RESUMEN
Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis (Mtb), which has a unique resistance to many antimicrobial agents. TB has emerged as a significant worldwide health issue because of the rise of multidrug-resistant strains causing drug-resistant TB (DR-TB). As a result, the development of new drugs or effective strategies is crucial for patients with TB. Mycobacterium marinum (Mm) and Mtb are both species of mycobacteria. In zebrafish, Mm proliferates and forms chronic granulomatous infections, which are similar to Mtb infections in lung tissue. Syringaldehyde (SA) is a member of the phenolic aldehyde family found in various plants. Here, we investigated its antioxidative and antibacterial properties in Mm-infected cells and zebrafish. Our results demonstrated that SA inhibits Mm-infected pulmonary epithelial cells and inhibits the proliferation of Mm in Mm-infected zebrafish, suggesting that SA provides an antibacterial effect during Mm infection. Further study demonstrated that supplementation with SA inhibits the production of malondialdehyde (MDA) and reactive oxygen species (ROS) and increases the levels of reduced glutathione (GSH) in Mm-infection-induced macrophages. SA inhibits the levels of MDA in Mm-infected zebrafish, suggesting that SA exerts antioxidative effects in vivo. Additionally, we found that SA promotes the expression of NRF2/HO-1/NQO-1 and the activation of the AMPK-α1/AKT/GSK-3ß signaling pathway. In summary, our data demonstrated that SA exerts antioxidative and antibacterial effects during Mm infection both in vivo and in vitro and that the antioxidative effects of SA may be due to the regulation of NRF2/HO-1/NQO-1 and the AMPK-α1/AKT/GSK-3ß signaling pathway.
RESUMEN
Cepharanthine (CEP), a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata, has been widely used for the treatment of various acute and chronic diseases, including leukopenia, and snake bites. Here, our objective was to investigate the anti-oxidative stress and anti-inflammatory response effects of CEP in lipopolysaccharide (LPS)-induced macrophages as well as dextran sulfate sodium (DSS)-induced colitis mice. Our findings demonstrated that supplementation with CEP effectively mitigates body weight loss and elevation of disease activity index (DAI), reduces the malondialdehyde (MDA) content to 2.45 nM/mL while increasing the reduced glutathione (GSH) content to 35.53 µg/mL, inhibits inflammatory response, and maintains proper intestinal epithelium tight junctions in DSS-induced wild type (WT) mice. However, it failed to provide protective effects in DSS-induced transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) knockout (NRF2-/-) mice. GSH content decreased to 10.85 µg/106 cells following LPS treatment, whereas supplementation with CEP increased the GSH content to 12.26 µg/106 cells. Moreover, CEP effectively attenuated ROS production in LPS-induced macrophages. Additionally, CEP exhibited inhibitory effects on pro-inflammatory cytokines and mediators in LPS-induced macrophages. Furthermore, we observed that supplementation with CEP promoted the expression of NRF2/heme oxygenase 1 (HO-1)/NADPH quinone oxidoreductase-1 (NQO-1) as well as the phosphorylation of the adenosine monophosphate-activated protein kinase alpha 1 (AMPK-α1)/protein kinase B (AKT)/glycogen synthase kinase-3 beta (GSK-3ß) signaling pathway in macrophages while inhibiting the phosphorylation of the extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B p65 (NF-κB p65) signaling pathway in LPS-induced macrophages. Although CEP did not demonstrate inhibitory effects on oxidative stress or promote the expression of HO-1/NQO-1, it effectively activated the phosphorylation of the AMPK-α1/AKT/GSK-3ß signaling pathway which is an upstream regulator of NRF2 in LPS-induced primary peritoneal macrophages from NRF2-/- mice. In summary, our findings suggest that CEP exerts protective effects against oxidative stress and inflammatory response by activating the AMPK-α1/AKT/GSK-3ß/NRF2 signaling pathway while concurrently inhibiting the activation of mitogen activated protein kinases (MAPKs) and the NF-κB p65 signaling pathway. These results not only elucidate the mechanisms underlying CEP's protective effects on colon oxidative stress and inflammation but also provide evidence supporting NRF2 as a potential therapeutic target for IBD treatment.
