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Terminally differentiated neurons are unable to reenter the cell cycle. Aberrant cell cycle activation provokes neuronal cell death, whereas cell cycle inhibition elevates neuronal survival. However, the molecular mechanism regulating the cell cycle and cell death in mature neurons remains elusive. Here we show that SRPK2, a protein kinase specific for the serine/arginine (SR) family of splicing factors, triggers cell cycle progression in neurons and induces apoptosis through regulation of nuclear cyclin D1. Akt phosphorylates SRPK2 on Thr-492 and promotes its nuclear translocation leading to cyclin D1 up-regulation, cell cycle reentry, and neuronal apoptosis. In addition, SRPK2 phosphorylates SC35 and, thus, inactivates p53, resulting in cyclin D1 up-regulation. 14-3-3 binding to SRPK2, regulated by Akt phosphorylation, inhibits these events. We find that SRPK2 is phosphorylated in ischemia-attacked brain, correlating with the observed increase in cyclin D1 levels. Hence, phosphatidylinositol 3-kinase/Akt mediates the cell cycle and cell death machinery in the nervous system through phosphorylation of SRPK2.
Interaction of Akt-phosphorylated SRPK2 with 14-3-3 Mediates Cell Cycle and Cell Death in Neurons*An external file that holds a picture, illustration, etc. Object name is sbox.jpg
Sung-Wuk Jang,‡ Xia Liu,‡ Haian Fu,§ Howard Rees,¶ Manuel Yepes,¶ Allan Levey,¶ and Keqiang Ye‡,1
2009 Sep 4;
To examine the relationship between sedation and pupillary function by comparing the effects of diazepam and diphenhydramine on arousal and pupillary activity.
Fifteen male volunteers participated in three weekly sessions in which they received (i) diazepam 10 mg, (ii) diphenhydramine 75 mg and (iii) placebo, according to a balanced, double-blind protocol. Pupil diameter was measured with infrared pupillometry under four luminance levels. Alertness was assessed by visual analogue scales (VAS) and by critical flicker fusion frequency (CFFF). Blood pressure, heart rate and skin conductance were recorded by conventional methods. Data were analysed with analysis of variance (anova) with multiple comparisons.
There were significant effects of ambient luminance (F3,42 = 305.7, P < 0.001) and treatment condition (F2,28 = 9.0, P < 0.01) on pupil diameter; diphenhydramine caused miosis at all luminance levels (P< 0.05). The light reflex response was not affected. Both active drugs reduced the pre-post treatment changes compared with placebo [mean difference from placebo (95% confidence interval)]: in CFFF (Hz), diazepam −0.73 (−1.63, 0.17), diphenhydramine −1.46 (−2.40, −0.52); and VAS alertness (mm), diazepam −11.49 (−19.19, −3.79), diphenhydramine −19.83 (−27.46, −12.20). There were significant effects of both session (F2,26 = 145.1, P < 0.001) and treatment (F2,26 = 5.5, P < 0.01) on skin conductance; skin conductance was reduced by both drugs (P< 0.05). Conclusions The miosis by diphenhydramine and the reduction in skin conductance by both drugs may indicate central sympatholytic effects. A lack of a sympatholytic effect of diazepam on the pupil may be due to the masking of the miosis by mydriasis resulting from the inhibition of the parasympathetic output to the iris.
arousal, diazepam, diphenhydramine, light reflex, pupil, skin conductance
Relationship between sedation and pupillary function: comparison of diazepam and diphenhydramine
Ruihua H Hou, Jessica Scaife, Clare Freeman, Rob W Langley, Elemer Szabadi, and Chris M Bradshaw
There are few data on the prevalence of obesity and its influence on achieving blood glucose, blood pressure, and blood lipid (3B) goals in Chinese type 2 diabetes outpatients.
Patient demographic data, anthropometric measurements, medications, and blood glucose and lipid profiles of 24,512 type 2 diabetes patients from a large, geographically diverse study (CCMR-3B) were analyzed. Using cut-points for body mass index (BMI) and waist circumference (WC) recommended by the Working Group on Obesity in China, overweight and obesity were defined as BMIs of 24-27.9kg/m2 and ≥28.0kg/m2. Central obesity was defined as a waist circumference ≥80cm in women and ≥85cm in men. The 3B therapeutic goals were HbA1c<7.0%, BP<140/90mmHg and LDL-C<2.6mmol/L. Results Overall, 43.0% of type 2 diabetes patients were overweight and 16.7% were obese; 13.3% of overweight and and10.1% of obese patients achieved all the 3B target goals. Overweight or obese patients were less likely to achieve 3B goals than those with normal BMIs. More than a half the overweight or obese patients (69.6%) were centrally obese. Patients with abdominal obesity were less likely to achieve cardiometabolic targets than those without abdominal obesity. In multivariate logistic regression analysis, female, higher BMI and waist circumference, smoking, drinking, sedentary lifestyle, and longer diabetes duration were significantly correlated with failure to achieve 3B control goals. Conclusions Obesity is highly prevalent and associated with poor 3B control in Chinese type 2 diabetes patients. In clinical practice, more attention and resources should focus on weight loss for such patients.
Prevalence of Obesity and Its Influence on Achievement of Cardiometabolic Therapeutic Goals in Chinese Type 2 Diabetes Patients: An Analysis of the Nationwide, Cross-Sectional 3B Study
Xianghai Zhou,1,2 Linong Ji,1,2,* Xingwu Ran,3 Benli Su,4 Qiuhe Ji,5 Changyu Pan,6 Jianping Weng,7 Changsheng Ma,8 Chuanming Hao,9 Danyi Zhang,10 Dayi Hu,11 and CCMR Advisory Board and CCMR-3B Study Investigators¶