机构:[1]Department of Neurosurgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China外科片神经外科云南省第一人民医院[2]Department of Neurology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China内科片神经内科云南省第一人民医院[3]The Affiliated Hospital of Kunming University of Science and Technology. Department of Neurosurgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China外科片神经外科云南省第一人民医院
Aims: We aimed to resolve the uncertainty as to whether betulin exerted neuroprotection on early brain injury (EBI) caused by subarachnoid hemorrhage (SAH), and to investigate the related molecular mechanisms. Methods: Bioinformatic analysis was performed to pre-study the differently expressed genes (DEGs) and the possible signaling pathways. Rat and cellular model of SAH were introduced in this study, and betulin, an activator of DJ-1 protein, was administered to reveal the effect. Gross assessment regarding mortality, neurofunctions, SAH grade, brain water content (BWC) along with multiple cellular and molecular studies in vivo or/and in vitro such as immunofluorescence (IF) staining, western blot (WB), reactive oxygen species (ROS) assay, and flow cytometry (FCM) were all conducted after SAH induction to verify the protective effect and the relevant mechanisms of DJ-1 in diverse levels. In addition, MK2206 (selective inhibitor of Akt) and iRNADj-1 (interfering RNA to Dj-1) were utilized to confirm the mechanisms of the effect. Results: The data from our study showed that DJ-1 protein was moderately expressed in neurons, microglia, and astrocytes; its level in brain tissue elevated and peaked at 24-72 h after SAH induction. Betulin could efficaciously induce the expression of DJ-1 which in turn activated Akt and Bcl-2, and anti-oxidative enzymes SOD2 and HO-1, functioning to reduce the activation of cleaved caspase-3 (c-Casp-3) and reactive oxygen species (ROS). The induced DJ-1 could upregulate the expression of Nrf2. However, Akt seemed no direct effect on elevating the expression of Nrf2. DJ-1 alone could as well activate Akt-independent antiapoptotic pathway via suppressing the activation of caspase-8 (Casp-8). Conclusions: Betulin which was a potent agonist of DJ-1 had the ability to induce its expression in brain tissue. DJ-1 had neuroprotective effect on EBI through comprehensive mechanisms, including facilitating intrinsic and extrinsic antiapoptotic pathway, and reducing oxidative injury by upregulating the expression of redox proteins. Betulin as an inexpensive drug showed the potential for SAH treatment.
基金:
Joint Projects of Yunnan Provincial
Science and Technology Department
and Kunming University of Science and
Technology, Grant/Award Number:
KUST-KH2023005Z; Joint Projects
of Yunnan Provincial Science and
Technology Department and Kunming
Medical University for Applied Basic
Research, Grant/Award Number:
202101AY070001-252; Innovation
Research Projects on Cerebrovascular
Diseases for Young Doctors, China
International Medical Foundation, Grant/
Award Number: Z-2016-20-2101; National
Natural Science Foundation of China,
Grant/Award Number: 82001278; Yunnan
Fundamental Research Projects, Grant/
Award Number: 202401CF070007; The
Fund for Young Doctors with the First
People's Hospital of Yunnan Province,
Grant/Award Number: KHBS-2022-018
第一作者机构:[1]Department of Neurosurgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
共同第一作者:
通讯作者:
通讯机构:[1]Department of Neurosurgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China[*1]Department of Neurosurgery, The First People's Hospital of Yunnan Province Kunhua Hospital/The Affiliated Hospital of Kunming University of Science and Technology, Yunnan 650032, China
推荐引用方式(GB/T 7714):
Lu Xiaoyang,Yang Shu,Lu Qixiong,et al.Betulin ameliorates neuronal apoptosis and oxidative injury via DJ-1/Akt/Nrf2 signaling pathway after subarachnoid hemorrhage[J].CNS NEUROSCIENCE & THERAPEUTICS.2024,30(9):doi:10.1111/cns.70019.
APA:
Lu, Xiaoyang,Yang, Shu,Lu, Qixiong,Zhang, Yuansheng,Cha, Zaihong...&Li, Tao.(2024).Betulin ameliorates neuronal apoptosis and oxidative injury via DJ-1/Akt/Nrf2 signaling pathway after subarachnoid hemorrhage.CNS NEUROSCIENCE & THERAPEUTICS,30,(9)
MLA:
Lu, Xiaoyang,et al."Betulin ameliorates neuronal apoptosis and oxidative injury via DJ-1/Akt/Nrf2 signaling pathway after subarachnoid hemorrhage".CNS NEUROSCIENCE & THERAPEUTICS 30..9(2024)