Clinacanthus nutans Mitigates Neuronal Apoptosis and Ischemic Brain Damage Through Augmenting the C/EBPβ-Driven PPAR-γ Transcription.
Jui-Sheng WuMei-Han KaoHsin-Da TsaiWai-Mui CheungJin-Jer ChenWei-Yi OngGrace Y SunTeng-Nan LinPublished in: Molecular neurobiology (2017)
Clinacanthus nutans Lindau (C. nutans) is a traditional herbal medicine widely used in Asian countries for treating a number of remedies including snake and insect bites, skin rashes, viral infections, and cancer. However, the underlying molecular mechanisms for its action and whether C. nutans can offer protection on stroke damage in brain remain largely unknown. In the present study, we demonstrated protective effects of C. nutans extract to ameliorate neuronal apoptotic death in the oxygen-glucose deprivation model and to reduce infarction and mitigate functional deficits in the middle cerebral artery occlusion model, either administered before or after hypoxic/ischemic insult. Using pharmacological antagonist and siRNA knockdown approaches, we demonstrated ability for C. nutans extract to protect neurons and ameliorate ischemic injury through promoting the anti-apoptotic activity of peroxisome proliferator-activated receptor-gamma (PPAR-γ), a stress-induced transcription factor. Reporter and chromatin immunoprecipitation promoter analysis further revealed C. nutans extract to selectively increase CCAAT/enhancer binding protein (C/EBP)β binding to specific C/EBP binding site (-332~-325) on the PPAR-γ promoter to augment its transcription. In summary, we report a novel transcriptional activation involving C/EBPβ upregulation of PPAR-γ expression to suppress ischemic neuronal apoptosis and brain infarct. Recognition of C. nutans to enhance the C/EBPβ → PPAR-γ neuroprotective signaling pathway paves a new way for future drug development for prevention and treatment of ischemic stroke and other neurodegenerative diseases.
Keyphrases
- cerebral ischemia
- transcription factor
- oxidative stress
- binding protein
- subarachnoid hemorrhage
- cell death
- stress induced
- middle cerebral artery
- blood brain barrier
- insulin resistance
- brain injury
- signaling pathway
- gene expression
- resting state
- anti inflammatory
- poor prognosis
- ischemia reperfusion injury
- cell cycle arrest
- dna binding
- white matter
- dna methylation
- endoplasmic reticulum stress
- metabolic syndrome
- functional connectivity
- squamous cell carcinoma
- induced apoptosis
- heart failure
- genome wide identification
- single cell
- coronary artery disease
- cell proliferation
- weight loss
- radiation therapy
- skeletal muscle
- percutaneous coronary intervention
- acute coronary syndrome
- spinal cord injury
- left ventricular
- aedes aegypti
- heat shock protein