summary

Introduction

The essential role of inflammation as part of the innate immune response has been widely reported. Engagement of PAMPs such as lipopolysaccharides (LPS) derived from Gram-negative bacteria into TLR-4 will induce recruitment of adaptor proteins into the cytoplasm This activates molecular cascades that are immediately transduced via signal transduction pathways including a protein tyrosine kinase, Src, and a MAPK kinase kinase (MAPKKK), TAK1, to mediate nuclear translocation and activate transcription factors such as nuclear factor (NF)-κB and activator protein (AP)-1 [3,4,5]. Regulating inflammatory responses through anti-inflammatory agents is considered as a method for preventing the development of various diseases

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Discussion

Conclusion