σ2 receptor and its role in cancer with focus on a multitarget directed ligand (Mtdl) approach

Sigma-2 (σ2) is an endoplasmic receptor identified as the Endoplasmic Reticulum (ER) transmembrane protein TMEM97. Despite its controversial identity, which was only recently solved, this protein has gained scientific interest because of its role in the proliferative status of cells; many tumor cells from different organs overexpress the σ2 receptor, and many σ2 ligands display cytotoxic actions in (resistant) cancer cells. These properties have shed light on the σ2 receptor as a potential druggable target to be bound/activated for the diagnosis or therapy of tumors. Additionally, diverse groups have shown how the σ2 receptor can be exploited for the targeted delivery of the anticancer drugs to tumors. As the cancer disease is a multifactorial pathology with multiple cell populations, a polypharmacological approach is very often needed. Instead of the simultaneous administration of different classes of drugs, the use of one molecule that interacts with diverse pharmacological targets, namely MultiTarget Directed Ligand (MTDL), is a promising and currently pursued strategy, that may overcome the pharmacokinetic problems associated with the administration of multiple molecules. This review aims to point out the progress regarding the σ2 ligands in the oncology field, with a focus on MTDLs directed towards σ2 receptors as promising weapons against (resistant) cancer diseases

Multi‐target directed ligands (Mtdls) binding the σ1 receptor as promising therapeutics: State of the art and perspectives

The sigma‐1 (σ1) receptor is a ‘pluripotent chaperone’ protein mainly expressed at the mitochondria–endoplasmic reticulum membrane interfaces where it interacts with several client proteins. This feature renders the σ1 receptor an ideal target for the development of multifunctional ligands, whose benefits are now recognized because several pathologies are multifactorial. Indeed, the current therapeutic regimens are based on the administration of different classes of drugs in order to counteract the diverse unbalanced physiological pathways associated with the pathology. Thus, the multi‐targeted directed ligand (MTDL) approach, with one molecule that exerts polypharmacological actions, may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. This review aims to point out the progress in the development of MTDLs directed toward σ1 receptors for the treatment of central nervous system (CNS) and cancer diseases, with a focus on the perspectives that are proper for this strategy. The evidence that some drugs in clinical use unintentionally bind the σ1 protein (as off‐target) provides a proof of concept of the potential of this strategy, and it strongly supports the promise that the σ1 receptor holds as a target to be hit in the context of MTDLs for the therapy of multifactorial pathologies

Multifunctional thiosemicarbazones targeting sigma receptors: in vitro and in vivo antitumor activities in pancreatic cancer models

Purpose: Association of the metal chelating portion of thiosemicarbazone with the cytotoxic activity of sigma-2 receptors appears a promising strategy for the treatment of pancreatic tumors. Here, we developed a novel sigma-2 receptor targeting thiosemicarbazone (FA4) that incorporates a moiety associated with lysosome destabilization and ROS increase in order to design more efficient antitumor agents. Methods: The density of sigma receptors in pancreatic cancer cells was evaluated by flow cytometry. In these cells, cytotoxicity (MTT assay) and activation of ER- and mitochondria-dependent cell death pathways (mRNA expression of GRP78, ATF6, IRE1, PERK; ROS levels by MitoSOX and DCFDA-AM; JC-1 staining) induced by the thiosemicarbazones FA4, MLP44, PS3 and ACthio-1, were evaluated. The expression of autophagic proteins (ATG5, ATG7, ATG12, beclin, p62 and LC3-I) was also studied. In addition, the in vivo effect of FA4 in xenograft models with and without gemcitabine challenge was investigated. Results: We found that FA4 exerted a more potent cytotoxicity than previously studied thiosemicarbazones (MLP44, PS3 and ACthio-1), which were found to display variable effects on the ER or the mitochondria-dependent pro-apoptotic axis. By contrast, FA4 activated pro-apoptotic pathways and decreased autophagy, except in MiaPaCa2 cells, in which autophagic proteins were expressed at lower levels and remained unmodified by FA4. FA4 treatment of PANC-1 xenografted mouse models, poorly responsive to conventional chemotherapy, significantly reduced tumor volumes and increased intratumor apoptosis compared to gemcitabine, with no signs of toxicity. Conclusions: Our data indicate that FA4 exhibits encouraging activity in pancreatic cancer cells unresponsive to gemcitabine. These results warrant further investigation in patient-derived pancreatic cancers, and hold promise for the development of therapies that can more efficiently target the specific characteristics of individual tumor types

MEG/EEG Group Analysis With Brainstorm

Brainstorm is a free, open-source Matlab and Java application for multimodal electrophysiology data analytics and source imaging [primarily MEG, EEG and depth recordings, and integration with MRI and functional near infrared spectroscopy (fNIRS)]. We also provide a free, platform-independent executable version to users without a commercial Matlab license. Brainstorm has a rich and intuitive graphical user interface, which facilitates learning and augments productivity for a wider range of neuroscience users with little or no knowledge of scientific coding and scripting. Yet, it can also be used as a powerful scripting tool for reproducible and shareable batch processing of (large) data volumes. This article describes these Brainstorm interactive and scripted features via illustration through the complete analysis of group data from 16 participants in a MEG vision study

New Pharmacological Strategies against Pancreatic Adenocarcinoma: The Multifunctional Thiosemicarbazone FA4

A new sigma-2 (σ2) receptor ligand (FA4) was efficiently synthesized and evaluated for cytotoxic, proapoptotic, and antimigratory activity on pancreatic ductal adenocarcinoma (PDAC) primary cell cultures, which restrained the aggressive and chemoresistant behavior of PDAC. This compound showed relevant antiproliferative activity with half maximal inhibitory concentration (IC50) values ranging from 0.701 to 0.825 µM. The cytotoxic activity was associated with induction of apoptosis, resulting in apoptotic indexes higher than those observed after exposure to a clinically relevant concentration of the gemcitabine, the first-line drug used against PDAC. Interestingly, FA4 was also able to significantly inhibit the migration rate of both PDAC-1 and PDAC-2 cells in the scratch wound-healing assay. In conclusion, our results support further studies to improve the library of thiosemicarbazones targeting the σ-2 receptor for a deeper understanding of the relationship between the biological activity of these compounds and the development of more efficient anticancer compounds against PDAC

Evaluating the effect of aging on interference resolution with time-varying complex networks analysis

In this study we used graph theory analysis to investigate age-related reorganization of functional networks during the active maintenance of information that is interrupted by external interference. Additionally, we sought to investigate network differences before and after averaging network parameters between both maintenance and interference windows. We compared young and older adults by measuring their magnetoencephalographic recordings during an interference-based working memory task restricted to successful recognitions. Data analysis focused on the topology/temporal evolution of functional networks during both the maintenance and interference windows. We observed that: (a) Older adults require higher synchronization between cortical brain sites in order to achieve a successful recognition, (b) The main differences between age groups arise during the interference window, (c) Older adults show reduced ability to reorganize network topology when interference is introduced, and (d) Averaging network parameters leads to a loss of sensitivity to detect age differencesThis work has been supported by the Spanish MINECO under project [FIS2013-41057], as well as Fundación Carolina Doctoral Scholarship Program and Colciencias Doctoral Program 56

Evaluating the effect of aging on interference resolution with time-varying complex networks analysis

In this study we used graph theory analysis to investigate age-related reorganization of functional networks during the active maintenance of information that is interrupted by external interference. Additionally, we sought to investigate network differences before and after averaging network parameters between both maintenance and interference windows. We compared young and older adults by measuring their magnetoencephalographic recordings during an interference-based working memory task restricted to successful recognitions. Data analysis focused on the topology/temporal evolution of functional networks during both the maintenance and interference windows. We observed that: (a) Older adults require higher synchronization between cortical brain sites in order to achieve a successful recognition, (b) The main differences between age groups arise during the interference window, (c) Older adults show reduced ability to reorganize network topology when interference is introduced, and (d) Averaging network parameters leads to a loss of sensitivity to detect age differencesThis work has been supported by the Spanish MINECO under project [FIS2013-41057], as well as Fundación Carolina Doctoral Scholarship Program and Colciencias Doctoral Program 56

Acetylome in Human Fibroblasts From Parkinson's Disease Patients

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder. The pathogenesis of this disease is associated with gene and environmental factors. Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent genetic cause of familial and sporadic PD. Moreover, posttranslational modifications, including protein acetylation, are involved in the molecular mechanism of PD. Acetylation of lysine proteins is a dynamic process that is modulated in PD. In this descriptive study, we characterized the acetylated proteins and peptides in primary fibroblasts from idiopathic PD (IPD) and genetic PD harboring G2019S or R1441G LRRK2 mutations. Identified acetylated peptides are modulated between individuals' groups. Although acetylated nuclear proteins are the most represented in cells, they are hypoacetylated in IPD. Results display that the level of hyperacetylated and hypoacetylated peptides are, respectively, enhanced in genetic PD and in IPD cells