Neuroprotective effects of G9a inhibition through modulation of peroxisome-proliferator activator receptor gamma-dependent pathways by miR-128

Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.

Numerical Simulation of the Blood Flow through a Brain Vascular Aneurysm with an Artificial Stent Using the SPH Method

We present numerical simulations of blood flow through a brain vascular aneurysm with an artificial stent using Smoothed Particle Hydrodynamics (SPH). The aim of this work is to analyze how the flow into an aneurysm changes using different stent configurations. The initial conditions for the simulations were constructed from angiographic images of a real patient with an aneurysm. The wall shear stresses, pressure and highest velocity within the artery, and other particular quantities are calculated which are of medical specific interest. The numerical simulations of the cerebral circulation help doctors to determine if the patient’s own vascular anatomy has the conditions to allow arterial stenting by endovascular method before the surgery or even evaluate the effect of different stent structure and materials. The results show that the flow downstream the aneurysm is highly modified by the stent configuration and that the best choice for reducing the flow in the aneurysm is to use a completely extended Endeavor stent.