Betulin Protects HT-22 Hippocampal Cells against ER Stress through Induction of Heme Oxygenase-1 and Inhibition of ROS Production

Abstract

A key pathologic event in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, is endoplasmic reticulum (ER) stress-induced neuronal cell death. ER stress-induced generation of reactive oxygen species (ROS) has been implicated in neurological disease processes. Betulin is one of the major triterpenoids found in Betula platyphylla that possesses several biological properties, including cytoprotective and antioxidative effects. Therefore, we investigated whether betulin could prevent ER stress-induced neurotoxicity in HT-22 hippocampal neuronal cells. We observed that betulin reduced the thapsigargin (TG, an ER stress inducer)-induced apoptosis of HT-22 cells. Moreover, the cytoprotective effects of betulin were comparable to those of tauroursodeoxycholic acid, a potent ER stress-reducing agent. In our study, we confirmed that the ER stress-induced accumulation of ROS plays an important role in HT-22 cell death. Betulin also displayed cytoprotective effects in TG-injured HT-22 cells by reducing ROS generation; these results were comparable to those for N-acetyl-L-cysteine, a known ROS inhibitor. In addition, SnPP, a heme oxygenase-1 (HO-1) inhibitor significantly blocked the cytoprotective effects and ROS scavenging activity of betulin. Based on these results, we believe that betulin-mediated induction of HO-1 may contribute to the neuroprotective effects against ER stress in HT-22 hippocampal cells. We also found that betulin significantly inhibited the TG-induced expression of CHOP and caspase-12. These results demonstrated that betulin could serve as a potential therapeutic agent against ER stress-induced neurodegenerative diseases.

Antioxidant‐rich fraction of Amomum subulatum fruits mitigates experimental methotrexate‐induced oxidative stress by regulating TNF‐α, IL‐1β, and IL‐6 proinflammatory cytokines

“…One of our previous studies has reported the anti-inflammatory potential of A. subulatum (Drishya et al, 2021). Results of the present study showed acid (Kilic & Yesiloglu, 2013;Pragasam et al, 2013), syringic acid (Li et al, 2018), ferulic acid (Mahmoud et al, 2020), gallic acid (Badhani et al, 2015;Kroes et al, 1992), catechin (Fan et al, 2017), naringenin (Chung et al, 2019;Rashmi et al, 2018), rutin (Selloum et al, 2003;Yang et al, 2008), costunolide (Eliza et al, 2010;Nan et al, 2020), betulin (Lee et al, 2019), villosin (Li et al, 2016), n-hexadecanoic acid (Aparna et al, 2012), and so forth are some of the bioactive phytoconstituents in MEAS, which were reported to exhibit antioxidant/ anti-inflammatory potential. Hence, it can be concluded that the presence of these bioactive phytoconstituents confers A. subulatum the protective effect against MTX toxicities, suggesting the possibility of a combined therapeutic approach with MEAS so as to subside severe toxicities of MTX therapy.…”

“…Mitigating effect of MEAS against MTX‐induced toxicities is attributed to the antioxidant and anti‐inflammatory properties exhibited by bioactive phytoconstituents in MEAS. Vanillic acid (Calixto‐Campos et al., 2015; Kumar et al., 2011), p‐coumaric acid (Kilic & Yesiloglu, 2013; Pragasam et al., 2013), syringic acid (Li et al., 2018), ferulic acid (Mahmoud et al., 2020), gallic acid (Badhani et al., 2015; Kroes et al., 1992), catechin (Fan et al., 2017), naringenin (Chung et al., 2019; Rashmi et al., 2018), rutin (Selloum et al., 2003; Yang et al., 2008), costunolide (Eliza et al, 2010; Nan et al., 2020), betulin (Lee et al, 2019), villosin (Li et al., 2016), n‐hexadecanoic acid (Aparna et al., 2012), and so forth are some of the bioactive phytoconstituents in MEAS, which were reported to exhibit antioxidant/anti‐inflammatory potential. Hence, it can be concluded that the presence of these bioactive phytoconstituents confers A .…”

1-Methoxylespeflorin G11 Protects HT22 Cells from Glutamate-Induced Cell Death through Inhibition of ROS Production and Apoptosis

“…1 ). Glutamate is a toxicant that induces oxidative stress in HT22 cells causing severe damage and neuroexcitotoxicity [ 17 ]. HT22 cells were exposed to glutamate (4 mM) in the presence of isolated compounds at the concentration ranging from 0.1 to 10 μM for 24 h ( Fig.…”

Parameter Optimization and Potential Bioactivity Evaluation of a Betulin Extract from White Birch Bark

“…Lee and co-workers revealed that betulin could protect Hom cells cultured in a medium. A betulin extract with a concentration of 15.625 µg/mL could protect T-22 hippocampal cell viability against reactive oxygen species-stressed cytotoxicity [32]. As a result of the zebrafish experiments, it was concluded that betulin extract has negative cytotoxicity and shows potential for use in food and pharmaceutical applications.…”

“…This can probably be attributed to the unfavorable effect of impurity compounds in the extract. Hofmann et al reported that each antioxidant activity assay is specific to certain types of antioxidants, and none of the assays evaluate the overall antioxidant capacity of a plant extract [32]. Therefore, combined multi-assay methods for antioxidant activity evaluation may be propitious to pursuing complex antioxidant properties in betulin extracts.…”