Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605) Reduces Asbestos-Induced Cytotoxicity in an Nrf2-Dependent and -Independent Manner

Our plain-English summary of Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605) Reduces Asbestos-Induced Cytotoxicity in an Nrf2-Dependent and -Independent Manner, by R.A. Pietrofesa, S. Chatterjee, K. Park, et al (Antioxidants, 2018).

The study

• Authors: R.A. Pietrofesa, S. Chatterjee, K. Park, E. Arguiri, S.M. Albelda, M. Christofidou-Solomidou
• Journal: Antioxidants
• Published: 2018;7(3)
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Asbestos exposure triggers inflammatory processes associated with oxidative stress and tissue damage linked to malignancy. LGM2605 is the synthetic lignan secoisolariciresinol diglucoside (SDG) with free radical scavenging, antioxidant, and anti-inflammatory properties in diverse inflammatory cell and mouse models, including exposure to asbestos fibers. Nuclear factor-E2 related factor 2 (Nrf2) activation and boosting of endogenous tissue defenses were associated with the protective action of LGM2605 from asbestos-induced cellular damage. To elucidate the role of Nrf2 induction by LGM2605 in protection from asbestos-induced cellular damage, we evaluated LGM2605 in asbestos-exposed macrophages from wild-type (WT) and Nrf2 disrupted (Nrf2-/-) mice. Cells were pretreated with LGM2605 (50 µM and 100 µM) and exposed to asbestos fibers (20 µg/cm²) and evaluated 8 h and 24 h later for inflammasome activation, secreted cytokine levels (interleukin-1β (IL-1β), interleukin-18 (IL-18), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα)), cytotoxicity and cell death, nitrosative stress, and Nrf2-regulated enzyme levels. Asbestos exposure induced robust oxidative and nitrosative stress, cell death and cytotoxicity, which were equally mitigated by LGM2605. Inflammasome activation was significantly attenuated in Nrf2-/- macrophages compared to WT, and the protective action of LGM2605 was seen only in WT cells. In conclusion, in a cell model of asbestos-induced toxicity, LGM2605 acts via protective mechanisms that may not involve Nrf2 activation.

In plain English

This was a laboratory experiment on mouse cells, not a study of people. The authors took peritoneal macrophages, a type of immune cell, from normal (wild-type) mice and from mice lacking Nrf2, a gene that helps switch on the cell's own antioxidant defenses. The cells were pretreated with LGM2605, a synthetic version of a flaxseed compound, four hours before exposure to crocidolite asbestos fibers at 20 micrograms per square centimetre. In wild-type cells, LGM2605 reduced asbestos-induced reactive oxygen species by 76.6% at 50 µM and 95.9% at 100 µM. Asbestos-related cell death fell by 74.3% and 96.3% in wild-type cells and by 73.4% and 96.9% in Nrf2-lacking cells. After asbestos, nitrosative stress was higher in Nrf2-lacking cells, and LGM2605 reduced it in both cell types. The inflammatory signals IL-1β and IL-18 were lower in Nrf2-lacking cells. LGM2605 significantly reduced them only in wild-type cells; the reductions in Nrf2-lacking cells were not statistically significant. The authors concluded that LGM2605 protected through both Nrf2-dependent and Nrf2-independent actions.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiment on immune cells taken from wild-type and Nrf2-deficient mice
• Who was studied: Peritoneal macrophages from 13-week-old C57BL/6 wild-type and Nrf2-deficient mice, housed at the Children's Hospital of Philadelphia. Imaging results came from n = 3 independent experiments. The number of mice is not stated.
• Exposure: UICC crocidolite asbestos fibers at 20 µg/cm2. Cells were pretreated with LGM2605 (synthetic secoisolariciresinol diglucoside) at 50 µM and 100 µM 4 hours before asbestos exposure.
• Main results:
  • In wild-type macrophages, LGM2605 reduced asbestos-induced reactive oxygen species by 76.6% at 50 µM and 95.9% at 100 µM. ROS generation was equally high in wild-type and Nrf2-deficient cells, and no significant differences were seen between the two cell types.
  • LGM2605 reduced asbestos-induced cell death in both cell types. In wild-type cells the reductions were 74.3% at 50 µM and 96.3% at 100 µM. In Nrf2-deficient cells they were 73.4% and 96.9%.
  • Asbestos raised total nitrates/nitrites (a marker of nitrosative stress) in wild-type cells at 24 h, from 10.15 µM in unexposed cells to 110.70 µM. Levels were higher in asbestos-exposed Nrf2-deficient cells: 148.86 µM versus 41.47 µM in wild-type at 8 h, and 160.72 µM versus 110.70 µM at 24 h.
  • LGM2605 (50 µM) significantly reduced nitrosative stress in both wild-type and Nrf2-deficient macrophages.
  • Asbestos-induced IL-1β and IL-18 were significantly lower in Nrf2-deficient cells than in wild-type cells. In wild-type cells, LGM2605 reduced IL-1β by 46.7% and IL-18 by 78.2% at 24 h.
  • In Nrf2-deficient cells, IL-1β and IL-18 were lower with LGM2605, but the differences were not statistically significant. For IL-1β at 24 h: 16.77 pg/mL with asbestos alone versus 9.55 pg/mL with LGM2605.
  • In wild-type cells, LGM2605 reduced IL-6 by 45.0% (8 h) and 62.9% (24 h), and TNFα by 30.6% (8 h) and 33.4% (24 h).
  • Asbestos increased antioxidant enzyme activity and abundance in wild-type cells. This response was significantly weaker in Nrf2-deficient cells.
  • In wild-type cells, LGM2605 raised asbestos-induced mRNA levels of TXNRD1 (by 106.1% and 76.4%) and GSTM1 (by 45.2% and 33.8%) at 8 h and 24 h. Asbestos-induced increases in these genes were not seen in Nrf2-deficient cells.
• The authors' conclusion: The authors concluded that LGM2605 had both Nrf2-dependent and Nrf2-independent protective actions against asbestos-induced cytotoxicity and cell death in this cell model.

Topics

Medical terms in this study, explained in our Lexicon: Asbestos Exposure, Oxidative Stress, Macrophage, Cytokine, Necrosis.

Related studies

• The Synthetic Lignan Secoisolariciresinol Diglucoside Prevents Asbestos-Induced NLRP3 Inflammasome Activation in Murine Macrophages — R.A. Pietrofesa, P. Woodruff, et al. (2017)
• Asbestos Induces Oxidative Stress and Activation of Nrf2 Signaling in Murine Macrophages: Chemopreventive Role of the Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605) — R.A. Pietrofesa, A. Velalopoulou, et al. (2016)
• Flaxseed lignans enriched in secoisolariciresinol diglucoside prevent acute asbestos-induced peritoneal inflammation in mice — R.A. Pietrofesa, A. Velalopoulou, et al. (2016)
• Synthetic secoisolariciresinol diglucoside (LGM2605) inhibits Libby amphibole fiber-induced acute inflammation in mice — M. Christofidou-Solomidou, R.A. Pietrofesa, et al. (2019)
• Synthetic Secoisolariciresinol Diglucoside (LGM2605) Prevents Asbestos-Induced Inflammation and Genotoxic Cell Damage in Human Mesothelial Cells — R.A. Pietrofesa, S. Chatterjee, et al. (2022)
• Late Inflammation Induced by Asbestiform Fibers in Mice Is Ameliorated by a Small Molecule Synthetic Lignan — R. Badger, K. Park, et al. (2021)

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