<p>Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease</p>

Abstract

BackgroundAlzheimer’s disease (AD), a leading cause of dementia, becomes a serious health issue for individuals and society around the world. AD is a neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFT) and the loss of large numbers of neurons. To date, there is no effective treatment for AD, and thus, to enhance neurogenesis in the AD brain may be a therapeutic strategy. RAS signaling pathway involves in synaptic plasticity and memory formation, which is overexpressed in brains with AD. This study used Aβ1-42-injected mice (Aβ1-42-mice) as the AD model to investigate the effects of S-trans, trans-farnesylthiosalicylic acid (FTS), a synthetic Ras inhibitor, on the impairment of neurogenesis and the spatial cognitive deficits.Materials and methodsAD model mice were manufactured through intracerebroventricular injection of Aβ1-42. Morris water maze (MWM) was performed to evaluate the capacity of spatial memory, and Nissl staining was applied to assess neuronal damage in the hippocampus CA1. Immunohistochemistry of 5-bromo-2-deoxyuridine (BrdU), BrdU/neuronal nuclei (NeuN), and doublecortin (DCX) were used to detect progenitor cell proliferation, maturation, and neurite growth, respectively. And the expression levels of RAS, ERK/ERK phosphorylation (p-ERK) and CREB/CREB phosphorylation (p-CREB) were detected by Western blot.ResultsThe results demonstrated that FTS could prevent Aβ1-42 to impair survival and neurite growth of newborn neurons in the hippocampal dentate gyrus (DG) in Aβ1-42-mice. Furthermore, behavioral indexes and morphological findings showed that FTS improved the learning and spatial memory abilities of Aβ1-42-mice. In addition, FTS could inhibit the levels of hippocampal p-ERK and p-CREB activated by Aβ, which is the underlying molecular mechanism.ConclusionIn conclusion, these findings suggest that FTS as a RAS inhibitor could be a potential therapeutic agent for the treatment of AD.

Identification of miRNA and Their Regulatory Effects Induced by Total Flavonoids From Dracocephalum moldavica in the Treatment of Vascular Dementia

“…The primary biological processes in which the target genes of these selected aberrant miRNAs were involved included a variety of binding processes, including the binding of nucleotides and chromatin, cell differentiation, vascular events involving blood vessel development, muscle structure development, branching morphogenesis, and extensive regulation of receptor activity. The pathway enrichment analysis indicated the involvement of RAGE, Ras/MAPK, TNF, gonadotropin-releasing hormone (GnRH), and estrogen pathways, which are known as implicated in the pathogenesis of VaD ( Emanuele et al, 2005 ; Belkhelfa et al, 2018 ; Wang et al, 2019 ; Yang et al, 2020b ). Among these enriched pathways, the RAGE signaling pathway plays a role in inflammatory reactions through the proinflammatory cytokine overproduction mediated by the nuclear factor-κB (NF-κB), such as TNF-α ( Vicente Miranda and Outeiro, 2010 ), both in the blood-brain barrier (BBB) and in the glial responses.…”

Modulation of MAPK- and PI3/AKT-Dependent Autophagy Signaling by Stavudine (D4T) in PBMC of Alzheimer’s Disease Patients

“…Notably, in this model, D4T did not have any effect on Aβ phagocytosis, but it stimulated autophagy-mediated Aβ-clearing [ 19 ], as witnessed by its ability to modulate ERK1/2 and AKT phosphorylation (p-ERK, p-AKT) and to upregulate LAMP-2A and phospho-p70-S6K, their downstream targets. Given that: (1) autophagy is necessary for the degradation of Aβ in microglia, (2) p-AKT [ 20 ] and p-ERK [ 21 ] associate with Aβ-accumulation and tau phosphorylation in AD animal models [ 22 , 23 ], and (3) autophagy is modulated by D4T [ 19 ], we aimed to explore in more detail the mechanisms responsible for the D4T-mediated autophagy clearing of Aβ. For this aim, we tested D4T involvement in NLRP3 assembly and activation and its possible effect on autophagy molecular signaling in peripheral blood mononuclear cells from AD patients.…”

Vitamin D protects against necrotising enterocolitis in newborn mice by activating the ERK signalling pathway

“…erK1/2 is a member of the mitogen-activated protein kinase family of proteins, the members of which transmit regulatory signals involved in cell proliferation, apoptosis or differentiation (11)(12)(13)(14). Bai et al (15) reported that sesamin enhances nadH-dependent flavin reductase subunit 2-mediated defence against oxidative stress and inflammation in ulcerative colitis by activating AKT/erK.…”