Contact (kallikrein/kinin) system activation in whole human blood induced by low concentrations of α-Fe2O3 nanoparticles

Iron-oxide nanoparticles (NPs) generated by environmental events are likely to represent health problems. α-Fe₂O₃ NPs were synthesized, characterized and tested in a model for toxicity utilizing human whole blood without added anticoagulant. MALDI-TOF of the corona was performed and activation markers for plasma cascade systems (complement, contact and coagulation systems), platelet consumption and release of growth factors, MPO, and chemokine/cytokines from blood cells were analyzed. The coronas formed on the pristine α-Fe₂O₃ NPs contained contact system proteins and they induced massive activation of the contact (kinin/kallikrein) system, as well as thrombin generation, platelet activation, and release of two pro-angiogeneic growth factors: platelet-derived growth factor and vascular endothelial growth factor, whereas complement activation was unaffected. The α-Fe₂O₃ NPs exhibited a noticeable toxicity, with kinin/kallikrein activation, which may be associated with hypotension and long-term angiogenesis in vivo, with implications for cancer, arteriosclerosis and pulmonary disease.     

Extracellular vesicles or free circulating DNA: where to search for BRAF and cKIT mutations?

Clinical evidence in oncology argues for the advantages of performing molecular analysis of blood biomarkers to provide information about systemic changes and tumor heterogeneity.Whereas the diagnostic value of cell-free circulating DNA (fcDNA) has successfully been demonstrated in several studies, DNA enclosed in extracellular vesicles (EV) has only recently been described, and its potential diagnostic value is unclear. We established a protocol for separation of EV and fc fractions and tested for presence of mutant BRAFV600E mediating resistance to Vemurafenib and cKITD816V mediating resistance to Imatinib in blood of patients with melanoma and mastocytosis. Our results show that EV contain significantly higher amounts of total DNA as compared to the fc fraction. However, about ten-fold higher copy numbers of the wild type and mutant BRAF and cKIT were detected in the fcDNA fraction supporting its diagnostic value and pointing to differences in fc and EV DNA content.     

Nephrotoxicity and Kidney Transport Assessment on 3D Perfused Proximal Tubules

Proximal tubules in the kidney play a crucial role in reabsorbing and eliminating substrates from the body into the urine, leading to high local concentrations of xenobiotics. This makes the proximal tubule a major target for drug toxicity that needs to be evaluated during the drug development process. Here, we describe an advanced in vitro model consisting of fully polarized renal proximal tubular epithelial cells cultured in a microfluidic system. Up to 40 leak-tight tubules were cultured on this platform that provides access to the basolateral as well as the apical side of the epithelial cells. Exposure to the nephrotoxicant cisplatin caused a dose-dependent disruption of the epithelial barrier, a decrease in viability, an increase in effluent LDH activity, and changes in expression of tight-junction marker zona-occludence 1, actin, and DNA-damage marker H2A.X, as detected by immunostaining. Activity and inhibition of the efflux pumps P-glycoprotein (P-gp) and multidrug resistance protein (MRP) were demonstrated using fluorescence-based transporter assays. In addition, the transepithelial transport function from the basolateral to the apical side of the proximal tubule was studied. The apparent permeability of the fluorescent P-gp substrate rhodamine 123 was decreased by 35% by co-incubation with cyclosporin A. Furthermore, the activity of the glucose transporter SGLT2 was demonstrated using the fluorescent glucose analog 6-NBDG which was sensitive to inhibition by phlorizin. Our results demonstrate that we developed a functional 3D perfused proximal tubule model with advanced renal epithelial characteristics that can be used for drug screening studies.     

Acaricidal activities of essential oils against two-spotted spider mite,Tetranychus urticae Koch

Eleven essential oils (EOs) were screened for their fumigant and repellent activity against two-spotted spider mite, Tetranychus urticae Koch (Acarina: Tetranychidae) under laboratory conditions. Results showed that, in fumigant toxicity assay, Mentha longifolia L. showed more toxic to T. urticae (LC₅₀?=?11.08?mg?L^?1 air) and was followed by Mentha piperita L. (LC₅₀?=?15.86?mg?L^?1 air), Cymbopogon flexuosus (Nees ex Steud.) W. Watson (LC₅₀?=?17.23?mg?L^?1 air) and Chrysopogon zizanioides (L.) (LC₅₀?=?18.82?mg L^?1 air). In repellent activity test, Acorus calamus (L.), M. piperita and C. flexuosus showed 100% repellent activity to T. urticae as compared to Cedrus deodara (Roxb.) and Aegle marmelos (L.) (76.67%).     

Identifying viable theoretical frameworks with essential parameters for real-time and real world alcohol craving research: a systematic review of craving models

Background: Substance use is known to be episodic, dynamic, complex, and highly influenced by the environment, therefore a situational and momentary focus to alcohol craving research is appropriate. Current advances in mobile and wearable technology provide novel opportunities for craving research. However, the lack of consensus within craving theory impedes the identification and prioritization of parameters to be monitored. The aim of this study is to critically review current craving models in order to determine viable theoretical frameworks of alcohol craving and its essential parameters.

Methods: Eighteen models of craving were reviewed by applying a literature search with a five-step strategy that accounted for the momentary nature of craving and included a snowballing search and a key term extraction algorithm. Based on this review, multiple decision criteria were defined upon which to evaluate the models.

Results: Six models for alcohol craving were supported by sufficient empirical research to be eligible. The inferences drawn on these six models resulted in three decision criteria: the model should (1) incorporate negative affect as a predictor of relapse; (2) explain that dependent drinkers have a higher attentional bias towards alcohol cues than nondependent drinkers; (3) incorporate increased risk of relapse with heightened stress levels.

Conclusions: The affective processing model of negative reinforcement, the cognitive processing model, the incentive sensitization theory of addiction and the theory of neural opponent motivation are classified as viable theoretical frameworks, resulting in negative affect and stress as relevant parameters to include in real-time craving monitoring research.     

The emerging role of stimulator of interferons genes signaling in sepsis: Inflammation,autophagy, and cell death

Stimulator of interferons genes (STING) is an adaptor protein that plays a critical role in the secretion of type I interferons and pro‐inflammatory cytokines in response to cytosolic nucleic acid. Recent research indicates the involvement of the STING pathway in uncontrolled inflammation, sepsis, and shock. STING signaling is significantly up‐regulated in human sepsis, and STING agonists are suggested to contribute to the pathogenesis of sepsis and shock. Nevertheless, little is known about the consequences of activated STING‐mediated signaling during sepsis. It has been shown that aberrant activation of the STING‐dependent way can result in increased inflammation, type I interferons responses, and cell death (including apoptosis, necroptosis, and pyroptosis). In addition, autophagy modulation has been demonstrated to protect against multiple organs injuries in animal sepsis model. However, impaired autophagy may contribute to the aberrant activation of STING signaling, leading to uncontrolled inflammation and cell death. Here we present a comprehensive review of recent advances in the understanding of STING signaling, focusing on the regulatory mechanisms and the roles of this pathway in sepsis.