Bioinformatics analysis for genes encoding
Bioinformatics analysis for genes encoding proteins (ESR1, IL6, TERT, DNMT3B) showed that NF-kB is one of the transcription factors that might be regulating their expression, especially for IL6, TERT and DNMT3B genes. Previous studies have demonstrated that PA induces NF-kB activation, thus increasing cytokine expression (Z. Wang, Liu, Wang, Liu, Zhao, et al., 2012). For instance, NF-kB can be activated through several cellular receptors such as toll like receptors (TLRs) and CD36 (Rocha et al., 2016), which are involved in PA effects on astrocytes as well (Gupta et al., 2012). Conversely, NF-kB activation is attenuated by tibolone and estradiol under stress conditions (Hidalgo-Lanussa et al., 2018). NF-kB plays an important role on several mechanisms in the brain, such as inflammation, neuroprotection, myelination and synaptic function (Kaltschmidt and Kaltschmidt, 2009). This transcription factor has been postulated as an important therapeutic target, since it has been involved in several neurological diseases (Camandola and Mattson, 2007; Koo et al., 2010).
In summary, our results suggest that i) protection against PA in T98G Losmapimod by tibolone is in part mediated through the activation of ERβ and ii) tibolone has anti-inflammatory effects and can modulate pathways associated to DNA methylation and telomeric complex. However, future studies are necessary to elucidate the role of epigenetic mechanisms and telomere-associated proteins on tibolone actions. Altogether, it is hypothesized that, in T98G cells, estrogen receptor agonists and tibolone reduced cell death by preserving mitochondrial membrane potential in PA-treated cells. Moreover, these estrogenic compounds might reverse the augmented expression of TERT, IL6, DNMT3B and MIR155-5p upon PA by a possible inhibitory action on NF-kB signaling (Fig. 7).
Conflicts of interest
Acknowledgments YG-G is supported by a PhD fellowship from Centro de Estudios Interdisciplinarios Básicos y Aplicados CEIBA (Rodolfo Llinás Program). VE was supported by the Fondecyt 1150194. This study was supported by a research grant from COLCIENCIAS (Grant No. 824-2017).
Introduction What determines this difference in learning and memory between men and women? The answer is gonadal hormones. The primary female sex hormones – the estrogens – are steroids and thus they have a common basic structure derived from cholesterol. Their biosynthesis takes place in endocrine organs, especially the ovaries and the placenta, but also in the testes and the adrenal glands albeit to a lesser extent . Moreover a high synthesis rate of estrogens can be found in the adipose tissue and the brain. The fertility of both sexes is not the only effect of sexual steroids, although from an evolutionary aspect, fertility is of prime importance. Especially the female hormone estrogen (or even more the specific form 17β-estradiol (E2)) seems to be highly involved in creating gender specific differences in incidence of certain ailments: Women suffer more often from cystic fibrosis and have a poorer prognosis , there are influences on the occurrence of myocardial infarctions  and we also find influence on the brain and neuronal cells (reviewed in ). Premenopausal women suffer more often from depressions than men  but less often from neurodegenerative disorders like Parkinson’s  or Alzheimer’s disease . Although the effects of E2 seem to be crucial, we still don’t know how these effects are mediated. The focus of this review is the effect of E2 on neuronal cells and the possible mechanisms behind its effects. The impact of E2 on neuronal cells is overall a protective one. This is actually lost with the sudden decline in E2 level at menopause. 2006 a randomized and placebo-controlled study has been published, reporting that estrogen therapy selectively enhanced the prefrontal cognitive processes . Clearly, E2 has manifold effects in the brain, many of which impact on human health. To research the influence on neuronal cells NGF-treated PC12 cells have been shown to work as a very good model system. These pheochromocytoma -derived cells can be differentiated to cells that exert neuronal features .