Engeletin alleviates cerebral ischemia reperfusion-induced neuroinflammation via the HMGB1/TLR4/NF-κB network.

High-mobility group box1 (HMGB1) induces inflammatory injury, and emerging reports suggest that it is critical for brain ischemia reperfusion. Engeletin, a natural Smilax glabra rhizomilax derivative, is reported to possess anti-inflammatory activity. Herein, we examined the mechanism of engeletin-mediated neuroprotection in rats having transient middle cerebral artery occlusion (tMCAO) against cerebral ischemia reperfusion injury. Male SD rats were induced using a 1.5 h tMCAO, following by reperfusion for 22.5 h. Engeletin (15, 30 or 60 mg/kg) was intravenously administered immediately following 0.5 h of ischemia. Based on our results, engeletin, in a dose-dependent fashion, reduced neurological deficits, infarct size, histopathological alterations, brain edema and inflammatory factors, namely, circulating IL-1ß, TNF-α, IL-6 and IFN-γ. Furthermore, engeletin treatment markedly reduced neuronal apoptosis, which, in turn, elevated Bcl-2 protein levels, while suppressing Bax and Cleaved Caspase-3 protein levels. Meanwhile, engeletin significantly reduces overall expressions of HMGB1, TLR4, and NF-κB and attenuated nuclear transfer of nuclear factor kappa B (NF-κB) p65 in ischemic cortical tissue. In conclusion, engeletin strongly prevents focal cerebral ischemia via suppression of the HMGB1/TLR4/NF-κB inflammatory network.

Can dynamic contrast-enhanced MRI evaluate VEGF expression in brain glioma? An MRI-guided stereotactic biopsy study.

PURPOSE: To investigate whether pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to evaluate vascular endothelial growth factor (VEGF) expression in brain glioma based on a point-to-point basis. MATERIALS AND METHODS: Forty-seven patients with treatment-naïve glioma received preoperative DCE-MRI before stereotactic biopsy. We histologically quantified VEGF from section of stereotactic biopsies, and co-registered biopsy locations with localized measurements of DCE-MRI parameters including volume transfer coefficient (Ktrans), reverse reflux rate constant (Kep), extracellular extravascular volume fraction (Ve) and blood plasma volume (Vp). The correlations between DCE-MRI parameters (Ktrans, Kep, Ve and Vp) and VEGF were determined using Spearman correlation coefficient. P≤.05 was considered statistically significant. RESULTS: Seventy-nine biopsy samples were obtained and graded into 45 high-grade gliomas (HGGs) and 34 low-grade gliomas (LGGs). Ktrans showed a significant positive correlation with VEGF expression in HGGs group (ρ=0.505, P<0.001) and in combined group (LGGs+HGGs) (ρ=0.549, P<0.001), but not in LGGs group (P>0.05). Kep, Ve or Vp was not correlated with VEGF even though a positive trend showed (P>0.05). CONCLUSIONS: DCE-MRI is a useful, non-invasive imaging technique for quantitative evaluation of VEGF, and its parameter Ktrans other than Kep, Ve or Vp may be used as a surrogate for VEGF expression in brain gliomas.

Correlation of dynamic contrast-enhanced MRI derived volume transfer constant with histological angiogenic markers in high-grade gliomas.

INTRODUCTION: To ascertain if the volume transfer constant (Ktrans ) derived from T1 dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) correlates with the immunohistological markers of angiogenesis in high-grade gliomas. METHODS: Fifty-one image-guided biopsy specimens in 34 patients with newly presenting high-grade gliomas (grade III = 16; grade IV = 18) underwent preoperative imaging (conventional imaging and T1 DCE-MRI). We correlated vascular endothelial growth factor (VEGF) expression and the microvessel density (MVD) of MRI-guided biopsy specimens with the corresponding DCE-derived Ktrans . Histological sections were stained with VEGF and CD34, and examined under light microscopy. These histological and molecular markers of angiogenesis were correlated with the Ktrans of the region of interest corresponding to the biopsy specimen. RESULTS: The Ktrans showed a significant positive correlation with VEGF expression (ρ = 0.582, P = 0.001) but not with MVD stained with CD34 antibody (ρ = 0.328, P = 0.072). CONCLUSION: The Ktrans derived from DCE-MRI can reflect the VEGF expression of high-grade gliomas but not the MVD.

Cornin protects SH­SY5Y cells against oxygen and glucose deprivation­induced autophagy through the PI3K/Akt/mTOR pathway.

It has been reported that cornin may reduce neuronal death during cerebral ischemia; however, little is known about the molecular mechanism of the role of corninin autophagy in SH­SY5Y neuronal cells. In the present study, oxygen­glucose deprivation (OGD)­treated cells were used as a cerebral ischemia model in vitro. The results demonstrated that cornin was able to reduce neuronal cell loss, increase the apoptosis regulator Bcl­2/apoptosis regulator BAX ratio, and decrease the protein levels of caspase­3. In addition, cornin decreased the microtubule­associated proteins 1A/1B light chain 3B (LC3)­II/LC3­I ratio and beclin­1 protein expression, and resulted in an upregulation in phosphorylated (p)­RAC­α serine/threonine­protein kinase (Akt), p­protein kinase mTOR (mTOR) in OGD­treated SH­SY5Y cells. Additionally, it was observed that following inhibition of PI3K/Akt by LY294002, the levels of p­Akt and p­mTOR were markedly decreased, and the LC3­II/LC3­I ratio and beclin­1 were increased. Similarly, following inhibition of mTOR by rapamycin, LC3­II/LC3­I and Beclin­1 were significantly increased in SH­SY5Y cells. These results indicated that cornin protected SH­SY5Y cells against OGD­induced autophagy through the PI3K/Akt/mTOR pathway.

Blood oxygenation level-dependent magnetic resonance imaging during carbogen breathing: differentiation between prostate cancer and benign prostate hyperplasia and correlation with vessel maturity.

OBJECTIVE: The aim of this study was to investigate whether the blood oxygenation level-dependent (BOLD) contrast magnetic resonance imaging (MRI) can evaluate tumor maturity and preoperatively differentiate prostate cancer (PCa) from benign prostate hyperplasia (BPH). PATIENTS AND METHODS: BOLD MRI based on transverse relaxation time*-weighted echo planar imaging was performed to assess PCa (19) and BPH (22) responses to carbogen (95% O2 and 5% CO2). The average signal values of PCa and BPH before and after carbogen breathing and the relative increased signal values were computed, respectively. The endothelial-cell marker, CD31, and the pericyte marker, α-smooth muscle actin (mature vessels), were detected with immunofluorescence, and were assessed by microvessel density (MVD) and microvessel pericyte density (MPD). The microvessel pericyte coverage index (MPI) was used to evaluate the degree of vascular maturity. The changed signal from BOLD MRI was correlated with MVD, MPD, and MPI. RESULTS: After inhaling carbogen, both PCa and BPH showed an increased signal, but a lower slope was found in PCa than that in BPH (P<0.05). PCa had a higher MPD and MVD but a lower MPI than BPH. The increased signal intensity was positively correlated with MPI in PCa and that in BPH (r=0.616, P=0.011; r=0.658, P=0.002); however, there was no correlation between the increased signal intensity and MPD or MVD in PCa than that in BPH (P>0.05). CONCLUSION: Our results confirmed that the increased signal values induced by BOLD MRI well differentiated PCa from BPH and had a positive correlation with vessel maturity in both of them. BOLD MRI can be utilized as a surrogate marker for the noninvasive assessment of the degree of vessel maturity.