Data_Sheet_1_How Is the Norepinephrine System Involved in the Antiepileptic Effects of Vagus Nerve Stimulation?.pdf

Vagus Nerve Stimulation (VNS) is an adjunctive treatment for patients suffering from inoperable drug-resistant epilepsy. Although a complete understanding of the mediators involved in the antiepileptic effects of VNS and their complex interactions is lacking, VNS is known to trigger the release of neurotransmitters that have seizure-suppressing effects. In particular, norepinephrine (NE) is a neurotransmitter that has been associated with the clinical effects of VNS by preventing seizure development and by inducing long-term plastic changes that could restore a normal function of the brain circuitry. However, the biological requisites to become responder to VNS are still unknown. In this review, we report evidence of the critical involvement of NE in the antiepileptic effects of VNS in rodents and humans. Moreover, we emphasize the hypothesis that the functional integrity of the noradrenergic system could be a determining factor to obtain clinical benefits from the therapy. Finally, encouraging avenues of research involving NE in VNS treatment are discussed. These could lead to the personalization of the stimulation parameters to maximize the antiepileptic effects and potentially improve the response rate to the therapy.</p

<i>Pmr-1</i> gene affects susceptibility of <i>Caenorhabditis elegans</i> to <i>Staphylococcus aureus</i> infection through glycosylation and stress response pathways' alterations

Calcium signaling can elicit different pathways involved in an extreme variety of biological processes. Calcium levels must be tightly regulated in a spatial and temporal manner in order to be efficiently and properly utilized in the host physiology. The Ca2+-ATPase, encoded by pmr-1 gene, was first identified in yeast and localized to the Golgi and it appears to be involved in calcium homeostasis. PMR-1 function is evolutionary conserved from yeast to human, where mutations in the orthologous gene ATP2C1 cause Hailey-Hailey disease. In this work, we used the Caenorhabditis elegans model system to gain insight into the downstream response elicited by the loss of pmr-1 gene. We found that pmr-1 knocked down animals not only showed defects in the oligosaccharide structure of glycoproteins at the cell surface but also were characterized by reduced susceptibility to bacterial infection. Although increased resistance to the infection might be related to lack of regular recognition of C. elegans surface glycoproteins by microbial agents, we provide genetic evidence that pmr-1 interfered nematodes mounted a stronger innate immune response to Gram-positive bacterial infection. Thus, our observations indicate pmr-1 as a candidate gene implicated in mediating the worm’s innate immune response.</p

Additional file 2 of CRISPR/Cas9-mediated deletion of Interleukin-30 suppresses IGF1 and CXCL5 and boosts SOCS3 reducing prostate cancer growth and mortality

Additional file 2. Supplemental Figure 1 (Neutralization of IGF1 by Human IGF-1 antibody) and 2 (A.B. Cytofluorimetric analyses of androgen receptor expression in human PC cells DU145 and PC3. C.D. Western blot analyses of STAT1 and STAT3 protein expression in IL30-DU145 and IL30-PC3 cells)

Sourcing the immune system to induce immunogenic cell death in Kras-colorectal cancer cells.

BACKGROUND: Current approaches aimed at inducing immunogenic cell death (ICD) to incite an immune response against cancer neoantigens are based on the use of chemotherapeutics and other agents. Results are hampered by issues of efficacy, combinatorial approaches, dosing and toxicity. Here, we adopted a strategy based on the use of an immunomolecule that overcomes pharmachemical limitations. METHODS: Cytofluorometry, electron microscopy, RT-PCR, western blotting, apotome immunofluorescence, MLR and xenografts. RESULTS: We report that an ICD process can be activated without the use of pharmacological compounds. We show that in Kras-mut/TP53-mut colorectal cancer cells the 15 kDa βGBP cytokine, a T cell effector with onco-suppressor properties and a potential role in cancer immunosurveillance, induces key canonical events required for ICD induction. We document ER stress, autophagy that extends from cancer cells to the corresponding xenograft tumours, CRT cell surface shifting, ATP release and evidence of dendritic cell activation, a process required for priming cytotoxic T cells into a specific anticancer immunogenic response. CONCLUSIONS: Our findings provide experimental evidence for a rationale to explore a strategy based on the use of an immunomolecule that as a single agent couples oncosuppression with the activation of procedures necessary for the induction of long term response to cancer

Additional file 1 of CRISPR/Cas9-mediated deletion of Interleukin-30 suppresses IGF1 and CXCL5 and boosts SOCS3 reducing prostate cancer growth and mortality

Additional file 1. Supplemental Methods and Table S1 (list of antibodies used in immunostaining)