Influence of FOX genes on aging and aging-associated diseases. Elena Tschumak
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Название: Influence of FOX genes on aging and aging-associated diseases

Автор: Elena Tschumak

Издательство: Bookwire

Жанр: Медицина

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isbn: 9783754131572

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СКАЧАТЬ a vitamin A deficiency also showed poor motor performance when they learned new movements. (Carta et al., 2006) In addition vitamin deficit had a negative impact on striatal development. Striatal progenitor cells could not differentiate without RA signals (Krezel et al., 1998), (Chatzi et al.,2011). Acute RA-level reduction in mice led to impaired induction in synaptic grading and impairment of hippocampal LTP and LTD, which was, however, reversible. Normal synaptic plasticity was quickly restored in this phenotype with the help of vitamin A supplementation. (Misner et al., 2001)

      According to Boccardi et al. „Beta-carotene, telomerase activity and Alzheimer's disease in old age subjects“, 2019 β-carotene significantly and positively correlated with telomerase activity, independent of gender, Β-carotene plasma level was associated with AD diagnosis and

      β-carotene may modulate telomerase activity in old age. Moreover, lower plasma β-carotene levels, correlating with peripheral telomerase activity, are associated with AD diagnosis independent of multiple covariates. This way FOXP2 genes can have a further effect on aging and tumorigenesis.

      According to Devanna et al. (2014) „FOXP2 drives neuronal differentiation by interacting with retinoic acid signalling pathways“ FOXP2 reduces the expression of DDL3 and RARβ (retinoic acid receptor). The CARET study showed that high-dose beta-carotene (a precursor of retinoic acid (vitamin A) for an extended period was suspect to cause by 18 percent smokers lung cancer and it is known that FoxP2 is high expressed in lungs (Li, et al., 2004; Zhou et al., 2008;Groszer et al., 2008). FoxP2-coexpression with the transcription factor homeodomain Nkx2.1 in the lung was described by Li et (2012) FoxP2 interaction with the CtBP1 co-repressor may be involved in tumor suppression of breast cancer. CtBp interacts with the oncofactor BRCA1 / 2 (Chinnadurai G., 2009) (Deng et al. 2012) It would be of great interest to investigate whether the pathogenic vitamin A effect in this case is due to the interactions with FOXP2 which play a role in many oncological processes.

       CDH4

      According to Liu et al., 2012 total cerebral brain volume depends on CDH4-level, involved also in AD.These findings suggest that Dicer1 may be a target in AD therapy.

       DICER1

      Yan et al. (2019) explained that Dicer1 is reduced in APPswe/PSEN1dE9 mice and is regulated by Nrf2 and Brain Dicer1 is down-regulated in a mouse model of Alzheimer’s disease via Aβ42-induced repression of nuclear factor erythroid 2-related factor 2. The researchers studied unexploited roles of Dicer1 in AD and a novel way of Dicer1 regulation. Their results make hope that Dicer1 may be a target in AD therapy.

       TARBP2

      

      According to Haroon et al., 2016 „A designed recombinant fusion protein for targeted delivery of siRNA to the mouse brain“TARBP2 Binding Protein fused to a brain targeting peptide that binds to monosialoganglioside GM1. “Conformation-specific binding of TARBP2 domain to siRNA led to the formation of homogenous serum-stable complex with targeting potential. Further, uptake of the complex in Neuro-2a, IMR32 and HepG2 cells analysed by confocal microscopy and fluorescence activated cell sorting, revealed selective requirement of GM1 for entry. Remarkably, systemic delivery of the fluorescently labelled complex (TARBP-BTP:siRNA) in ΑβPP-PS1 mouse model of Alzheimer's disease (AD) led to distinctive localization in the cerebral hemisphere. Further, the delivery of siRNA mediated by TARBP-BTP led to significant knockdown of BACE1 in the brain, in both ΑβPP-PS1 mice and wild type C57BL/6. The study establishes the growing importance of fusion proteins in delivering therapeutic siRNA to brain tissues.” (Haroon et al., 2016, p. 1)

       PIK3K

      Gabbouj et al. (2019) describe in „Altered Insulin Signaling in Alzheimer's Disease Brain - Special Emphasis on PI3K-Akt Pathway“ the PI3K-Akt signalling pathway, involved in microglia and astrocytes, as an important player in T2D pathogenesis and insulin mediation. Decreased levels of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) subunits and decreased Akt kinase phosphorylation is associated with AD, amyloid-β and tau pathologies. TWD intake leads to altered PI3K subunits-levels and of intranasal insulin to enhancement of PI3K-Akt signalling, improved memory in human trials.

      

       PIM1

      

      PRAS40 phosphorylation is regulated by Pim1 Velazquez et al. (2016) gave a strong evidence for interconnection between the mammalian target of rapamycin (mTOR), proline-rich AKT substrate, PRAS40-phosphorylation-levels and Aβ, tau pathologies and cognitive deficits.

       BACE1

      

      Das, B. and Yan, R. (2017) described in „Role of BACE1 in Alzheimer's synaptic function“ that Aβ is generated from amyloid precursor protein (APP) via proteolytic cleavage by β-site APP cleaving enzyme 1 (BACE1) and BACE1 inhibition reduces Aβ-level in humans. BACE1 inhibitors could be an effective AD remedy.

      

       NFE2L2

      

      Otter et al. (2010) illustrated in „Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer's disease and age-related cataract“ how one haplotype allele of NFE2L2 gene, encoding the main regulators of the defence system against oxidative stress, age-related cataract and AD, Nrf2-protein, was associated with 2 years earlier age at AD onset and 4 years earlier age at surgery for posterior subcapsular cataract.

      

      

      According to Joshi and Johnson (2012)“The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases“ neurodegenerative relevant NF-E2 related factor-overexpression has a positive impact on Amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson. A cis-acting antioxidant response element regulates phase II detoxification enzymes via ARE-Nrf2 binding with the help of Keap1, a culin 3-based E3 ligase that targets Nrf2 for degradation, sequesters Nrf2 in cytoplasm. Disruption of Keap1-Nrf2 interaction or genetic overexpression of Nrf2 has a positive effect on oxidative stress.

      Pajares et al. (2016) identified in „Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes“ the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) as a regulator of autophagy gene expression and its relevance to amyloid β precursor protein, MAPT/TAU and AD. According to ENCODE for BACH1 and MAFK, that bind the NFE2L2-regulated enhancer ARE, 27 putative AREs in 16 autophagy-related genes were identified and twelve of these sequences were validated as NFE2L2 regulated AREs in 9 autophagy genes after NFE2L2 activation with sulforaphane.

      Saad El-Din et al. (2020) describe in „Active form of vitamin D analogue mitigates neurodegenerative changes in Alzheimer's disease in rats by targeting Keap1/Nrf2 and MAPK-38p/ERK signaling pathways“ the Nrf2 as a promising target for the prevention of Alzheimer's disease and vitamin D, its analogue, Maxacalcitol as crucial for improving AD cognitive functions via Keap1-Nrf2 signalling pathway.

      Rojo et al. (2017) also confirmed in „NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology“ СКАЧАТЬ