Chronic inflammation and pro-inflammatory cytokines are important mediators of pancreatic b-cell destruction in type 1 diabetes (T1D). We presently show that the cytokines IL-1b þ IFN-c and different ER stressors activate the Bcl-2 homology 3 (BH3)-only member death protein 5 (DP5)/harakiri (Hrk) resulting in b-cell apoptosis. Chemical ER stress-induced DP5 upregulation is JNK/c-Jun-dependent. DP5 activation by cytokines also involves JNK/c-Jun phosphorylation and is antagonized by JunB. Interestingly, cytokine-inducted DP5 expression precedes ER stress: mitochondrial release of cytochrome c and ER stress are actually a consequence of enhanced DP5 activation by cytokine-mediated nitric oxide formation. Our findings show that DP5 is central for b-cell apoptosis after different stimuli, and that it can act up-and downstream of ER stress. These observations contribute to solve two important questions, namely the mechanism by which IL-1b þ IFN-c induce b-cell death and the nature of the downstream signals by which ER stress 'convinces' b-cells to trigger apoptosis.

Subarachnoid hemorrhage (SAH) is a devastating disease with high mortality. The mechanisms underlying its pathological complications have not been fully identified. Here, we investigate the potential involvement of the glymphatic system in the neuropathology of SAH. We demonstrate that blood components rapidly enter the paravascular space following SAH and penetrate into the perivascular parenchyma throughout the brain, causing disastrous events such as cerebral vasospasm, delayed cerebral ischemia, microcirculation dysfunction and widespread perivascular neuroinflammation. Clearance of the paravascular pathway with tissue-type plasminogen activator ameliorates the behavioral deficits and alleviates histological injury of SAH. Interestingly, AQP4−/− mice showed no improvements in neurological deficits and neuroinflammation at day 7 after SAH compared with WT control mice. In conclusion, our study proves that the paravascular pathway dynamically mediates the pathological complications following acute SAH independently of glymphatic control.

Background:The prognostic value of CDKN2A promoter hypermethylation in colorectal cancer remains controversial. We systematically reviewed the evidence for assessment of CDKN2A methylation in colorectal cancer to elucidate this issue.Methods:Pubmed, Embase and ISI web of knowledge were searched to identify eligible studies to evaluate the association of CDKN2A hypermethylation and overall survival and clinicopathological features of colorectal cancer patients. Combined hazard ratios (HRs) or odds ratios (ORs) with 95% confidence interval (95% CI) were pooled using a random-effects model.Results:A total of 11 studies encompassing 3440 patients were included in the meta-analysis. CDKN2A hypermethylation had an unfavourable impact on OS of patients with colorectal cancer (HR 1.65, 95% CI 1.29–2.11). Subgroup analysis indicated that CDKN2A hypermethylation was significantly correlated with OS in Europe (HR 1.49; 95% CI 1.28–1.74) and Asia (HR 3.30; 95% CI 1.68–6.46). Furthermore, there was a significant association between CDKN2A hypermethylation and lymphovascular invasion (OR 1.68, 95% CI 1.15–2.47), lymph node metastasis (OR 1.68, 95% CI 1.09–2.59) and proximal tumour location (OR 2.09, 95% CI 1.34–3.26) of colorectal cancer.Conclusion:This meta-analysis indicated that CDKN2A hypermethylation might be a predictive factor for unfavourable prognosis of colorectal cancer patients.

Oxidative stress is a major cause of sporadic Parkinson's disease (PD). Here, we demonstrated that c-Abl plays an important role in oxidative stress-induced neuronal cell death. C-Abl, a nonreceptor tyrosine kinase, was activated in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced acute PD model. Conditional knockout of c-Abl in neurons or treatment of mice with STI571, a c-Abl family kinase inhibitor, reduced the loss of dopaminergic neurons and ameliorated the locomotive defects induced by short-term MPTP treatment. By combining the SILAC (stable isotope labeling with amino acids in cell culture) technique with other biochemical methods, we identified p38α as a major substrate of c-Abl both in vitro and in vivo and c-Ablmediated phosphorylation is critical for the dimerization of p38α. Furthermore, p38α inhibition mitigated the MPTP-induced loss of dopaminergic neurons. Taken together, these data suggested that c-Abl-p38α signaling may represent a therapeutic target for PD. Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by bradykinesia, rigidity, tremor, and loss of dopaminergic neurons. 1 Familial mutations that cause PD have been identified, including in the genes that encode α-synuclein and leucine-rich repeat kinase 2 (LRRK2) that cause autosomal-dominant PD, and DJ-1, PINK1, and parkin that cause autosomal-recessive PD. 2 However, the majority of PD cases are sporadic. The cause of sporadic PD remains unknown, and the role of environmental toxins and genetic factors in sporadic PD is unclear. However, the evidence regarding postencephalitic PD and the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced Parkinsonism suggest that environmental toxins may be a major cause of sporadic PD. 3,4 The neurotoxins used to induce dopaminergic neurodegeneration, including 6-hydroxydopamine, MPTP, and rotenone, induce the formation of reactive oxygen species (ROS). ROS react with nucleic acids, proteins, and lipids to induce mitochondrial damage. Although oxidative stress plays a critical role in causing PD, the mechanisms underlying oxidative stress-induced PD remain unclear.The nonreceptor tyrosine kinase c-Abl is ubiquitously expressed and mediates a variety of extrinsic and intrinsic cell signaling activities, including growth factor signaling, cell adhesion, oxidative stress, and DNA damage. 5 Our group and other groups have reported that c-Abl plays an important role in oxidative stress-induced neuronal death. 6-8 Recently, Ko et al. 9 and Imam et al. 10 have reported that c-Abl phosphorylated Parkin and inhibited its E3 ligase activity that led to the neurotoxic accumulation of Parkin's substrates. α-Synuclein has also been reported to be substrates of c-Abl and to participate in PD pathogenesis. 9-11 The c-Abl inhibitor Nilotinib and INNO-406 have been reported prevents the loss of dopamine neurons and improves motor behavior in a murine PD model. [12][13][14] In this study, we demonstrated that c-Abl ...