Original ArticleCentipeda minima extract exerts antineuroinflammatory effects via the inhibition of NF-κB signaling pathway
Graphical abstract
Introduction
Neuroinflammation is implicated in the pathogenesis of many brain diseases, especially neurodegenerative diseases (Ransohoff, 2016), in which the activation of microglia is one of the main characteristics. In response to inflammatory stimuli, microglia is quickly activated and recruited to the neurinflammatory site, then contributing to the development of neuroinflammation via the production of inflammatory mediators (Simon et al., 2019) .
A variety of inflammatory stimuli such as LPS can directly activate microglia through a cascade of molecular changes. As an inflammatory transcriptional factor, NF-κB is critical in mediating the activation of microglia. Normally, NF-κB is sequestered in the cytoplasm by the inhibitor IκB-α, whereas the inflammatory signal downregulates IκB-α and induces the phosphorylation and nuclear translocation of NF-κB (Li et al., 2013). Once activated, NF-κB stimulates the transcription of genes encoding inflammatory cytokines and inflammatory enzymes, leading to the expression of iNOS and COX2 and the generation of proinflammatory mediators, such as IL-1β, TNF-α, nitric oxide and PGE2, which extensively contribute to microglia-mediated neurotoxicity (Cunningham et al., 2009). Moreover, oxidative stress that induced by chronic inflammation can further contribute to the development of neuroinflammation (Block et al., 2007). For example, LPS can directly activate the NADPH oxidase, including NOX2 and NOX4, which significantly increase microglia-derived ROS, activate inflammatory-related signaling, and severely accelerate the neuronal damage (Haslund-Vinding et al., 2017; Qin et al., 2004). Therefore, targeting microglia has been regarded as a prospective therapeutic strategy for the treatment of neuroinflammatory diseases.
Medicinal formula and plant extracts have been used for centuries to treat inflammatory diseases. C. minima is widely distributed in East and Southeast Asia and used in the treatment of a number of diseases, such as asthma, rhinitis, sinusitis and diarrhea (Liu et al., 2005; Wu et al., 1991). Recently, the major chemical components of C. minima extract, including terpenoids, polyphenol, phenolics, organic acid and flavonoids, have been determined based on the HPLC-MS/MS system (Ding et al., 2009; Wu et al., 2012). For example, isochlorogenic acid A and 6-O-angeloylplenolin, have been found to be most abundantly distributed in the herb and proposed to be used for the quality control of C. minima extract (Chan et al., 2016, 2019). Pharmacological studies have demonstrated that C. minima and its active components harbors antibacterial, anticancer, antiallergy, antioxidant and anti-inflammatory activities, with good pharmacological profiles and less toxicity (Liu et al., 2011, 2015; Taylor and Towers, 1998; Wu et al., 2012). For example, both the aqueous and hydroalcoholic extract of C. minima have been demonstrated to exert anti-inflammatory and antioxidant activities (Huang et al., 2013). Our recent study also find that ECM significantly alleviates the oxidative stress in the hippocampus and exerts neuroprotective effects (Wang et al., 2019); moreover, 6-O-angeloylplenolin, the major chemical constituents of ECM, has been shown to inhibit the inflammatory response in the central nervous system (CNS) (Li et al., 2019; Zhou et al., 2019), suggesting that ECM has potential anti-inflammatory activities in the CNS.
In this study, ECM with a good quality was prepared to examine the antineuroinflammatory activities and the underlying mechanisms. We found that ECM exhibits neuroprotective effect via the inhibition of LPS-induced neuroinflammation in microglial cells. ECM inhibits the activation of NF-κB signaling and the induction of inflammatory enzymes, leading to the decreased production of proinflammatory mediators. Taken together, this study demonstrates that ECM has a therapeutic potential for the treatment of neuroinflammatory diseases.
Section snippets
Reagents and antibodies
Methanol, acetonitrile, and acetic acid with HPLC grade were purchased from Merck (Darmstad, Germany). Reference compounds of caffeic acid, chlorogenic acid, isochlorogenic acid A, isochlorogenic acid B, isochlorogenic acid C and rutin were purchased from Meilun Biotechnology Co., Ltd. (Dalian, China), 6-O-angeloylplenolin (also referred to as brevilin A (Taylor and Towers, 1998)) was obtained from C. minima extract and purified by Cheng group as described (26). The purity of all reference
Quantitative analysis of the main components in ECM
HPLC-MS/MS analysis was firstly performed to determine the main components in ECM by matching retention times and mass spectra of the standard compounds with those of ECM. Standard solutions containing the reference compounds were used to optimize the retention times according to a previous report (Chan et al., 2016). The main components in ECM, including chlorogenic acid, caffeic acid, rutin, isochlorogenic acid A, isochlorogenic acid B, isochlorogenic acid C and 6-O-angeloylplenolin, were
Discussion
Neuroinflammation has been demonstrated to be associated with neuronal damage and multiple CNS diseases, owning to the fact that inflammatory stimulus induces the activation of NF-κB and the expression of inflammatory enzymes, which entail the release of a large amount of toxic proinflammatory mediators in the CNS. C. minima has been used in traditional Chinese medicine for centuries to treat certain inflammatory diseases; however, the effect of C. minima on CNS diseases has rarely been
Author contributions
SYL, YLZ, HFP, YXC, and YQL designed the research, YLZ, SYL, DHH, WL, and XZF performed the experiments, YLZ, SYL, DHH, WL, and YQL analyzed the data, YLZ, SYL, YXC, and YQL wrote the manuscript, SYL, YLZ, XZF, YXC, QW, and YQL reviewed the manuscript. All authors have read and approved the final submitted manuscript.
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (81802776), Guangzhou Science Technology and Innovation Commission Technology Research Projects (201805010005), the National Science Fund for Distinguished Young Scholars (81525026), and the National Key Research and Development Program of China “Research and Development of Comprehensive Technologies on Chemical Fertilizer and Pesticide Reduction and Synergism” (2017YFD0201402).
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These authors have contributed equally to this work