Protective Effect of Piplartine against LPS-Induced Sepsis through Attenuating the MAPKs/NF-κB Signaling Pathway and NLRP3 Inflammasome Activation.

Chi-Han Huang,Shu-Chi Wang,Hsin-Chih Yeh,Ching-Chih Liu,Shih-Hua Fang,Shu-Pin Huang,Chia-Yang Li,Po-Len Liu,Yi-Ting Chen,Chia-Cheng Su,I-Chen Chen,Po-Yen Lee,Hsin-En Wu,Yuan-Ru Chen,Tzu-Chieh Lin,Wei-Chung Cheng

doi:10.3390/ph14060588

Abstract

Piplartine (or Piperlongumine) is a natural alkaloid isolated from Piper longum L., which has been proposed to exhibit various biological properties such as anti-inflammatory effects; however, the effect of piplartine on sepsis has not been examined. This study was performed to examine the anti-inflammatory activities of piplartine in vitro, ex vivo and in vivo using murine J774A.1 macrophage cell line, peritoneal macrophages, bone marrow-derived macrophages and an animal sepsis model. The results demonstrated that piplartine suppresses iNOS and COX-2 expression, reduces PGE2, TNF-α and IL-6 production, decreases the phosphorylation of MAPKs and NF-κB and attenuates NF-κB activity by LPS-activated macrophages. Piplartine also inhibits IL-1β production and suppresses NLRP3 inflammasome activation by LPS/ATP- and LPS/nigericin-activated macrophages. Moreover, piplartine reduces the production of nitric oxide (NO) and TNF-α, IL-6 and IL-1β, decreases LPS-induced tissue damage, attenuates infiltration of inflammatory cells and enhances the survival rate. Collectively, these results demonstrate piplartine exhibits anti-inflammatory activities in LPS-induced inflammation and sepsis and suggest that piplartine might have benefits for sepsis treatment.

Highlights

Sepsis, a life-threatening condition with 30–50% in-hospital mortality, has excessive inflammation in response to infection [1]
Our experimental results showed that piplartine significantly inhibited differ significantly when J774A.1 cells were treated with piplartine 0–10 μM (Figure 1a)
Our results pointed out that LPS significantly increased PGE2, NO, IL-6 and tumor necrosis factor (TNF)-α secretions and promoted iNOS and COX-2 expressions by macrophages, while piplartine treatment exhibited anti-inflammatory effects by repressing PGE2, NO, IL-6 and TNF-α secretions and attenuating iNOS and COX-2 expressions by LPS-activated macrophages

Summary

Introduction

A life-threatening condition with 30–50% in-hospital mortality, has excessive inflammation in response to infection [1]. In the United States, 1.7 million adults experience inflammation annually, resulting in over 250,000 deaths [2,3]. Immune dysregulation is the core mechanism underlying the development of sepsis, which includes intense inflammatory response and cytokine storm [4]. Persistent increase in tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 produced primarily by macrophages are associated with septic death [5]. Monocytes are recruited and differentiate into inflammatory macrophages [6] that play a critical role in the maintenance of tissue homeostasis and contribute to the clearance of microorganisms and dying cells. The dysregulation of macrophage production has been demonstrated to be associated with adverse prognosis [7]

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Conclusion