EUPATOROXIN,10-EPI/Euphorbia Factor L1/Benzeneacetic acid, (1aR,4aR,6S,7S,7aR,8S,9R,11aS)-4a,8-bis(acetyloxy)-1,1a,4,4a,5,6,7,7a,8,10,11,11a-dodecahydro-1,1,3,6-tetramethyl-4-oxospiro[9H-cyclopenta[a]cyclopropa[f]cycloundecene-9,2'-oxiran]-7-yl ester/(1aR,2Z,4aR,6S,7S,7aR,8R,9S,11aS)-4a,8-Diacetoxy-1,1,3,6-tetramethyl-4-oxo-1,1a,4,4a,5,6,7,7a,8,10,11,11a-dodecahydrospiro[cyclopenta[a]cyclopropa[f]annulene-9,2'-oxiran]-7-yl phenylacetate/Benzeneacetic acid, (1aR,2Z,4aR,6S,7S,7aR,8R,9S,11aS)-4a,8-bis(acetyloxy)-1,1a,4,4a,5,6,7,7a,8,10,11,11a-dodecahydro-1,1,3,6-tetramethyl-4-oxospiro[9H-cyclopenta[a]cyclopropa[f]cycloundecene-9,2'-oxiran]-7-yl ester/(1aR,4aR,6S,7S,7aR,8S,9R,11aS)-4a,8-Diacetoxy-1,1,3,6-tetramethyl-4-oxo-1,1a,4,4a,5,6,7,7a,8,10,11,11a-dodecahydrospiro[cyclopenta[a]cyclopropa[f]annulene-9,2'-oxiran]-7-yl phenylacetate/10-epi-Eupatoroxin
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Euphorbia factor L1 (EFL1) is a lathyrane-type diterpenoid from the medicinal herb Euphorbia lathyris L., and has been reported with intestinal toxicity, but the potential mechanisms remain unknown.
The objective of this study was to investigate the intestinal toxicity of EFL1 and the underlying mechanisms using nematode Caenorhabditis elegans.
C. elegans were exposed to 0-200 μM EFL1 for 72 h, then the survival rate, body length and body width, locomotion and chemoreception behavior, intestinal ROS and lipofuscin accumulation, intestinal permeability, and defecation rhythm were detected. The γ-aminobutyric acid（GABA) energic neurons AVL and DVB were shown via green fluorescent protein under a laser scanning confocal microscope. The structure of GABA transporter UNC-47 were predicted by homology modeling, and the interaction between EFL1 and UNC-47 was simulated by molecular docking. The mRNA expression of genes related to oxidative stress, intestinal permeability and defecation after EFL1 exposure were detected by RT-qPCR.
EFL1 did not induce lethality of nematodes. The general toxicity was characterized by abnormal growth, locomotion and chemoreception. The intestinal barrier was leaky, due to down-regulated cell junction and active cation transport. The mean defecation cycle length in nematodes was decreased, relating to disorder vesicular and ion transport, enhanced rhythm behavior and muscle contraction. The dysfunctional defecation also attributed to injured UNC-47 protein, as well as GABAergic neurons AVL and DVB. Excessive ROS and lipofuscin accumulation were observed in intestine, along with activation of antioxidant enzymes of SOD, COQ7 and CAT.
This study elucidated the EFL1-induced intestinal toxicity in nematodes, characterized as leaky intestinal barrier and accelerated defecation behavior. The underlying mechanisms were involved in oxidative stress, cell junctions, transportation, rhythm behavior, muscle contraction, and GABAergic neurons.
Copyright © 2019. Published by Elsevier GmbH.
Caenorhabditis elegans; Defecation behavior; Euphorbia factor L1; Intestinal permeability; Oxidative stress; γ-aminobutyric acid
Effect of Euphorbia factor L1 on intestinal barrier impairment and defecation dysfunction in Caenorhabditis elegans.
Zhu A1, Ji Z1, Zhao J1, Zhang W2, Sun Y1, Zhang T1, Gao S3, Li G4, Wang Q5.
Euphorbia factor L1 (EFL1), a lathyrane-type diterpenoid from the medicinal herb Euphorbia lathyris L. (Euphorbiaceae), has been reported for many decades to induce gastric irritation, but the underlying mechanisms remain unclear.
The objective of this study was to investigate EFL1-induced cytotoxicity and the potential mechanisms of action on the human normal gastric epithelial cell GES-1.
GES-1 cells were treated with EFL1 (12.5-200 μM) for different time intervals, and cell survival, LDH release, intracellular reactive oxygen species (ROS), malondialdehyde (MDA) content, and superoxide dismutase (SOD) activity were detected. Mitochondrial membrane potential (MMP) assay, DAPI staining, DNA fragment assay, and annexin V-FITC/PI staining were performed. The interaction between EFL1 and Bcl-2, cytochrome c, caspase-9, caspase-3, PI3K, AKT, and mTOR proteins was simulated by molecular docking. The mRNA and protein expression of apoptosis and autophagy factors were detected by RT-qPCR and Western blotting.
EFL1 decreased survival, increased LDH leakage, and induced abnormal production of ROS, MDA and SOD in GES-1 cells. Mitochondria-mediated apoptosis was characterized by decreased MMP, condensed nuclei, fragmented DNA, and increased apoptosis rate. EFL1 interacted with proteins via hydrogen bonding. The mRNA, total or phosphorylated protein expression of Bcl-2, mitochondrial cytochrome c, PI3K, AKT, mTOR and p62 were downregulated; in contrast, those of cytoplasmic cytochrome c, cleaved caspase-9, cleaved caspase-3, LC3-ll and Beclin-1 were upregulated.
These findings indicated that EFL1 decreased the survival of GES-1 cells through EFL1-induced oxidative stress, activation of the mitochondria-mediated apoptosis as well as autophagy via inhibition of the PI3K/AKT/mTOR pathway.
Copyright © 2019 Elsevier GmbH. All rights reserved.
Apoptosis; Autophagy; Euphorbia factor L1; Gastric toxicity; Mitochondria; Oxidative stress
Effect of euphorbia factor L1 on oxidative stress, apoptosis, and autophagy in human gastric epithelial cells.
Zhu A1, Sun Y1, Zhong Q1, Yang J1, Zhang T1, Zhao J1, Wang Q2.
Excessive bone resorption caused by increased osteoclast number or activity leads to a variety of bone diseases including osteoporosis, rheumatoid arthritis and periodontitis. Thus, the therapeutic strategy for these diseases has been focused primarily on the inhibition of osteoclast formation and function. This study shows that euphorbia factor L1 (EFL1), a diterpenoid isolated from Euphorbia lathyris, inhibited osteoclastogenesis and induced osteoclast apoptosis. EFL1 suppressed osteoclast formation and bone resorption at both initial and terminal differentiation stages. EFL1 inhibited receptor activator of NF-κB ligand (RANKL)-induced NFATc1 induction with attenuated NF-κB activation and c-Fos expression. EFL1 decreased the level of reactive oxygen species by scavenging them or activating Nrf2, and inhibited PGC-1β that regulates mitochondria biogenesis. In addition, EFL1 induced apoptosis in differentiated osteoclasts by increasing Fas ligand expression followed by caspase activation. Moreover, EFL1 inhibited inflammation-induced bone erosion and ovariectomy-induced bone loss in mice. These findings suggest that EFL1 inhibits osteoclast differentiation by regulating cellular redox status and induces Fas-mediated apoptosis in osteoclast, and may provide therapeutic potential for preventing or treating bone-related diseases caused by excessive osteoclast.
Copyright © 2017 Elsevier Inc. All rights reserved.
Apoptosis; Bone resorption; Osteoclast; Reactive oxygen species
Euphorbia factor L1 inhibits osteoclastogenesis by regulating cellular redox status and induces Fas-mediated apoptosis in osteoclast.
Hong SE1, Lee J1, Seo DH2, In Lee H1, Ri Park D1, Lee GR1, Jo YJ1, Kim N1, Kwon M1, Shon H1, Kyoung Seo E3, Kim HS2, Young Lee S1, Jeong W4.