Lonicerae japonicae flos ameliorates radiotherapy-induced mesenteric artery endothelial dysfunction through GTPCH1/BH4/eNOS pathway.

BACKGROUND: As a traditional Chinese medicine, Lonicerae japonicae flos (LJF) and its main component chlorogenic acid (CGA) have anti-oxidant, anti-bacterial and anti-tumor effects. However, there is no research on the potential of LJF for vascular protection in radiotherapy. PURPOSE: To elucidate the potential and possible mechanisms of the LJF extract and CGA in alleviating endothelial dysfunction caused by abdominal radiotherapy. METHODS: LJF was extracted with water and the CGA content was analyzed by HPLC. Male Sprague-Dawley rats received abdominal radiotherapy for 21 days. Seven days after irradiation, Laser Doppler and ex vivo vascular tension experiments were performed. Nitric oxide (NO), superoxide anion levels and tetrahydrobiopterin (BH4) content were detected. Western blot, flow cytometry and molecular docking were used. RESULTS: In the radiotherapy group, the mesenteric arterial blood perfusion, NO, and superoxide anion levels were significantly reduced; rats treated with the LJF extract or CGA showed a certain extent of recovery of these indicators. Vascular tension experiments showed that CGA and the LJF extract improved the vasodilation of mesenteric arteries. Cell experiments demonstrated that CGA increased the NO content and reduce superoxide anion production and cell apoptosis. The expression levels of GTPCH1/BH4/eNOS signaling pathway were significantly increased due to the use of the LJF extract or CGA in vivo and in vitro. CONCLUSIONS: Our study demonstrated for the first time that LJF and its main component, CGA could prevent abdominal radiotherapy-induced vascular endothelial dysfunction via GTPCH1/BH4/eNOS pathway. LJF could be a potential therapeutic herbal agent.

Inhibition of Radiation-Induced Ccl2 Signaling Protects Lungs from Vascular Dysfunction and Endothelial Cell Loss.

Aims: Radiation-induced normal tissue toxicity often precludes the application of curative radiation doses. Here we investigated the therapeutic potential of chemokine C-C motif ligand 2 (Ccl2) signaling inhibition to protect normal lung tissue from radiotherapy (RT)-induced injury. Results: RT-induced vascular dysfunction and associated adverse effects can be efficiently antagonized by inhibition of Ccl2 signaling using either the selective Ccl2 inhibitor bindarit (BIN) or mice deficient for the main Ccl2 receptor CCR2 (KO). BIN-treatment efficiently counteracted the RT-induced expression of Ccl2, normalized endothelial cell (EC) morphology and vascular function, and limited lung inflammation and metastasis early after irradiation (acute effects). A similar protection of the vascular compartment was detected by loss of Ccl2 signaling in lungs of CCR2-KO mice. Long-term Ccl2 signaling inhibition also significantly limited EC loss and accompanied fibrosis progression as adverse late effect. With respect to the human situation, we further confirmed that Ccl2 secreted by RT-induced senescent epithelial cells resulted in the activation of normally quiescent but DNA-damaged EC finally leading to EC loss in ex vivo cultured human normal lung tissue. Innovation: Abrogation of certain aspects of the secretome of irradiated resident lung cells, in particular signaling inhibition of the senescence-associated secretory phenotype-factor Ccl2 secreted predominantly by RT-induced senescent epithelial cells, resulted in protection of the endothelial compartment. Conclusions: Radioprotection of the normal tissue via Ccl2 signaling inhibition without simultaneous protection or preferable radiosensitization of tumor tissue might improve local tumor control and survival, because higher doses of radiation could be used.