Neuroscience
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Mesenchymal stem cells (MSCs)-derived exosomes are demonstrated to exert neuroprotective effects in stroke. We aimed to explore the role and mechanism of long non-coding RNA (lncRNA) KLF3 antisense RNA 1 (KLF3-AS1) in bone marrow mesenchymal stem cells-derived exosomes (BMSCs-Exos) in cerebral ischemia/reperfusion (I/R) injury. Exosomes were isolated from the culture medium of BMSCs. ⋯ KLF3-AS1 was found to recruit ETS variant transcription factor 4 (ETV4), which upregulated Sirt1 expression. Knockdown of KLF3-AS1 neutralized the protective effects of BMSCs-Exos on MCAO-induced brain injury, which was then reversed by the treatment with Sirt1 inhibitor EX527. We concluded that KLF3-AS1 derived from BMSCs-Exos promoted autophagy to alleviate I/R injury via ETV4/Sirt1 axis.
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To examine whether resveratrol (RSV), an activator of silent mating-type information regulation 2 homolog 1 (SIRT1), can reverse the disruption of lipid metabolism caused by β-amyloid peptide (Aβ), APP/PS1 mice or cultured primary rat neurons were treated with RSV, suramin (inhibitor of SIRT1), ZLN005, a stimulator of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), or PGC-1α silencing RNA. In the brains of the APP/PS1 mice, expressions of SIRT1, PGC-1α, low-density lipoprotein receptor (LDLR) and very LDLR (VLDLR) were reduced at the protein and, in some cases, mRNA levels; while the levels of the proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein E (ApoE), total cholesterol and LDL were all elevated. ⋯ Furthermore, activation of PGC-1α, but inhibition of SIRT1, decreased the levels of PCSK9 and ApoE, while increased those of LDLR and VLDLR in the neurons exposed to Aβ, and silencing PGC-1α, but activation of SIRT1, did not influence the levels of any of these proteins. These findings indicate that RSV can attenuate the disruption of lipid metabolism observed in the brains of APP mice and in primary neurons exposed to Aβ by activating SIRT1, in which the mechanism may involve subsequently affecting PGC-1α.
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Parkinson's Disease (PD) is a neurodegenerative disease with loss of dopaminergic neurons in the nigrostriatal pathway resulting in basal ganglia (BG) dysfunction. This is largely why much of the preclinical and clinical research has focused on pathophysiological changes in these brain areas in PD. The cerebellum is another motor area of the brain. ⋯ D1R expression was higher in PD animals compared to sham animals in both hemispheres in the purkinje cell layer (PCL) and granule cell layer (GCL) of the cerebellar cortex. Interestingly, D2R expression was higher in PD animals than sham animals mostly in the posterior lobe of the PCL, but no discernible pattern of D2R expression was seen in the GCL between PD and sham animals. To our knowledge, we are the first to report these findings, which may lay the foundation for further interrogation of the role of the cerebellum in PD therapy and/or pathophysiology.
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Mitochondrial damage is a central mechanism involved in neurological disorders as Alzheimer's, and Parkinson's diseases and amyotrophic lateral sclerosis. Energy production is the most studied mitochondrial function; however, mitochondria are also involved in processes like calcium buffering homeostasis, and cell death control during apoptosis and necrosis. Using transmission electron microscopy, in this in vivo study in male rats, we describe ultrastructural mitochondrial alterations of spinal motor neurons along chronic AMPA-induced excitotoxicity, which has been described as one of the most relevant mechanisms in ALS disease. ⋯ In addition, by combining the TUNEL assay and immunohistochemistry for mitochondrial enzymes, we show evidence of mitochondrial DNA damage. Evidence of mitochondrial alterations during an AMPA-excitotoxic event is relevant because resembles the mitochondrial alterations previously reported in ALS patients and in transgenic familial ALS models, suggesting that a chronic excitotoxic model can be related to sporadic ALS (as has been shown in recent papers), which represent more than the 90% of the ALS cases. Understanding the mechanisms involved in motor neuron degenerative process, such as the ultrastructural mitochondrial changes permits to design strategies for MN-degeneration treatments in ALS.
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Ischemic stroke is a neurological disorder that causes pathological changes by increasing oxidative stress. Retinoic acid is one of the metabolites of vitamin A. It regulates oxidative stress and exerts neuroprotective effects. ⋯ However, the mitigation effects of retinoic acid were lower in thioredoxin siRNA-transfected neurons than in non-transfected neurons. These results demonstrate that retinoic acid regulates oxidative stress and thioredoxin expression, maintains the interaction between thioredoxin and ASK1, and modulates apoptosis-associated proteins. Taken together, these results suggest that retinoic acid has neuroprotective effects by regulating thioredoxin expression and modulating apoptotic pathway.