Network Pharmacology Reveals the Mechanism of Activity of Tongqiao Huoxue Decoction Extract Against Middle Cerebral Artery Occlusion-Induced Cerebral Ischemia-Reperfusion Injury.

Article

作者: Wang, Ning ; Zhao, Li ; Wu, Si-Peng

Several clinical therapies such as tissue repair by replacing injured tissues with functional ones have been reported; however, there is great potential for exploring traditional herbal-induced regeneration with good safety. Tongqiao Huoxue Decoction (TQHXD), a well-known classical traditional Chinese medicinal formula, has been widely used for clinical treatment of stroke. However, biological activity and mechanisms of action of its constituents toward conferring protection against cerebral ischemia-reperfusion (I/R) injury remain unclear. In this present study, we evaluated TQHXD quality using HPLC; then, it was screened for its potential active ingredients using a series of indices, such as their drug-likeness and oral bioavailability. Subsequently, we analyzed the potential mechanisms of TQHXD anti-I/R using gene ontology functional enrichment analyses. The network pharmacological approach enabled us to screen 265 common targets associated with I/R, indicating that TQHXD had remarkable protective effects on infarction volume, neurological function scores, and blood-brain barrier (BBB) injury. In addition, TQHXD significantly promoted the recovery of regional cerebral blood flow (rCBF) 7 days after reperfusion compared to rats in the vehicle group. Immunofluorescence results revealed a significantly higher CD34 expression in TQHXD-treated rats 7 days after reperfusion. TQHXD is not merely effective but eventually develops a secretory profile composed of VEGF and cerebral blood flow, a typical signature termed the angiogenesis-associated phenotype. Mechanistically, our data revealed that TQHXD (6 g/kg) treatment resulted in a marked increase in expression of p-focal adhesion kinase (FAK) and p-Paxillin proteins. However, Ki8751-mediated inhibition of VEGFR2 activity repealed its angiogenesis and protective effects and decreased both p-FAK and p-Paxillin protein levels. Taken together, these findings affirmed the potential of TQHXD as a drug for the management of stroke, which might be exerted by increasing the angiogenesis via the VEGF pathway. Therefore, these results provide proof-of-concept evidence that angiogenesis is a major contributor to TQHXD-treated I/R and that TQHXD is a promising traditional ethnic medicine for the management of this condition.

Journal of Translational Medicine

VEGFR2 blockade inhibits glioblastoma cell proliferation by enhancing mitochondrial biogenesis

Article

作者: Guo, Min ; Gao, Lifen ; Han, Jiang ; Liu, Meijuan ; Ni, Hao ; Liu, Yaou ; Hu, Yingyue ; Sun, Yang ; Zhang, Junhao ; Li, Nailin ; Liao, Wangjun ; Li, Shuijie ; Ma, Chunhong ; Yuan, Juan

Abstract:

Background:

Glioblastoma is an aggressive brain tumor linked to significant angiogenesis and poor prognosis. Anti-angiogenic therapies with vascular endothelial growth factor receptor 2 (VEGFR2) inhibition have been investigated as an alternative glioblastoma treatment. However, little is known about the effect of VEGFR2 blockade on glioblastoma cells per se.

Methods:

VEGFR2 expression data in glioma patients were retrieved from the public database TCGA. VEGFR2 intervention was implemented by using its selective inhibitor Ki8751 or shRNA. Mitochondrial biogenesis of glioblastoma cells was assessed by immunofluorescence imaging, mass spectrometry, and western blot analysis.

Results:

VEGFR2 expression was higher in glioma patients with higher malignancy (grade III and IV). VEGFR2 inhibition hampered glioblastoma cell proliferation and induced cell apoptosis. Mass spectrometry and immunofluorescence imaging showed that the anti-glioblastoma effects of VEGFR2 blockade involved mitochondrial biogenesis, as evidenced by the increases of mitochondrial protein expression, mitochondria mass, mitochondrial oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) production, all of which play important roles in tumor cell apoptosis, growth inhibition, cell cycle arrest and cell senescence. Furthermore, VEGFR2 inhibition exaggerated mitochondrial biogenesis by decreased phosphorylation of AKT and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which mobilized PGC1α into the nucleus, increased mitochondrial transcription factor A (TFAM) expression, and subsequently enhanced mitochondrial biogenesis.

Conclusions:

VEGFR2 blockade inhibits glioblastoma progression via AKT-PGC1α-TFAM-mitochondria biogenesis signaling cascade, suggesting that VEGFR2 intervention might bring additive therapeutic values to anti-glioblastoma therapy.

100 项与 Ki8751 相关的药物交易

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