Betulinic Acid Alleviates Spleen Oxidative Damage Induced by Acute Intraperitoneal Exposure to T-2 Toxin by Activating Nrf2 and Inhibiting MAPK Signaling Pathways

Abstract

T-2 toxin, which is mainly produced by specific strains of Fusarium in nature, can induce immunotoxicity and oxidative stress, resulting in immune organ dysfunction and apoptosis. Betulinic acid (BA), a pentacyclic triterpenoids from nature plants, has been demonstrated to possess immunomodulating and antioxidative bioactivities. The purpose of the study was to explore the effect of BA on T-2 toxin-challenged spleen oxidative damage and further elucidate the underlying mechanism. We found that BA not only ameliorated the contents of serum total cholesterol (TC) and triglyceride (TG) but also restored the number of lymphocytes in T-2 toxin-induced mice. BA dose-dependently reduced the accumulation of reactive oxygen species (ROS), enhanced superoxide dismutase (SOD) activity, and decreased malondialdehyde (MDA) content, as well as increased the total antioxidant capacity (T-AOC) in the spleen of T-2-toxin-exposed mice. Moreover, BA reduced inflammatory cell infiltration in the spleen, improved the morphology of mitochondria and enriched the number of organelles in splenocytes, and dramatically attenuated T-2 toxin-triggered splenocyte apoptosis. Furthermore, administration of BA alleviated the protein phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases (ERK); decreased the protein expression of kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein1 (Keap1); and increased the protein expression of nuclear factor erythroid 2 [NF-E2]-related factor (Nrf2) and heme oxygenase-1 (HO-1) in the spleen. These findings demonstrate that BA defends against spleen oxidative damage associated with T-2 toxin injection by decreasing ROS accumulation and activating the Nrf2 signaling pathway, as well as inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway.

The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis

“…Interestingly, Shen et al ( 2019 ) recently reported that the suppression of the nuclear factor-kappa B pathway increased downstream oxidant effectors, thereby promoting the generation of reactive oxygen species (ROS) in BA-stimulated multiple myeloma cells. Although BA is known to have antioxidant activity that blocks the accumulation of ROS due to oxidative stress in normal cells (Cheng et al 2019 ; Cheng et al 2019 ; Kong et al 2021 ), their results well support the previous studies that BA promotes ROS production in cancer cells (Wang et al 2017 , 2019 ; Xu et al 2017 ; Goswami et al 2018 ; Shen et al 2019 ). However, the underlying anti-cancer mechanism of BA and associated molecular targets and the role of ROS are poorly identified in multiple cancer types.…”

“…Excessive accumulation of ROS can lead to cell cycle arrest and apoptosis through the regulation of various pathways (Moloney and Cotter 2018 ; Rodrigues and Ferraz 2020 ). After referencing a lot of literature, we found that BA can induce ROS formation in cancer cells (Wang et al 2017 , 2019 ; Xu et al 2017 ; Goswami et al 2018 ; Shen et al 2019 ), but may reduce ROS production in normal cells (Cheng et al 2019 ; Cheng et al 2019 ; Kong et al 2021 ), which means that BA has potent antioxidant activity in normal cells. Therefore, we measured the ROS content after BA treatment and found that BA was able to effectively increase ROS production at the initial time point of BA treatment, which was directly involved in BA-induced G2/M phase arrest and apoptosis.…”

“…(Rastogi et al 2015 ; Ríos and Máñez 2018 ). Accumulated evidence demonstrates that BA possesses various biological activities, including antioxidant, anti-inflammatory, hepatoprotective, and anti-tumor effects (Saneja et al 2018 ; An et al, 2020 ; Li et al 2021 ; Kong et al 2021 ). Among them, the anti-tumor potential has recently received great attention, showing that the anti-cancer mechanisms of BA are complex and depends on the type of cancer cells, without causing toxicity toward normal cells (Mullauer et al 2010 ; Gheorgheosu et al 2014 ; Kumar et al 2018 ; Zuco et al 2020 ; Kutkowska et al 2021 ).…”

Betulinic acid accelerates diabetic wound healing by modulating hyperglycemia-induced oxidative stress, inflammation and glucose intolerance

“…It has been reported that BA attenuates oxidative stress by activation of the Nrf2 signaling pathway [ 23 , 50 ]. Our results showed that BA treatment significantly increased Nrf2 transcriptional activity but showed no effect on Nrf2 expression [ 25 ], subsequently ameliorating hyperglycemia-mediated ROS generation, 8-oxo-dG formation and MG formation, and decreased the GSH/GSSG ratio in the circulatory system.…”

Protective Mechanism of Humanin Against Oxidative Stress in Aging-Related Cardiovascular Diseases

“…Mitogen-activated protein kinases (MAPKs), including ERK1/2, JNK, and p38 MAPK, are evolutionarily conserved enzymes that connect cell surface receptors and intracellular regulatory targets (84,85). MAPK inhibition protects cells from oxidative stress (86). Previous studies have found that HN protected neurons by inhibiting JNK and p38 MAPK (87)(88)(89).…”