The interaction between silver nanoparticles and herpesviruses is attracting great interest due to their antiviral activity and possibility to use as microbicides for oral and anogenital herpes. In this work, we demonstrate that tannic acid modified silver nanoparticles sized 13 nm, 33 nm and 46 nm are capable of reducing HSV-2 infectivity both in vitro and in vivo. The antiviral activity of tannic acid modified silver nanoparticles was size-related, required direct interaction and blocked virus attachment, penetration and further spread. All tested tannic acid modified silver nanoparticles reduced both infection and inflammatory reaction in the mouse model of HSV-2 infection when used at infection or for a post-infection treatment. Smaller-sized nanoparticles induced production of cytokines and chemokines important for anti-viral response. The corresponding control buffers with tannic acid showed inferior antiviral effects in vitro and were ineffective in blocking in vivo infection. Our results show that tannic acid modified silver nanoparticles are good candidates for microbicides used in treatment of herpesvirus infections.
There is currently no standardised approach to arteriovenous malformation (AVM) reporting. Existing AVM classification systems focuses on angioarchitectural features and omit haemodynamic, anatomical and topological parameters intuitively used by therapists.
Apoptotic cell death is critical for maintaining integrity of the epithelia as well as for removal of the virus infected cells. We assessed the role of Fas/FasL-dependent pathway in apoptosis of genital epithelium during HSV-2 infection using a murine model of HSV-2 infection applied to C57BL6, MRL-Fas(lpr)/J (Fas-/-) and C3-Fasl(gld)/J (FasL-/-) mice and an in vitro model of HSV-2 infection in monocyte RAW 264.7 and keratinocyte 291.03C cell cultures and peritoneal macrophages. In contrast to keratinocyte in vitro cultures, HSV-2 infection of the monocytic cell cultures led to early induction of apoptosis. HSV-2 infection of peritoneal macrophages isolated from Fas- and FasL-deficient mice showed decreased activation of apoptosis, which could be further blocked by caspase-9 inhibitor. Infection of Fas and FasL-deficient mice increased the percentage of apoptotic cells and activation of caspase-9 in the vaginal tissue in comparison to C57BL6 wild type strain. Furthermore, Fas and FasL-deficient mice showed increased infiltration of neutrophiles in the vaginal mucosal epithelium at 3 and 7 day of infection in contrast to HSV-2 infected wild-type mice. Our results show that while the Fas/FasL pathway during HSV-2 infection of the vaginal epithelium plays an important role in controlling early local inflammatory response, mitochondrial apoptotic pathway also becomes activated by the inflammatory reaction.
Hydrolyzable tannins are known to exhibit diverse biological effects, which can be used in combination with silver nanoparticles (AgNPs). In this study, we tested toxic and inflammatory properties of tannic-acid modified 13, 33, 46 nm and unmodified 10-65 nm AgNPs using murine 291.03C keratinocyte and RAW 264.7 monocyte cell lines. Both cell lines exposed for 24h to 1-10 ?g/ml of 13 nm, 33 nm, 46 nm and unmodified AgNPs showed dose-dependent toxicity and decreased cell proliferation. Only small-sized AgNPs induced production of ROS by monocytes, but not keratinocytes. Monocytes internalized large aggregates of 33, 46 nm and 10-65 nm AgNPs in cytoplasmic vacuoles, whereas keratinocytes accumulated less particles. AgNPs of 13 nm were localized ubiquitously within both cell types. The tested AgNPs strongly down-regulated production of tumor necrosis factor-? (TNF-?) by monocytes, whereas keratinocytes exposed to AgNPs showed an opposite effect. Unmodified but not tannic acid-modified AgNPs increased production of the pro-inflammatory MCP-1 by monocytes and keratinocytes. In summary, low inflammatory potential and lack of ROS production by tannic-acid modified AgNPs sized above 30 nm suggests that tannic acid modification of large silver nanoparticles may help to increase AgNPs biosafety.
Monocytic cells represent important cellular elements of the innate and adaptive immune responses in viral infections. We assessed the role of Fas/FasL in promoting monocyte apoptosis during HSV-2 infection by using an in vitro model based on the murine RAW 264.7 monocytic cell line and an in vivo murine model of HSV-2 infection applied to C57BL6, MRL-Fas(lpr)/J (Fas-/-) and C3-Fasl(gld)/J (FasL-/-) mice. HSV-2 infection of the monocytic cell line led to early induction of apoptosis, with no protective expression of anti-apoptotic Bcl-2. HSV-2 infected monocytes up-regulated Fas and FasL expression early during in vitro infection but were susceptible to Fas induced apoptosis. The vaginal monocytes in the HSV-2 murine model of infection up-regulated FasL expression and were susceptible to Fas induced apoptosis. HSV-2 infection of Fas and FasL- deficient mice led to decreased apoptosis of monocytes and impaired recruitment of NK, CD4+ and CD8+ T cells within the infection sites. The vaginal lavages of HSV-2 infected Fas and FasL- deficient showed decreased production of CXCL9, CXCL10 and TNF-? in comparison to HSV-2 infected wild-type mice strain. The decreased recruitment of immune competent cells was accompanied by delayed virus clearance from the infected tissue. Triggering of the Fas receptor on HSV-2 infected monocytes in vitro up-regulated the expression of CXCL9 chemokines and the cytokine TNF-?. Our study provides novel insights on the role of Fas/FasL pathway not only in apoptosis of monocytes but also in regulating local immune response by monocytes during HSV-2 infection.
The objective of the study was to determine the effect of carbon nanoparticles produced by different methods on the growth of brain tumor and the development of blood vessels. Glioblastoma multiforme cells were cultured on the chorioallantoic membrane of chicken embryo and after 7 days of incubation, were treated with carbon nanoparticles administered in ovo to the tumor. Both types of nanoparticles significantly decreased tumor mass and volume, and vessel area. Quantitative real-time polymerase chain reaction analysis showed downregulated fibroblast growth factor-2 and vascular endothelial growth factor expression at the messenger ribonucleic acid level. The present results demonstrate antiangiogenic activity of carbon nanoparticles, making them potential factors for anticancer therapy.
The identification of salvageable brain tissue is a major challenge at stroke presentation. Standard techniques used in this context, such as the perfusion-diffusion mismatch, remain controversial. There is thus a need for new methods to help guide treatment. The potential role of pH imaging in this context is currently being investigated. Intracellular pH varies as a function of local perfusion, intracellular energy stores and time. Low pH triggers the production of free radicals and affects the calcium balance of the cells, which may lead to apoptosis and cell death. Thus, the characterization of pH dynamics may have predictive value for cell death after stroke, particularly when combined with novel imaging techniques. Therefore, we have extended an existing model of brain cellular metabolism to simulate the pH response of cells to ischaemia. Simulation results for conditions of reduced cerebral blood flow show good agreement for the evolution of intracellular pH with previously reported measurements and encourage the development of quantitative pH imaging to validate the predictive value of pH.
This paper presents a patient-derived model for the simulation of the hemodynamics of arteriovenous malformations of the brain (BAVM). This new approach is a step toward the simulation of the outcome of the embolization of the BAVM during treatment planning. More specifically, two aspects of the planning are pursued: simulation of the change of blood flow in the brain vasculature after the blocking of the malformation and simulation of the transport of the embolic liquid. The method we propose is tested on 3 BAVM cases of varying complexity. Twenty two out of 24 main BAVM flow paths have been identified well by simulation.
Treatment of arteriovenous malformations (AVMs) of the brain often requires the injection of a liquid embolic material to reduce blood flow through the malformation. The type of the liquid and the location of injection have to be carefully planned in a pre-operative manner. We introduce a new model of the interaction of liquid embolic materials with blood for the simulation of their propagation and solidification in the AVM. Solidification is mimicked by an increase of the materials viscosity. Propagation is modelled by using the concept of two-fluids modelling and that of scalar transport. The method is tested on digital phantoms and on one anatomically derived patient AVM case. Simulations showed that intuitive behaviour of the two-fluid system can be confirmed and that two types of glue propagation through the malformation can be reproduced. Distinction between the two types of propagation could be used to identify fistulous and plexiform compartments composing the AVM and to characterize the solidification of the embolic material in them.
The objective of the present investigation was to evaluate the morphologic characteristics of self-assemblies of diamond (nano-D), silver (nano-Ag), gold (nano-Au), and platinum (nano-Pt) nanoparticles with Staphylococcus aureus (bacteria) and Candida albicans (fungi), to determine the possibility of constructing microorganism-nanoparticle vehicles.
Stroke is a major cause of death and disability worldwide. Therapeutic hypothermia is a potentially useful neuroprotective treatment. A mathematical model of brain metabolism during stroke is extended here to simulate the effect of hypothermia on cell survival. Temperature decreases were set to reduce chemical reaction rates and slow diffusion through ion channels according to the Q10 rule. Heat delivery to tissues was set to depend on metabolic heat generation rate and perfusion. Two cooling methods, scalp and vascular, were simulated to approximate temperature variation in the brain during treatment. Cell death was assumed to occur at continued cell membrane depolarization. Simulations showed that hypothermia to 34.5°C induced within 1-1.5 hours of stroke onset could extend cell survival time by at least 5 hours in tissue with perfusion reduced by 80% of normal. There was good agreement between simulated metabolite dynamics and those reported in rat model studies.
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