Inhibition of HIF-1α through Suppression of NF-κB Activation by Compounds Isolated from Senecio graveolens

One of the characteristics of cancer is that the lack of oxygen in the cancer cells triggers changes in their gene expression. This hypoxia activates hypoxia-inducible factor 1-alpha and this in turn sets in motion the whole family of important angiogenic genes for the tumour. Hypoxia-inducible factor 1-alpha therefore increases the density and vascular permeability within the tumours, facilitating their rapid growth and, later, the metastasis. Senecio graveolens is a South American medicinal plant commonly used for mountain sickness (lack of adaptation of the organism to hypoxia). Additionally, pharmacological studies showed that its alcoholic extracts have cytotoxic properties. This research aimed to perform a guided phytochemical study of S. graveolens to identify compounds capable of inhibiting hypoxia-inducible factor 1-alpha through suppression of nuclear factor kappa-light-chain-enhancer of activated B cell activation. The isolation led to the characterisation of phanurane (1), damsine (2), and scoparone (3), first reported in the S. graveolens species. Phanurane (1) showed inhibitory activity of hypoxia-inducible factor 1-alpha on the cancer cell lines U-373 MG (IC50 = 20.66 ± 0.04 μM), A549 (IC50 =25.80 ± 0.04 μM), Hep G2 (IC50 =29.21 ± 0.03 μM), and Caco-2 (IC50 =38.58 ± 0.02 μM). Damsine (2) hypoxia-inducible factor 1-alpha displayed inhibitory activity of hypoxiainducible factor 1-alpha on the cancer cell lines U-373 MG (IC50 =2.29 ± 0.07 μM), A549 (IC50 =4.13 ± 0.04 μM), Hep G2 (IC50 =6.40 ± 0.03 μM), and Caco-2 (IC50 =9.80 ± 0.04 μM). Finally, scoparone (3) displayed inhibitory activity of y poxiainducible factor 1-alpha on the cancer cell lines U-373 MG (IC50 =15.22±0.01μM), A549 (IC50 =17.47±0.02μM), Hep G2 (IC50=18.26±0.06μM), and Caco-2 (IC50=19.75±0.04μM). In addition, phanurane (1) displayed inhibitory activity over nuclear factor kappa-light-chain-enhancer of activated B cells on cancer cell lines U-373 MG (IC50 =7.13 ± 0.03 μM), A549 (IC50 = 8.64 ± 0.03 μM), Hep G2 (IC50 = 8.87 ± 0.04 μM), and Caco-2 (IC50 =15.11 ± 0.01 μM). Likewise, damsine (2) showed inhibitory activity over nuclear factor kappa-light-chainenhancer of activated B cells on cancer cell lines U-373 MG (IC50 =2.28 ± 0.01 μM), A549 (IC50 =3.79 ± 0.02 μM), Hep G2 (IC50 = 3.98 ± 0.05 μM), and Caco-2 (IC50 = 6.41 ± 0.02 μM). Lastly, scoparone (3) displayed inhibitory activity of nuclear factor kappa-light-chain-enhancer of activated B cells on cancer cell lines U-373 MG (IC50 = 3.62 ± 0.06 μM), A549 (IC50 = 4.48 ± 0.03 μM), Hep G2 (IC50 = 5.25 ± 0.01 μM), and Caco-2 (IC50 =11.90 ± 0.02 μM). This study corroborates the cytotoxic activity of the isolated compounds through the inhibition of hypoxia-inducible factor 1-alpha as well as its modulator nuclear factor kappa-light-chain-enhancer of activated B cellsThis work was supported by the National Herbarium of Bolivia, the Fundación de la Universidad Autónoma de Madrid (FUAM

Synthesis and impact of neuroestradiol on hippocampal neuronal networks

The production of estradiol within the brain, that is, neuroestradiol (nE2), is widely documented. nE2 deeply impacts adult brain physiology and synaptic plasticity. In the hippocampus, a region of the brain essential for cognitive function, multiple cellular sources, and targets of nE2 have been identified. The impact of estradiol in excitatory and inhibitory neurotransmission suggests a role for regulated nE2 synthesis in the coordination of the activity of different cellular elements of hippocampal network. Here, we review the role of nE2 in the physiology of the hippocampal circuits taking into account the cellular heterogeneity of the hippocampus. We aspire at expanding the consideration of neuron-derived estradiol as a neuromodulator of hippocampal network activities underlying cognition