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. 2021 Nov 22;10(11):1219.
doi: 10.3390/biology10111219.

Terretonin as a New Protective Agent against Sepsis-Induced Acute Lung Injury: Impact on SIRT1/Nrf2/NF-κBp65/NLRP3 Signaling

Gamal A Mohamed  1 , Sabrin R M Ibrahim  2   3 , Dina S El-Agamy  4   5 , Wael M Elsaed  6 , Alaa Sirwi  1 , Hani Z Asfour  7 , Abdulrahman E Koshak  1 , Sameh S Elhady  1
Affiliations

Terretonin as a New Protective Agent against Sepsis-Induced Acute Lung Injury: Impact on SIRT1/Nrf2/NF-κBp65/NLRP3 Signaling

Gamal A Mohamed et al. Biology (Basel). .

Abstract

Endophytic fungi are proving to be an excellent source of chemical entities with unique structures and varied bioactivities. Terretonin (TE) and its structurally related derivatives are a class of meroterpenoids, possessing the same unique tetracyclic core skeleton, which have been reported from the Aspergillus genus. This study was carried out to assess the potential protective effects of TE separated from the endophytic fungus A. terreus against LPS (lipopolysaccharide)-induced ALI (acute lung injury) in mice. The results revealed that TE alleviated pulmonary edema as it lowered both the W/D lung ratio and protein content. The inflammatory response represented by inflammatory cell infiltration into the lung tissues was greatly repressed by TE. That was supported by the improved histopathological results and also by the reduced level of myeloperoxidase in the lung. TE showed a potent antioxidant activity as it attenuated lipid peroxidative markers (malondialdehyde, 4-hydroxynonenal, and protein carbonyl) and enhanced endogenous antioxidants (reduced glutathione, superoxide dismutase, and catalase) in lung tissues. Similarly, TE increased the mRNA expression of SIRT1, Nrf2, and its genes (HO-1, NQO1, and GCLm). On the other hand, TE restrained the activation of NF-κB (nuclear factor-κB) in the lung. Consequently, TE depressed the pro-inflammatory cytokines: nitric oxide (NOx), TNF-α (tumor necrosis factor-α), and interleukins (IL-6 and -1β). Additionally, TE inhibited NLRP3 signaling and interrupted apoptosis by decreasing the levels of proapoptotic markers (Bax and caspase-3) and increasing the level of an anti-apoptotic marker (Bcl-2). In conclusion, TE had a remarkable protective potential on LPS-induced lung damage via antioxidant and anti-inflammatory mechanisms. This finding encourages further investigations on this promising candidate.

Keywords: Aspergillus terreus; LPS; NF-κB; Nrf2; anti-inflammatory; endophytic fungi; terretonin.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Chemical structure of terretonin (TE).
Figure 2
Figure 2
1H (850 MHz) and 13C (214 MHz) NMR spectra of terretonin in CDCl3.
Figure 3
Figure 3
Terretonin (TE) attenuated biochemical and histopathological indices of lipopolysaccharide (LPS)-induced ALI. (I) (A) Lung W/D ratio; (B) total protein content; and (C) lactate dehydrogenase (LDH) activity in BALF. (II) Lung sections of: (A) Control and (B) TE 40 groups showed normal lung histology (normal alveolar capillaries (black arrows), thin alveolar walls (between arrow heads), and clear alveoli (star)). (C) Lungs of the LPS group exhibited many pathological features such as congested alveolar capillaries and alveolar hemorrhage (tailed black arrows), thick edematous alveolar walls (between arrow heads), edema fluid exudates in the alveoli (star), infiltration of inflammatory cells (curved arrows). (D) TE 20 + LPS and (E) TE 40 + LPS groups showed much improvement of all LPS-induced pathological changes in the lung. H&E stain ×400, scale bar 25 µm. Semiquantitative assessment of pathological changes in lung tissue in all groups. Data are the mean ± SE (n = 8). * p < 0.05, ** p < 0.01, *** p < 0.001 vs. control group; # p < 0.05, ## p < 0.01, ### p < 0.001 vs. LPS group (one-way ANOVA followed by Tukey’s Kramer multiple comparisons test).
Figure 4
Figure 4
Terretonin (TE) ameliorated lipopolysaccharide (LPS)-induced inflammatory cell infiltration into the lung and suppressed myeloperoxidase (MPO) activity. (A–E) Total and differential cell counts in bronchoalveolar lavage fluid (BALF). (F) MPO activity in lung tissue. Data are the mean ± SE (n = 8). * p < 0.05, ** p < 0.01, *** p < 0.001 vs. control group; # p < 0.05, ## p < 0.01, ### p < 0.001 vs. LPS group (one-way ANOVA followed by Tukey’s Kramer multiple comparisons test).
Figure 5
Figure 5
Terretonin (TE) attenuated lipopolysaccharide (LPS)-induced lipid peroxidation and augmented antioxidants in the lungs. (A) Malondialdehyde (MDA); (B) 4-hydroxynonenal (4-HNE); (C) protein carbonyl (PC); (D) reduced glutathione (GSH); (E) superoxide dismutase (SOD); (F) catalase (CAT); (G) total antioxidant capacity (TAC). Data are the mean ± SE (n = 8). * p < 0.05, ** p < 0.01, *** p < 0.001 vs. control group; # p < 0.05, ## p < 0.01, ### p < 0.001 vs. LPS group (one-way ANOVA followed by Tukey’s Kramer multiple comparisons test).
Figure 6
Figure 6
Terretonin (TE) counteracted the LPS-induced suppression of SIRT1/Nrf2 signaling and targeted genes in the lung. (I) (A–F) Gene expressions of SIRT1, Nrf2, NQO1, GCLm, GCLc, and HO-1. (II) (A) Nrf2 binding activity; (B) HO-1 level in the lung. Data are the mean ± SE (n = 8). * p < 0.05, ** p < 0.01, *** p < 0.001 vs. control group; # p < 0.05, ## p < 0.01, ### p < 0.001 vs. LPS group (one-way ANOVA followed by Tukey’s Kramer multiple comparisons test).
Figure 7
Figure 7
Terretonin (TE) suppressed the LPS-induced activation of NF-κB/NLRP3 signaling and its downstream pro-inflammatory markers in the lung. (I) (A) Gene expression; (B) level of NF-κB; (C) gene expression of NLRP3; (D) gene expression of caspase-1. (II) Immuno-expression of NF-κB protein: (A,B) lung sections of both the control and TE 40 groups, showing minimal cytoplasmic brownish staining; (C) LPS group showing marked nuclear and cytoplasmic brown immunostaining of inflamed lung tissue; (D) TE 20 + LPS and (E) TE 40 + LPS groups exhibiting marked improvement with moderate to minimal nuclear and cytoplasmic brown staining; NF-ĸB immunostain ×400, scale bar 25 µm; (F) % of immunopositive cells among different groups. (III) (A–D) Gene expression of iNOS, TNF-α, IL-1β, and IL-6; (E–H) levels of NOx, TNF-α, IL-1β, and IL-6. Data are the mean ± SE (n = 8). * p < 0.05, ** p < 0.01, *** p < 0.001 vs. control group; # p < 0.05, ## p < 0.01, ### p < 0.001 vs. LPS group (one-way ANOVA followed by Tukey’s Kramer multiple comparisons test).
Figure 8
Figure 8
Terretonin (TE) decreased LPS-induced pulmonary apoptosis. (A) B-cell leukemia/lymphoma 2(Bcl-2); (B) Bcl-2-associated X protein (Bax); (C) caspase 3. Data are the mean ± SE (n = 8). * p < 0.05, ** p < 0.01, *** p < 0.001 vs. control group; # p < 0.05, ## p < 0.01, ### p < 0.001 vs. LPS group (one-way ANOVA followed by Tukey’s Kramer multiple comparisons test).
Figure 9
Figure 9
Schematic diagram demonstrating the molecular targets of terretonin (TE), which control its protective activity against LPS-induced acute lung injury.
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