## 4 Discussion
Therefore, stimulated SIRT1 activity eventually inhibits HIF-1\(\alpha\)-induced transcriptional activation during ischemia and hypoxia. On the other hand, SIRT1 was reported to dissociate from the DBC1 protein and be activated by AMPK, indicating that AMPK is a main activator of SIRT1 and can therefore inhibit HIF-1\(\alpha\)[31; 32]. PPAR\(\alpha\) and PGC-1\(\alpha\) are activated directly by AMPK. PPAR\(\alpha\) increases protein expression of downstream events and consequently leads to NF-\(\kappa\)B inhibition [33]. PGC-1 \(\alpha\) is a transcription coactivator of PPAR, which regulates cytokine production and expression of adhesion molecules to reduce inflammation [34]. The AMPK/PPAR\(\alpha\)/PGC-1\(\alpha\) signaling pathway was previously confirmed in hypoxia/re-oxygenation injury, with NF-\(\kappa\)B being a key mediator of inflammation in the pathological mechanism control of many diseases and injuries. NF-\(\kappa\)Bp65 is activated by the phosphorylation of \(\kappa\)B\(\alpha\), which acts as an inhibitor of NF-\(\kappa\)Bp65 [35]. In the present study, we found that BA decreased HIF-1\(\alpha\), p-\(\kappa\)B\(\alpha\), and p-NF-\(\kappa\)B-p65 expression and increased the levels of AMPK, PPAR-\(\alpha\), and PGC-1\(\alpha\) in the brains of MCAO rats and OGD/R cells. Betulinic acid has a wide range of pharmacological activities, including anti-tumor, anti-HIV, and anti-inflammatory properties [36]. Betulinic acid was originally reported to possess specific cytotoxicity and biological activities toward many cancer cells, with its mechanism of action involving directly acting on mitochondria and inducing tumor cell apoptosis [37]. In previous studies, BA was proven to protect kidneys and the heart from ischemia/reperfusion injuries. BA inhibits the activation of inflammation and regulates the expression of TNF-\(\alpha\) and other inflammatory factors from myocardial and renal ischemia/reperfusion injury [10; 11]. In addition, BA exhibits mild anti-inflammatory effects, thereby inhibiting the inflammation of mice induced with carrageenan, phorbol, and bryostatin-1, but showing no inhibitory effect toward arachidonic acid-induced inflammation and neurogenic inflammation models [38; 39]. Isoflurane-induced brain neuron injuries in rats were shown to be improved by BA in that oxygen electrodes and ultraviolet spectrophotometer demonstrated that mitochondrial respiratory levels and intracellular ATP contents improved after treatment [40]. This suggested that BA has effects on mitochondrial stability, energy metabolic homeostasis, and neuronal apoptosis. In conclusion, the benefits of BA included relieving ischemia/reperfusion injury through HIF-1\(\alpha\)/AMPK/PPAR\(\alpha\)/PGC-1\(\alpha\)/NF-\(\kappa\)B-mediated inflammation. **Author Contributions:** Investigation, [PERSON]; Methodology, [PERSON]; Supervision, [PERSON]; Validation, [PERSON]; Writing (original draft), [PERSON]; Writing (review and editing), [PERSON] All authors have read and agreed to the published versionof the manuscript. **Funding:** This research was supported by Natural Science Foundation of China (Grants 81773826), The Drug Innovation Major Project (Grants 2018 ZX09711001), 111 Incubation Project (BC2018024). **Conflicts of Interest:** The authors declare no conflict of interest.