Voltage-gated sodium (NaV) channels have been related with cell migration and invasiveness in human cancers. We previously reported the contribution of NaV1.6 channels activity with the invasion capacity of cervical cancer (CeCa) positive to Human Papilloma Virus type 16 (HPV16), which accounts for 50% of all CeCa cases. Here, we show that NaV1.6 gene (SCN8A) overexpression is a general characteristic of CeCa, regardless of the HPV type. In contrast, no differences were observed in NaV1.6 channel expression between samples of non-cancerous and cervical intraepithelial neoplasia. Additionally, we found that CeCa cell lines, C33A, SiHa, CaSki and HeLa, express mainly the splice variant of SCN8A that lacks exon 18, shown to encode for an intracellularly localized NaV1.6 channel, whereas the full-length adult form was present in CeCa biopsies. Correlatively, patch-clamp experiments showed no evidence of whole-cell sodium currents (INa) in CeCa cell lines. Heterologous expression of full-length NaV1.6 isoform in C33A cells produced INa, which were sufficient to significantly increase invasion capacity and matrix metalloproteinase type 2 (MMP-2) activity. These data suggest that upregulation of NaV1.6 channel expression occurs when cervical epithelium have been transformed into cancer cells, and that NaV1.6-mediated invasiveness of CeCa cells involves MMP-2 activity. Thus, our findings support the notion about using NaV channels as therapeutic targets against cancer metastasis.

Background: Most scorpion venom peptides adopt a single structural scaffold around four strictly conserved cysteines. Results: Two K ϩ channel-blocking peptides from Tityus venoms share this cysteine spacing but fold into a distinct cystine-

Edited by Maurice MontalScorpine-like peptides are two domain peptides found in different scorpion venoms displaying various antimicrobial, cytolytic, and potassium channelblocking activities. The relative contribution of each domain to their different activities remains to be elucidated. Here, we report the recombinant production, solution structure, and antiparasitic activity of Hge36, first identified as a naturally occurring truncated form of a Scorpine-like peptide from the venom of Hoffmannihadrurus gertschi. We also show that removing the first four residues from Hge36 renders a molecule with enhanced potassium channel-blocking and antiparasitic activities. Our results are important to rationalize the structure-function relationships of a pharmacologically versatile molecular scaffold.

The scorpion toxin tamapin displays the most potent and selective blockage against KCa2.2 channels known to date. In this work, we report the biosynthesis, three-dimensional structure, and cytotoxicity on cancer cell lines (Jurkat E6-1 and human mammary breast cancer MDA-MB-231) of recombinant tamapin and five related peptides bearing mutations on residues (R6A,R7A, R13A, R6A-R7A, and GS-tamapin) that were previously suggested to be important for tamapin's activity. The indicated cell lines were used as they constitutively express KCa2.2 channels. The studied toxin-like peptides displayed lethal responses on Jurkat T cells and breast cancer cells; their effect is dose- and time-dependent with IC50 values in the nanomolar range. The order of potency is r-tamapin>GS-tamapin>R6A>R13A>R6A-R7A>R7A for Jurkat T cells and r-tamapin>R7A for MDA-MB-231 breast cancer cells. Our structural determination by NMR demonstrated that r-tamapin preserves the folding of the αKTx5 subfamily and that neither single nor double alanine mutations affect the three-dimensional structure of the wild-type peptide. In contrast, our activity assays show that changes in cytotoxicity are related to the chemical nature of certain residues. Our results suggest that the toxic activity of r-tamapin on Jurkat and breast cancer cells could be mediated by the interaction of charged residues in tamapin with KCa2.2 channels via the apoptotic cell death pathway.

The brain is one of the most sensitive organs damaged during aging due to its susceptibility to the aging-related oxidative stress. Hence, in this study, the sensory nerve pathway integrity and the memory were evaluated and related to the redox state, the antioxidant enzymes function, and the protein oxidative damage in the brain cortex (Cx) and the hippocampus (Hc) of young (4-month-old) and old (24-month-old) male and female Wistar rats. Evoked potentials (EP) were performed for the auditory, visual, and somatosensory pathways. In both males and females, the old rat groups' latencies were larger in almost all waves when compared to the young same-sex animals. The novel object test was performed to evaluate memory. The superoxide dismutase and catalase antioxidant activity, as well as the protein oxidative damage, and the redox state were evaluated. Magnetic resonance (MR) imaging was used to obtain the diffusion tensor imaging, and the brain volume, while MR spectroscopy was used to obtain the brain metabolite concentrations (glutamine, glutamate, Myo-inositol, N-acetyl-aspartate, creatine) in the Cx and the Hc of young and old females. Our data suggest that, although there are limited variations regarding memory and nerve conduction velocity by sex, the differences concerning the redox status might be important to explain the dissimilar reactions during brain aging between males and females. Moreover, the increment in Myo-inositol levels in the Hc of old rats