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

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.

Nrf2 Deficiency Exacerbated CLP-Induced Pulmonary Injury and Inflammation through Autophagy- and NF-κB/PPARγ-Mediated Macrophage Polarization

“…In vivo and in vitro experiments showed that Honokiol inhibited NLRP3-inflammasome-mediated pyroptosis through Nrf2 activation, thereby alleviating LPS-induced ALI [ 5 ]. In a recent study of terretonin, a meroterpenoid against LPS-induced ALI, researchers revealed that LPS induced the downregulation of Nrf2 expression as well as its binding activity [ 40 ]. By using siRNA-mediated Nrf2-knockdown and Nrf2-activation methods, researchers found that Nrf2 inhibited LPS-induced inflammation by promoting polarization of M2 macrophages and inhibiting polarization of M1 macrophages, which is similar to our results [ 11 ].…”

Fungal Naphthalenones; Promising Metabolites for Drug Discovery: Structures, Biosynthesis, Sources, and Pharmacological Potential

“…They are acknowledged as one of the wealthiest pools of natural metabolites among living organisms due to their unique metabolic system and their capacities to synthesize diverse kinds of metabolites with quite intriguing chemical skeletons [8,9]. These metabolites possess a wide range of applications as agrochemicals, antibiotics, immune-suppressants, anti-parasitic, and anticancer agents [10][11][12][13][14][15][16][17][18][19][20]. Naphtalenones are among the naphthalene derivatives produced by fungi that are strictly related to napthoquinones and involved in the branched pathway of fungal DHN (1,8-dihydroxynaphthalene)-melanin biosynthesis [21,22].…”

The protective effect of natural medicines against excessive inflammation and oxidative stress in acute lung injury by regulating the Nrf2 signaling pathway

“…When stimulated by endogenous or exogenous oxidative stress, an intricate molecular mechanism facilitated by sensor cysteines within Keap1 allows Nrf2 to escape ubiquitination and enter the nucleus, where it binds to downstream antioxidant response elements (ARE) and activates the transcription of antioxidant genes, including heme oxygenase-1 (HO-1), NAD(P)H-quinone oxidoreductase 1 (NQO1), superoxide dismutase (SOD), and catalase ( Figure 1 ) ( Dinkova-Kostova et al, 2017 ; Baird and Yamamoto, 2020 ). In addition, the upregulation of Nrf2 signaling limits NF-κB activation, leading to inhibition of the excessive production of pro-inflammatory cytokines and chemokines, thereby mitigating signs of pulmonary inflammation ( Mohamed et al, 2021 ). p300/CBP-associated factor (PCAF), a histone acetyltransferase, enhances the transcriptional activity of NF-κB ( Sheppard et al, 1999 ).…”