Neuroglobin boosts axon regeneration during ischemic reperfusion via p38 binding and activation depending on oxygen signal.

Cerebral ischemia causes severe cell death or injury including axon breakdown or retraction in the brain. Axon regeneration is crucial for the functional recovery of injured neurons or brains after ischemia/reperfusion (I/R); however, this process has been proved extremely difficult in adult brains and there is still no effective therapy for it. Here we reported that neuroglobin (Ngb), a novel oxygen-binding or sensor protein existing predominantly in neurons or brains, functions as a driving factor for axon regeneration during I/R. Ngb was upregulated and accumulated in growth cones of ischemic neurons in primary cultures, rat, and human brains, correlating positively to the elevation of axon-regeneration markers GAP43, neurofilament-200, and Tau-1. Ngb overexpression promoted while Ngb knockdown suppressed axon regeneration as well as GAP43 expression in neurons during oxygen-glucose deprivation/reoxygenation (OGD/Re). By using specific pharmacological inhibitors, we identified p38 MAPK as the major downstream player of Ngb-induced axon regeneration during OGD/Re. Mechanistically, Ngb directly bound to and activated p38 in neurons upon OGD/Re. Serial truncation and point mutation of Ngb revealed that the 7-105 aa fragment of Ngb was required and the oxygen-binding site (His64) of Ngb was the major regulatory site for its p38 interaction/activation. Finally, administration of exogenous TAT-Ngb peptides significantly enhanced axon regeneration in cultured neurons upon OGD/Re. Taken together, Ngb promotes axon regeneration via O2-Ngb-p38-GAP43 signaling during I/R. This novel mechanism suggests potential therapeutic applications of Ngb for ischemic stroke and other related axonopathy.

Identification of repaglinide as a therapeutic drug for glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the gene expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients.

Ru-Catalyzed Regioselective Direct Hydroxymethylation of (Hetero)Arenes via C-H Activation.

An efficient and direct ruthenium-catalyzed regioselective hydroxymethylation of (hetero)arenes via C-H activation with paraformaldehyde as a hydroxymethylating reagent is described. The corresponding products can be obtained in good to excellent yield. A number of aryl aldehydes can also be used in place of paraformaldehyde giving the desired alcohol products with similarly good results.

Downregulation of NAD-Dependent Deacetylase SIRT2 Protects Mouse Brain Against Ischemic Stroke.

Sirtuin 2 (SIRT2) is a member of NAD+-dependent protein deacetylases involved in a wide range of pathophysiological processes including myocardial injury, Parkinson's disease, and Huntington's disease. However, the direct implication of SIRT2 in ischemic stroke is still unclear. In the present study, we observed that SIRT2 protein was mainly expressed in the cytoplasm of neurons, but not in astrocyte and microglia. SIRT2 was upregulated in ischemic neurons in the oxygen-glucose deprivation cell model and in the transient middle cerebral artery occlusion (tMCAo) mouse model. Moreover, expression of SIRT2 was evaluated by immunohistochemistry in human brains consisting of ischemic penumbra of cerebral stroke, and their age-matched normal controls without diagnosed neurological disorders. The results revealed that SIRT2 was mainly expressed in the cytoplasm and neurites of neurons in the brains of normal subjects, while an elevated expression and nuclear translocation of SIRT2 were detected in the ischemic penumbra of cerebral stroke. Downregulation of SIRT2 using the SIRT2-specific inhibitor AGK2 or SIRT2 knockout had neuroprotective effects in tMCAo model, which could decrease the infract volume and neurological impairment scores. In summary, our findings revealed that SIRT2 was upregulated during neuronal ischemia and translocated into neuronal nuclei, while downregulation of SIRT2 could significantly protect neurons against cerebral ischemia.

[Shang Ring versus disposable circumcision suture device in the treatment of phimosis or redundant prepuce].

OBJECTIVE: To compare the clinical efficiency of Shang Ring with that of the disposable circumcision suture device (DCSD) in the treatment of phimosis or redundant prepuce. METHODS: From June 2013 to March 2015, we treated 320 patients with phimosis or redundant prepuce using Shang Ring (n=158) or DCSD (n=162). We compared the operation time, intra-operative blood loss, incision healing time, postoperative complications, postoperative satisfaction, and treatment cost between the two groups of patients. RESULTS: Comparison between the Shang Ring and DCSD groups showed that the operation time was (5.6±1.3) vs (5.4±1.2) min, intra-operative blood loss (1.2±0.8) vs (1.3±0.9) ml, postoperative delayed hemorrhage 3.16% (5/158) vs 4.32% (7/162), incision healing time (16.1±7.2) vs (7.5±2.3) d, wound infection 15.82% (25/158) vs 7.41% (12/162), 1-month postoperative incision edema 29.11% (46/158) vs 9.26% (15/162), overall postoperative satisfaction rate 63.92% (101/158) vs 90.12% (146/162), and treatment cost (1121.2±15.6) vs (2142.6±10.8) RMB ¥. There were statistically significant differences between the two groups in the latter five parameters (P<0.05 ), but not in the first three (P>0.05 ). CONCLUSIONS: The DSCD has an obvious superiority over Shang Ring for its relatively lower complication rate, shorter incision healing time, and better cosmetic appearance.

Piperlongumine inhibits migration of glioblastoma cells via activation of ROS-dependent p38 and JNK signaling pathways.

Piperlongumine (PL) is recently found to kill cancer cells selectively and effectively via targeting reactive oxygen species (ROS) responses. To further explore the therapeutic effects of PL in cancers, we investigated the role and mechanisms of PL in cancer cell migration. PL effectively inhibited the migration of human glioma (LN229 or U87 MG) cells but not normal astrocytes in the scratch-wound culture model. PL did not alter EdU(+)-cells and cdc2, cdc25c, or cyclin D1 expression in our model. PL increased ROS (measured by DCFH-DA), reduced glutathione, activated p38 and JNK, increased IκBα, and suppressed NFκB in LN229 cells after scratching. All the biological effects of PL in scratched LN229 cells were completely abolished by the antioxidant N-acetyl-L-cysteine (NAC). Pharmacological administration of specific p38 (SB203580) or JNK (SP600125) inhibitors significantly reduced the inhibitory effects of PL on LN229 cell migration and NF κ B activity in scratch-wound and/or transwell models. PL prevented the deformation of migrated LN229 cells while NAC, SB203580, or SP600125 reversed PL-induced morphological changes of migrated cells. These results suggest potential therapeutic effects of PL in the treatment and prevention of highly malignant tumors such as glioblastoma multiforme (GBM) in the brain by suppressing tumor invasion and metastasis.

[Partial least squares regression variable screening studies on apple soluble solids NIR spectral detection].

Abstract To improve the predictive ability and robustness of the NIR correction model of the soluble solid content (SSC) of apple, the reverse interval partial least squares method, genetic algorithm and the continuous projection method were implemented to select variables of the NIR spectroscopy of the soluble solid content (SSC) of apple, and the partial least squares regression model was established. By genetic algorithm for screening of the 141 variables of the correction model, prediction has the best effect. And compared to the full spectrum correction model, the correlation coefficient increased to 0.96 from 0.93, forecast root mean square error decreased from 0.30 degrees Brix to 0.23 degrees Brix. This experimental results show that the genetic algorithm combined with partial least squares regression method improved the detection precision of the NIR model of the soluble solid content (SSC) of apple.