Effect of Sirtuin-1 and Wnt/ß-Catenin Signaling Pathway in Rat Model of Spinal Cord Injury.

Sirtuin-1 (SIRT1) has anti-inflammatory and antioxidant effects and has been reported to be involved in spinal cord injury (SCI). Wnt/ß-catenin signal has been shown to play a critical role in the pathogenesis of chronic diseases, and it participated in the recovery of nerve function after SCI. However, the specific link between them in SCI is unclear. In addition, targeting posttraumatic astrocyte apoptosis is crucial for improving neural degeneration and locomotor function. Therefore, in this article, we studied the relationship of ß-catenin and SIRT1 using in the SCI rat model and primary astrocyte treated with hydrogen peroxide (H2O2) or lithium chloride (LiCl). Results showed that after SCI, SCI area and motor function recover over time, and ß-catenin is gradually increased to the seventh day and then in turn decreases until 4 weeks, positively correlated with cell apoptosis. The expression of SIRT1 and downstream FOXO4 gradually increased, and ß-catenin is negatively correlated with SIRT1 expression. Moreover, treatment with H2O2 in primary cultured astrocyte significantly increased ß-catenin and Caspase-3 expression, while decreased SIRT1 and Forkhead box O- (FOXO-) 4. The immunofluorescence results are consistent with this. Administration of LiCl further aggravates the above results. These findings suggest that SIRT1 is negatively correlated with ß-catenin in SCI, which promotes the apoptosis of motor neuron cells, which may be related to the participation of FOXO4.

Effects of Sirtuin 1 on microglia in spinal cord injury: involvement of Wnt/ß-catenin signaling pathway.

Because posttraumatic inflammation contributes to the progression of neuron degeneration, attenuating inflammation is important for reducing neural degeneration. Sirtuin 1 (SIRT1) has been shown to play a critical role in the chronic diseases, such as neurodegenerative diseases and aging. However, the role that SIRT1 plays in regulating neuroinflammation in spinal cord injuries (SCIs) remains unclear. In this study, we investigate the effect of SIRT1 on the SCI model and on lipopolysaccharide (LPS)-treated primary microglia using a pharmacological intervention (SRT1720, an agonist of SIRT1). Results showed that SIRT1 levels gradually decreased in spinal cord until the fourth week after SCI, while the level of 8-hydroxy-2'-deoxyguanosine increased. SIRT1 was negatively correlated with the expression of ß-catenin following SCI. The administration of SRT1720 significantly improved number of neurons and the Basso, Beattie, and Bresnahan score after SCI. The number of ionizing calcium-binding adaptor molecule 1 (Iba1)-positive microglia, levels of ß-catenin and NF-kB p65, and proinflammatory cytokines [tumor necrosis factor alpha and interleukin (IL) 12] decreased significantly after SRT1720 treatment, while IL-10 increased after SCI. Furthermore, both SIRT1 and SRT1720 significantly inhibited ß-catenin gene and protein expression; ß-catenin transcriptional activity also decreased in a dose-dependent manner following SIRT1 treatment of LPS-treated microglia. These findings suggest that SIRT1 may have a neuroprotective effect by suppressing microglial activation via downregulation of the Wnt/ß-catenin signal following SCI.

The Role of Tumor Oxygenation Tested by Magnetic Resonance Imaging (MRI) in Prostate Cancer Grading.

BACKGROUND Prostate cancer is a common malignant tumor in males. Prostate cancer grading is an important basis for evaluation of invasion. The purpose of this article was to use dynamic enhanced scan magnetic resonance imaging (MRI) to quantitatively investigate the relationship between tumor oxygenation value and prostate cancer pathological Gleason score. MATERIAL AND METHODS A total of 312 prostate cancer patients diagnosed by needle biopsy who received MRI dynamic enhanced scan were enrolled in this study. Multiparameter oxygen concentration image based on MRI was applied to test pO2 in tumors. Multiple spin resonance image relaxation time edit sequence and weak field diffusion model were used to estimate oxygen saturation level and pO2. hematoxylin and eosin staining and Gleason score were used to determine biological behavior and prognosis. RESULTS According to the Gleason score system, there were 28 cases with a score of 10, 112 cases with a score of 9, 56 cases with a score of 8, and 116 cases with a score lower than 7. The enrolled patients were divided into groups: 116 cases into the middle-to-well differentiation group (Gleason score ≤7) and 196 cases into the poorly differentiation group (Gleason score at 8 to 10). Prostate cancer tumor oxygenation value was positively correlated with Gleason score (r=0.349, P<0.05) or PSA (r=0.432, P<0.05). Tumor oxygenation value in Gleason ≤7 group was obviously different from that in the group with Gleason score between 9 and 10 (P<0.05). CONCLUSIONS Tumor oxygenation value in prostate cancer was positively correlated with Gleason score. Tumor oxygenation value might be useful in clinics to evaluate prostate cancer grading and prognosis.

Epothilone B impairs functional recovery after spinal cord injury by increasing secretion of macrophage colony-stimulating factor.

The microtubule-stabilizing drug epothilone B (epoB) has shown potential value in the treatment of spinal cord injury (SCI) through diverse mechanisms. However, it remains elusive why a limited overall effect was observed. We aim to investigate the limiting factors underlying functional recovery promoted by epoB. The same SCI model treated by epoB was established as discussed previously. We used a cerebrospinal fluid (CSF) sample to assess the changes in cytokines in milieu of the SCI lesion site after epoB treatment. We then analyzed the source of cytokines, the state of microglia/macrophages/monocytes (M/Ms), and the recruitment of neutrophil in the lesion site by using the results of antibody array. Following these findings, we further evaluated the motor functional recovery caused by the reshaped microenvironment. Systemic administration of epoB significantly increased levels of several cytokines in the CSF of the rat SCI model; macrophage colony-stimulating factor (M-CSF) secreted by intact central nervous system (CNS) cells was one of the cytokines with increased levels. Along with epoB and other cytokines, M-CSF reshapes the SCI milieu by activating the microglias, killing bone marrow-derived macrophages, polarizing the M/M to M1 phenotype, and activating downstream cytokines to exacerbate the SCI injury, but it also increases the expression of neurotrophic factors. Anti-inflammatory therapy using a neutralizing antibody mix shows encouraging results. Using in vivo experiments, our findings indicate that epoB inhibits the SCI functional recovery in many ways by reshaping the milieu, which counteracts the therapeutic efficacy that led to the limited overall effectiveness.

Netrin-1 Improves Functional Recovery through Autophagy Regulation by Activating the AMPK/mTOR Signaling Pathway in Rats with Spinal Cord Injury.

Autophagy is an process for the degradation of cytoplasmic aggregated proteins and damaged organelles and plays an important role in the development of SCI. In this study, we investigated the therapeutic effect of Netrin-1 and its potential mechanism for autophagy regulation after SCI. A rat model of SCI was established and used for analysis. Results showed that administration of Netrin-1 not only significantly enhanced the phosphorylation of AMP-activated protein kinase (AMPK) but also reduced the phosphorylation of mammalian target of rapamycin (mTOR) and P70S6K. In addition, the expression of Beclin-1 and the ratio of the light-chain 3B-II (LC3B-II)/LC3B-I in the injured spinal cord significantly increased in Netrin-1 group than those in SCI group. Moreover, the ratio of apoptotic neurons in the anterior horn of the spinal cord and the cavity area of spinal cord significantly decreased in Netrin-1 group compared with those in SCI group. In addition, Netrin-1 not only preserved motor neurons but also significantly improved motor fuction of injured rats. These results suggest that Netrin-1 improved functional recovery through autophagy stimulation by activating the AMPK/mTOR signaling pathway in rats with SCI. Thus, Netrin-1 treatment could be a novel therapeutic strategy for SCI.