Low serum 25-hydroxyvitamin D3 levels and late delayed radiation-induced brain injury in patients with nasopharyngeal carcinoma: A case-control study.

BACKGROUND AND PURPOSE: Inflammatory reaction plays a critical role in the pathogenesis of late delayed radiation-induced brain injury (RBI). Low vitamin D levels are closely associated with various immuno-inflammatory diseases, but the relationship with late delayed RBI remains unknown. Here, we aimed to determine the association of serum vitamin D levels with clinical parameters in late delayed RBI patients with nasopharyngeal carcinoma. METHODS: 25-Hydroxyvitamin D3 levels and clinical and cerebrospinal fluid parameters were evaluated in 21 patients with RBI and compared with 90 age-, sex-, and season-matched healthy controls. RESULTS: 25-(OH)D3 levels were lower in patients with RBI compared to controls (40.39 ± 22.11 vs. 64.54 ± 19.89 nmol/L, p < .001), especially for aged ≥60 years (vs. <60 years, p = .038), females (vs. males, p = .012), short latency (<5 years) (vs. ≥5 years, p = .015), and severe impairment (LENT/SOMA score ≥3) (vs. LENT/SOMA score <3, p = .010). Serum 25-(OH)D3 levels were associated with age (r = -.464, p = .015), Latency of RBI (r = .416, p = .031) and LENT/SOMA Scale (r = -.488, p = .010). CONCLUSIONS: Our data showed that serum 25-(OH)D3 levels were reduced in late delayed RBI patients with nasopharyngeal carcinoma.

Endothelial progenitor cell transplantation restores vascular injury in mice after whole-brain irradiation.

Vascular damage plays an important role in the pathogenesis of radiation-induced brain injury (RBI). Endothelial progenitor cells (EPCs) are responsible for maintaining and repairing endothelial function, and have become a promising method for the treatment of cerebrovascular diseases. However, whether EPC transplantation plays a protective role in RBI has not been fully elucidated. Therefore, the present study investigated the effects of bone marrow-derived EPC transplantation in a whole-brain irradiation (WBI) mouse model. Mice were divided into the three groups: control group, irradiation group and EPCs group. Phosphate buffered saline or EPCs were intravenously injected into mice one week after irradiation, and brains were analyzed eight weeks after injection. Flow cytometry demonstrated that irradiation led to a significant reduction in the peripheral blood EPC count; however, EPC transplantation led to a significant increase in the circulating EPCs. Intravital two-photon imaging and western blotting demonstrated that EPC transplantation reversed the effects of irradiation by decreasing blood-brain barrier permeability and increasing the expression of tight junction proteins in the brain. Additionally, immunofluorescence staining revealed that the brain microvascular density was higher in the EPCs group than the irradiation group. Therefore, EPC transplantation may restore damage caused by WBI to the blood-brain barrier, tight junctions, and cerebral capillary density. These results highlight the potential beneficial effects of EPC transplantation on vascular damage induced by RBI.

Astrocytes-derived VEGF exacerbates the microvascular damage of late delayed RBI.

Overexpression of vascular endothelial growth factor (VEGF) is considered the most critical factor in radiation-induced brain injury (RBI). To investigate the role of VEGF and the mechanism underlying microvascular damage in RBI, wild type mice, and transgenic mice overexpressing VEGF derived from astrocytes, were separately and randomly exposed to whole-brain or sham irradiation. Pathophysiologic changes in the brain tissue were detected 90 days after irradiation. Compared with wild type mice, the secretion of VEGF and angiopoietin-2 (Ang-2) was up-regulated in transgenic mice, whether irradiated or not, while elevated expression of VEGF, Ang-2, and glial fibrillary acidic protein (GFAP) was detected after whole-brain irradiation using western blotting. Impairment of the blood-brain barrier (BBB) was demonstrated by the leakage of dyes observed using two-photon imaging and decreased expression of zonula occludens-1 (ZO-1) and Occludin. Hematoxylin-eosin (HE) staining revealed obvious structural damage in the irradiated brains. Furthermore, damage to the BBB and histopathology in the transgenic mice were worse than those of wild type mice in the irradiated groups. There was a positive correlation among VEGF and Ang-2 expression and RBI severity. These data reveal that VEGF and Ang-2 expression is closely associated with the microvascular injury in RBI. Further, overexpression of VEGF can cause up-regulation of Ang-2 and exacerbation of RBI. Therefore, Ang-2 might be the cytokine that acts as a mediator between VEGF and microvascular injury, and is likely a new intervention target for RBI.

MicroRNA-221 regulates endothelial nitric oxide production and inflammatory response by targeting adiponectin receptor 1.

Adiponectin exerts anti-atherosclerosis property through its 2 receptors (AdipoR1 and AdipoR2). The mechanism regulating the expression of adiponectin receptors is unclear. Bioinformatics analysis showed that miR-221 targeted the 3'-untranslated region (3'UTR) of the AdipoR1 mRNA. The protein level and the mRNA level of AdipoR1 were reduced when miR-221 was expressed in human umbilical vein endothelial cells (HUVECs). Meanwhile, miR-221 repressed the activity of luciferase reporter containing the 3'UTR of AdipoR1. The inhibitory effect of miR-221 was abolished when the miR-221 binding site within the AdipoR1 3'UTR was deleted. Overexpression of miR-221 inhibited adiponectin-stimulated nitric oxide (NO) production in HUVECs. Furthermore, miR-221 abolished the inhibitory effect of adiponectin on NF-kB activation and the expression of adhesion molecules. Altogether, these results indicated that miR-221 targets AdipoR1 to regulate endothelial inflammatory response.