Cleome rutidosperma and Euphorbia thymifolia Suppress Inflammatory Response via Upregulation of Phase II Enzymes and Modulation of NF-κB and JNK Activation in LPS-Stimulated BV2 Microglia

Abstract

Cleome rutidosperma DC. and Euphorbia thymifolia L. are herbal medicines used in traditional Indian and Chinese medicine to treat various illnesses. Reports document that they have antioxidant and anti-inflammatory activities; nonetheless, the molecular mechanisms involved in their anti-inflammatory actions have not yet been elucidated. The anti-neuroinflammatory activities and underlying mechanisms of ethanol extracts of Cleome rutidosperma (CR) and Euphorbia thymifolia (ET) were studied using lipopolysaccharide (LPS)-stimulated microglial cell line BV2. The morphology changes and production of pro-inflammatory mediators were assayed. Gene expression of inflammatory genes such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, interleukin (IL)-1β, and CC chemokine ligand (CCL)-2, as well as phase II enzymes such as heme oxygenase (HO)-1, the modifier subunit of glutamate cysteine ligase (GCLM) and NAD(P)H quinone dehydrogenase 1 (NQO1), were further investigated using reverse transcription quantitative-PCR (RT-Q-PCR) and Western blotting. The effects of CR and ET on mitogen activated protein kinases (MAPKs) and nuclear factor (NF)-κB signaling pathways were examined using Western blotting and specific inhibitors. CR and ET suppressed BV2 activation, down-regulated iNOS and COX-2 expression and inhibited nitric oxide (NO) overproduction without affecting cell viability. They reduced LPS-mediated tumor necrosis factor (TNF) and IL-6 production, attenuated IL-1β and CCL2 expression, but upregulated HO-1, GCLM and NQO1 expression. They also inhibited p65 NF-κB phosphorylation and modulated Jun-N terminal kinase (JNK) activation in BV2 cells. SP600125, the JNK inhibitor, significantly augmented the anti-IL-6 activity of ET. NF-κB inhibitor, Bay 11-7082, enhanced the anti-IL-6 effects of both CR and ET. Znpp, a competitive inhibitor of HO-1, attenuated the anti-NO effects of CR and ET. Our results show that CR and ET exhibit anti-neuroinflammatory activities by inhibiting pro-inflammatory mediator expression and production, upregulating HO-1, GCLM and NQO1, blocking NF-κB and modulating JNK signaling pathways. They may offer therapeutic potential for suppressing overactivated microglia and alleviating neurodegeneration.

Induction of peroxisome proliferator activated receptor γ (PPARγ) mediated gene expression and inhibition of induced nitric oxide production by Maerua subcordata (Gilg) DeWolf

“…Several plant derived natural products were shown to exert anti-inflammatory effects via inhibition of the NF-κB/iNOS pathway mediated NO production [33,[62][63][64][65]. Therefore, the screened candidate constituents may act by this mechanism and may contribute to the NO production inhibition effect by the extracts.…”

Vernonia patula (Dryand.) Merr. and Leucas chinensis (Retz.) R. Brown exert anti-inflammatory activities and relieve oxidative stress via Nrf2 activation

“…Small molecules that activate Nrf2 signaling are under active study for their potential to become anti-inflammatory and cancer preventive agents ( Wu et al, 2010 ). Plants are rich sources of Nrf2 activing phytochemicals; therefore, development of anti-inflammatory Nrf2 activators from plant extracts has attracted attention in biomedical field ( Ahmed et al, 2017 ; Ding et al, 2016 ; Wu et al, 2015 , 2018 ).…”

Triterpenoids from Euphorbia maculata and Their Anti-Inflammatory Effects

“…As many tumor promoters can cause inflammatory symptoms, the inhibitory effect against TPA-induced ear inflammation has a close correlation with the inhibition of TPA-induced tumor promotion in a two-stage carcinogenesis. Thus, we chose the medicinal plants of the genus Euphorbia (Euphorbiaceae) which contained triterpenoids to study their chemical constituents and pharmacological activity [ 11 ]. We found that the lanostane-type triterpenes of E. kansui markedly possessed the inhibitory activity against TPA-induced inflammation, and the predominant triterpene in this plant, euphol, significantly inhibited the tumor-promoting activity induced by TPA [ 12 ].…”