Anticholinergic drugs and the risk of dementia: A systematic review and meta-analysis.

Dementia is one of the greatest global challenges for public health; however, the relationship between anticholinergic drugs and dementia remains unclear. The aim of the present study was to perform a systematic review and meta-analysis of the predictive roles of anticholinergic drugs in dementia risk. After pooling fourteen longitudinal and case-control studies with a total of 1,564,181 subjects, anticholinergic drug use was associated with an increased risk of all-cause dementia and Alzheimer's disease. Both low and high anticholinergic drug burdens were associated with dementia. Moreover, there was a dose-dependent relationship between anticholinergic drugs and risk of dementia. With respect to the categories of anticholinergic drugs, antiparkinson, urological drugs, and antidepressants increased the risk for dementia; however, cardiovascular and gastrointestinal drugs played potentially protective roles. These findings underscore the importance of anticholinergic drugs as a potential modifiable risk factor for dementia and provide treatment priorities to optimize dementia prevention.

Organocatalytic asymmetric cascade 1,6-addition/hemiketalization/retro-Henry reaction of ortho-hydroxyphenyl-substituted p-QMs with α-nitroketones.

A novel organocatalytic asymmetric cascade 1,6-addition/hemiketalization/retro-Henry reaction of ortho-hydroxyphenyl-substituted p-QMs with α-nitroketones is described. A variety of novel chiral 2-(1-(4-hydroxyphenyl)ethyl)phenols are constructed for the first time with high yields (up to 92%) and excellent enantioselectivities (up to >99% ee) under mild reaction conditions. A gram-scale experiment of this process is also presented.

Nrf2 protects against diabetic dysfunction of endothelial progenitor cells via regulating cell senescence.

Diabetes is associated with an increased risk of cardiovascular disease. A decrease in the number and functionality of endothelial progenitor cells (EPCs) leads to reduced endothelial repair and the development of cardiovascular disease. The aim of the present study was to explore the effect and underlying mechanisms of nuclear factor erythroid 2­related factor 2 (Nrf2) on EPC dysfunction caused by diabetic mellitus. The biological functions of EPCs in streptozotocin­induced diabetic mice were evaluated, including migration, proliferation, angiogenesis and the secretion of vascular endothelial growth factor (VEGF), stromal­derived growth factor (SDF) and nitric oxide (NO). Oxidative stress levels in diabetic EPCs were also assessed by detecting intracellular reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA). EPC senescence was evaluated by measuring p16 and b­gal expression and observing the senescence­associated secretory phenotype. In addition, the function of EPCs and level of oxidative stress were assessed following Nrf2 silencing or activation. Nrf2 silencing resulted in a decrease of EPC biological functions, accelerated cell senescence and increased oxidative stress, as indicated by ROS and MDA upregulation accompanied with decreased SOD activity. Furthermore, Nrf2 silencing inhibited migration, proliferation and secretion in EPCs, while it increased oxidative stress and cell senescence. Nrf2 activation protected diabetic EPCs against the effects of oxidative stress and cell senescence, ameliorating the biological dysfunction of EPCs derived from mice with diabetes. In conclusion, Nrf2 overexpression protected against oxidative stress­induced functional damage in EPCs derived from diabetic mice by regulating cell senescence.

[Microsatellite DNA polymorphism of adrenomedullin gene and atherosclerotic cerebral infarction].

OBJECTIVE: To detect the correlation between the microsatellite DNA polymorphism of adrenomedullin(ADM) gene (repeated sequences of CA) and the atherosclerotic cerebral infarction (ACI). METHODS: With PCR, ADM genotype was monitored from 189 normotensive subjects and 283 cerebral infarction patients. By using radioimmunoassay, their plasma ADM concentration was measured, so as the biochemical index. RESULTS: The genotype distribution of ADM between the health control and ACI groups was significantly different, chi square was 28.732, P < 0.05. As one of the four alleles, including 11, 13, 14 and 19 alleles, the frequency of 19 allele in ACI groups was much higher than that in the health control group, chi square was 26.929, P < 0.05. However, there was no significant difference in plasma ADM concentration among the different genotypes of the ACI patients. CONCLUSION: Microsatellite DNA polymorphism of ADM gene may be associated with the genetic predisposition to ACI.

[Effect of adrenomedullin on neuron apoptosis and early growth response gene-1 after focal ischemia/ reperfusion in rats].

OBJECTIVE: To explore the influence of adrenomedullin (ADM) on apoptosis of neuron, volume of infarction and the expression of early growth response gene-1 (Egr-1) mRNA in the rat with focal ischemia/reperfusion (I/R) injury. METHODS: Fifty-four SD rats were randomly divided into sham operation group, ADM femoral vein group, internal carotid artery group and lateral cerebral ventricle group. The model was reproduced by ligating the middle cerebral artery (MCA) with a ligature for 2 hours followed by injection of ADM through femoral artery, internal carotid artery and lateral cerebral ventricle before reperfusion for 22 hours. The volume of infarction was estimated with tetrazolium chloride (TTC) staining, apoptosis of the neuron was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method, the positive expression of Egr-1 mRNA was detected by in-situ hybridization. RESULTS: The volume of infarction were smaller after the injection of ADM through different ways than that of I/R group. The result was better when the internal carotid artery and the lateral cerebral ventricle were used than that after injection by the way of the femoral vein (both P<0.05). There were few positive cells with TUNEL staining in the cerebral cortex and hippocampus CA1 zone in the sham operation group, and more apoptotic cells were seen in the group with focal brain I/R injury (both P<0.01). After the administration of ADM, especially through the internal carotid artery and the lateral cerebral ventricle, the number of the positive cells with TUNEL staining was decreased obviously compared with I/R group (both P<0.01). There was a little positive expression of Egr-1 mRNA in the cerebral cortex and hippocampus CA1 zone in sham operation group. The expression was enhanced in the group with focal brain I/R injury (both P<0.01). With the injection of ADM, the expression was much more enhanced, especially when internal carotid artery and the lateral cerebral ventricle were used for injection compared with those in I/R group (both P<0.01). CONCLUSION: The injection of ADM through different ways can reduce the neural injury, decrease the apoptosis of the neurons and the volume of the infarction, and increase the expression of Egr-1 mRNA. Therefore, it is efficacious in the treatment of cerebral ischemia.

Effect of adrenomedullin on neuron apoptosis, infarction volume and expression of Egr-1 mRNA after focal ischemia-reperfusion in rats.

Objective To observe the influence of adrenomedullin (ADM) on neuron apoptosis, infarction volume of brain, and the expression of early growth response 1 (Egr-1) mRNA in ischemia-reperfusion rats. Methods The arteria cerebri media was tied for 2 h to construct the ischemia model. Infarction volume was detected by triphenltetrazolium chloride (TTC) staining, neuronal apoptosis and necrosis was detected with terminal deoxynucleotidyl transferase nick labeling (TUNEL) method, and the Egr-1 mRNA expression was examined by in situ hybridization (ISH). Results Infarction volume after ischemia-reperfusion is (269 +/- 20) mm(3). Infarction volume after injection of ADM through different ways are femoral vein (239 +/- 17) mm(3) (decreased by 11.2%), arteria carotis (214 +/- 14) mm(3) (by 20.4%) and lateral cerebral ventricle (209 +/- 13) mm(3) (by 22.3%), respectively. The results indicate that injecting ADM through arteria carotis and lateral cerebral ventricle is much more effective than it through femoral vein (P < 0.05). The TUNEL-positive cells in cerebral cortex or hippocampus are few in the sham operation group, but much more in the ischemia-reperfusion group. After being supplied with ADM, especially through arteria carotis interna or lateral cerebral ventricle way, the TUNEL-positive cells decreased obviously. Expression of Egr-1 mRNA was low in the cerebral cortex of the sham operation group rats, enhanced in the ischemia and reperfusion group rats, and enhanced markedly after treatment with ADM, especially through arteria carotis interna or lateral cerebral ventricle way (P < 0.01). Conclusion Injection of ADM through different ways could alleviate neural dysfunction, decrease neuron apoptosis and brain infarction volume, and increase the expression of Egr-1 mRNA.