Repurposing the Antiplatelet Agent Ticlopidine to Counteract the Acute Phase of ER Stress Condition: An Opportunity for Fighting Coronavirus Infections and Cancer

Different pathological conditions, including viral infections and cancer, can have a massive impact on the endoplasmic reticulum (ER), causing severe damage to the cell and exacerbating the disease. In particular, coronavirus infections, including SARS coronavirus-2 (SARS-CoV-2), responsible for COVID-19, cause ER stress as a consequence of the enormous amounts of viral glycoproteins synthesized, the perturbation of ER homeostasis and the modification of ER membranes. Therefore, ER has a central role in the viral life cycle, thus representing one of the Achilles’ heels on which to focus therapeutic intervention. On the other hand, prolonged ER stress has been demonstrated to promote many pro-tumoral attributes in cancer cells, having a key role in tumor growth, metastasis and response to therapies. In this report, adopting a repurposing approach of approved drugs, we identified the antiplatelet agent ticlopidine as an interferent of the unfolded protein response (UPR) via sigma receptors (SRs) modulation. The promising results obtained suggest the potential use of ticlopidine to counteract ER stress induced by viral infections, such as COVID-19, and cancer.     

The importance of centralities in dark network value chains

This paper introduces three novel centrality measures based on the nodes’ role in the operation of a joint task, i.e., their position in a criminal network value chain. For this, we consider networks where nodes have attributes describing their “capabilities” or “colors”, i.e., the possible roles they may play in a value chain. A value chain here is understood as a series of tasks to be performed in a specific order, each requiring a specific capability. The first centrality notion measures how many value chain instances a given node participates in. The other two assess the costs of replacing a node in the value chain in case the given node is no longer available to perform the task. The first of them considers the direct distance (shortest path length) between the node in question and its nearest replacement, while the second evaluates the actual replacement process, assuming that preceding and following nodes in the network should each be able to find and contact the replacement. In this report, we demonstrate the properties of the new centrality measures using a few toy examples and compare them to classic centralities, such as betweenness, closeness and degree centrality. We also apply the new measures to randomly colored empirical networks. We find that the newly introduced centralities differ sufficiently from the classic measures, pointing towards different aspects of the network. Our results also pinpoint the difference between having a replacement node in the network and being able to find one. This is the reason why “introduction distance” often has a noticeable correlation with betweenness. Our studies show that projecting value chains over networks may significantly alter the nodes’ perceived importance. These insights might have important implications for the way law enforcement or intelligence agencies look at the effectiveness of dark network disruption strategies over time.     

Electrochemical Studies of an Iron Porphyrin Immobilized on Nb2O5/SiO2 and Its Application for Simultaneous Determination of Dopamine and Ascorbic Acid Using Multivariate Calibration Methodology

This paper shows an application of a first generation porphyrin, FeTPPCl 5,10,25,20‐tetraphenylporphyrin iron(III) chloride (FeTPPCl or FeTPP⁺) immobilized on a inorganic matrix, SiO₂/Nb₂O₅ (niobium oxide grafted on silica gel surface, designated as SiNb) to the preparation of a carbon paste electrode (CPE). The carbon paste modified with a FeTPP⁺ immobilized on SiO₂/Nb₂O₅ (SiNb), designated as CPE/SiNb/FeTPP, was applied for simultaneous electrochemical determination of dopamine (DA) and ascorbic acid (AA). Because of the overlapping of the voltammetric peaks of DA and AA, the multivariate calibration methodology based on partial least square regression (PLSR) was proposed. The data pre‐treatment used in this process was mean centering and to choose the principal components number a cross validation procedure was used (leave‐one‐out). Five principal components were necessary to obtain the lowest PRESS (prediction residual error sum of squares). The statistics showed that this model explains approximately 95.2% of the variance from the data set. Using this model, high correlation between actual and predicted concentrations was observed, mainly for higher dopamine (maximum relative error of 8%) and ascorbic acid (maximum relative error of 10%) concentrations. For low analytes concentrations the relative error increases to 35% for AA. Considering the similarity of the voltammetric response of the analytes, the results obtained were satisfactory and showed the promissory capability of the CPE/SiNb/FeTPP coupled multivariate calibration methods for simultaneous voltammetric analysis of DA and AA.     

Effect of DODAB Nano-Sized Cationic Bilayer Fragments against Leishmania amazonensis

The dioctadecyldimethylammonium bromide (DODAB) is a double-chained cationic lipid with potent bactericide and fungistatic activities; however, its toxicity on protozoan parasites is still unknown. Here, we show the antileishmanial activity of DODAB nano-sized cationic bilayer fragments on stationary-phase promastigotes and amastigotes of Leishmania amazonensis, the causative agent of cutaneous leishmaniasis. Upon treatment with DODAB, we analyzed the parasite surface zeta-potential, parasite viability, cellular structural modifications, and intracellular proliferation. The DODAB cytotoxic effect was dose-dependent, with a median effective concentration (EC₅₀) of 25 µM for both life-cycle stages, comparable to the reported data for bacteria and fungi. The treatment with DODAB changed the membrane zeta-potential from negative to positive, compromised the parasite’s morphology, affected the cell size regulation, caused a loss of intracellular organelles, and probably dysregulated the plasma membrane permeability without membrane disruption. Moreover, the parasites that survived after treatment induced small parasitophorous vacuoles and failed to proliferate inside macrophages. In conclusion, DODAB displayed antileishmanial activity, and it remains to be elucidated how DODAB acts on the protozoan membrane. Understanding this mechanism can provide insights into the development of new parasite-control strategies.     

Chemical Compounds and Biologic Activities: A Review of Cedrela Genus

The genus Cedrela P. Browne, which belongs to the Meliaceae family, has eighteen species. Trees of this genus are of economic interest due to wood quality, as well as being the focus of studies because of relevant biologic activities as in other Meliaceae species. These activities are mainly related to limonoids, a characteristic class of compounds in this family. Therefore, the aim of this review is to perform a survey of the citations in the literature on the Cedrela genus species. Articles were found on quantitative and qualitative phytochemical studies of the Cedrela species, revealing the chemical compounds identified, such as aliphatics acid and alcohol, flavonoids, tocopherol, monoterpenes, sesquiterpenes, triterpenes, cycloartanes, steroids, and limonoids. Although some activities were tested, the majority of studies focused on the insecticidal, antifeedant, or insect growth inhibitor activities of this genus. Nonetheless, the most promising activities were related to their antimalarial and antitripanocidal effects, although further investigations are still needed.     

A local monotonicity formula for an inhomogenous singular perturbation problem and applications

In this paper we prove a local monotonicity formula for solutions to an inhomogeneous singularly perturbed diffusion problem of interest in combustion. This type of monotonicity formula has proved to be very useful for the study of the regularity of limits u of solutions of the singular perturbation problem and of ∂{u > 0}, in the global homogeneous case. As a consequence of this formula we prove that u has an asymptotic development at every point in ∂{u > 0} where there is a nonhorizontal tangent ball. These kind of developments have been essential for the proof of the regularity of ∂{u > 0} for Bernoulli and Stefan free boundary problems. We also present applications of our results to the study of the regularity of ∂{u > 0} in the stationary case including, in particular, its regularity in the case of energy minimizers. We present as well a regularity result for traveling waves of a combustion model that relies on our monotonicity formula and its consequences.The fact that our results hold for the inhomogeneous problem allows a very wide applicability. Indeed, they may be applied to problems with nonlocal diffusion and/or transport. The research of the authors was partially supported by Fundación Antorchas Project 13900-5, Universidad de Buenos Aires grant X052, ANPCyT PICT No 03-13719, CONICET PIP 5478. The authors are members of CONICET.