Acute systemic exposure to silver-based nanoparticles induces hepatotoxicity and NLRP3-dependent inflammation

Nanoparticles (NPs) are increasingly being commercialized for use in biomedicine. NP toxicity following acute or chronic exposure has been described, but mechanistic insight into this process remains incomplete. Recent evidence from in vitro studies suggested a role for NLRP3 in NP cytotoxicity. In this study, we investigated the effect of systemic administration of composite inorganic NP, consisting of Ag:Cu:B (dose range 1–20?mg/kg), on the early acute (4–24?h post-exposure) and late phase response (96?h post-exposure) in normal and NLRP3-deficient mice. Our findings indicate that systemic exposure (≥2?mg/kg) was associated with acute liver injury due to preferential accumulation of NP in this organ and resulted in elevated AST, ALT and LDH levels. Moreover, within 24?h of NP administration, there was a dose-dependent increase in intraperitoneal neutrophil recruitment and upregulation in gene expression of several proinflammatory mediators, including TNF-α, IL-1β and S100A9. Histological analysis of liver tissue revealed evidence of dose-dependent hepatocyte necrosis, increase in sinusoidal Kupffer cells, lobular granulomas and foci of abscess formation which were most pronounced at 24?h following NP administration. NP deposition in the liver led to a significant upregulation in gene expression of S100A9, an endogenous danger signal recognition molecule of phagocytes, IL-1β and IL-6. The extent of proinflammatory cytokine activation and hepatotoxicity was significantly attenuated in mice deficient in the NLRP3 inflammasome, demonstrating the critical role of this innate immune system recognition receptor in the response to NP.     

Involvement of the dopaminergic receptors of the rat basolateral amygdala in anxiolytic-like effects of the cholinergic system

Cholinergic system stimulation in some parts of the brain may affect anxiety-related behaviors. This system has many interactions with dopaminergic neurotransmission in the brain. We have studied the effect of cholinergic system activation in the basolateral amygdala on anxiety-related behaviors in adult male wistar rats using the acetylcholinesterase inhibitor physostigmine. Furthermore, the possible involvement of dopamine D(1) and D(2) receptors of basolateral amygdala in physostigmine induced effects has been evaluated. The elevated plus-maze task was used to assess anxiety parameters and all drugs were delivered into basolateral amygdala via bilaterally implanted chronic cannulas. Physostigmine (20 μg/rat) increased the percentage of open arm time (%OAT) and open arm entries (%OAE), revealing an anxiolytic-like effect. However, muscarinic receptor antagonist scopolamine (8 μg/rat) decreased %OAT indicating anxiogenic-like effect. A sub-effective dose of scopolamine (2 μg/rat) plus physostigmine decreased %OAT and %OAE in comparison to saline plus physostigmine (20 μg/rat). Muscarinic receptor agonist pilocarpine (5 μg/rat), dopamine D(1) receptor antagonist SCH23390 (1 μg/rat) and dopamine D(2) receptor antagonist sulpiride (5 μg/rat) significantly increased %OAT which may show anxiolytic-like effects of drugs. Sulpiride (5 μg/rat) also increased %OAE parameter. Pre-treatment with SCH23390 (0.5 and 1 μg/rat) or sulpiride (5 μg/rat) blocked anxiolytic-like effect of physostigmine (20 μg/rat). All drugs were devoid of any significant effect on locomotor activity. It is concluded that intra-basolateral amygdala administration of physostigmine has anxiolytic-like effects which may be via muscarinic mechanisms. Furthermore, dopaminergic system activation probably via dopamine D(1) and D(2) receptors is necessary for mediating anxiolytic-like effects of physostigmine.     

Dermal delivery of doxorubicin-loaded solid lipid nanoparticles for the treatment of skin cancer

Objective: Dermal delivery of Doxorubicin (Dox) would be an ideal way in maximising drug efficiency against skin cancer accompanying with minimising side effects. We investigated the potential of Dox-loaded Solid lipid nanoparticles (SLNs) for topical delivery against skin cancer.

Methods: In vitro and in vivo cytotoxicity of optimised formulation were evaluated on murine melanoma (B16F10) cells by MTT assay and melanoma induced Balb/C mice, respectively. Animal study followed by histological analysis.

Results: Optimised formulation showed mean particle size and encapsulation efficiency (EE) of 92?nm and 86% w/w (0.86% w/w value of encapsulated Dox in the lipid matrix), respectively. FTIR experiment confirmed drug–lipid interaction interpreting the observed high EE value for Dox. In vitro and in vivo results indicated the superiority of cytotoxic performance of Dox-loaded SLN compared to Dox solution.

Conclusion: Our findings may open the possibilities for the topical delivery of Dox to the skin cancerous tissues.     

Application of ɑ-Tocotrienol-Loaded Biocompatible Precirol in Attenuation of Doxorubicin Dose-Dependent Behavior in HUH-7 Hepatocarcinoma Cell Line

Abstract

Tumor-targeted nanoparticle delivery system has been known as a substitute and capable achievement in cancer treatment compared to conventional methods. In this study, we examined potential application of ɑ-tocotrienol-Precirol formulation to enhance efficiency of doxorubicin (DOX) in induction of apoptosis in HUH-7 hepatocarcinoma cells. ɑ-tocotrienol-loaded nanoparticles were characterized at the point of zeta potential, particle size, scanning electron microscope (SEM), and cell internalization. To evaluate antiproliferative effects of formulation, apoptosis, cell cycle procedure, flow cytometry, and MTT assays were employed. Optimum size of the ɑ-tocotrienol formulation revealed narrow size distribution with mean average of 78?±?3?nm. IC₅₀ values for ɑ-tocotrienol and ɑ-tocotrienol-nano structured lipid carriers after 24?h were 15?±?0.6 and 10?±?0.03?µM, respectively. After incubation of cells with ɑ-tocotrienol-loaded careers, the rate of cell proliferation decreased from 53?±?6.1 to 34?±?7.1% (P?<?0.05). A significant improvement in the apoptosis percentage was revealed after treatment of the HUH-7 cell line with DOX and ɑ-tocotrienol careers (P?<?0.05). Gene expression results demonstrated a marked decrease in survivin and increase in Bid and Bax levels. Our findings suggest that ɑ-tocotrienol-loaded nanoparticles elevate DOX efficacy in HUH-7 hepatocarcinoma cell.     

Inactivation methods for whole influenza vaccine production

Despite tremendous efforts toward vaccination, influenza remains an ongoing global threat. The induction of strain‐specific neutralizing antibody responses is a common phenomenon during vaccination with the current inactivated influenza vaccines, so the protective effect of these vaccines is mostly strain‐specific. There is an essential need for the development of next‐generation vaccines, with a broad range of immunogenicity against antigenically drifted or shifted influenza viruses. Here, we evaluate the potential of whole inactivated vaccines, based on chemical and physical methods, as well as new approaches to generate cross‐protective immune responses. We also consider the mechanisms by which some of these vaccines may induce CD8⁺ T‐cells cross‐reactivity with different strains of influenza. In this review, we have focused on conventional and novel methods for production of whole inactivated influenza vaccine. As well as chemical modification, using formaldehyde or β‐propiolactone and physical manipulation by ultraviolet radiation or gamma‐irradiation, novel approaches, including visible ultrashort pulsed laser, and low‐energy electron irradiation are discussed. These two latter methods are considered to be attractive approaches to design more sophisticated vaccines, due to their ability to maintain most of the viral antigenic properties during inactivation and potential to produce cross‐protective immunity. However, further studies are needed to validate them before they can replace traditional methods for vaccine manufacturing.     

Influence of mode of birth and collection on WBC yields of umbilical cord blood units

BACKGROUND: The aim of this study was to determine the influence of mode of birth and umbilical cord blood (CB) collection before (in utero) or after delivery of the placenta (ex utero) on total number of WBCs and CD34+ cells in CB units. STUDY DESIGN AND METHODS: Consecutively donated, banked CB units were assessed for net volume, WBC concentration, total number of WBCs, proportion of CD34+ cells, and total number of CD34+ cells. These parameters were then correlated with the mode of birth and the mode of CB collection relative to the delivery of the placenta. RESULTS: A significantly higher CB volume was seen following cesarean section (n = 61) than following vaginal delivery (n = 157; median volume, 76 vs. 63 mL, respectively; p < 0.0001). In contrast, CB from vaginal delivery had a significantly higher WBC concentration compared with CB from cesarean section (medians, 17.1 x 10(9) and 13.6 x 10(9) WBCs/L, respectively; p < 0.0001). The mode of birth did not influence the proportion of CD34+ cells. A correlation was demonstrated between the total number of CD34+ cells and the total number of WBCs. As a consequence of the opposing effects on volume and WBC counts by cesarean section and vaginal delivery, there were no significant differences in the total number of WBCs or CD34+ cells for the CB units with mode of delivery in this study. No significant differences were found in CB with mode of CB collection (in utero [n = 58] or ex utero [n = 99]) following vaginal delivery. CONCLUSIONS: The mode of birth influences the CB WBC concentration and volume collected and should be taken into consideration for establishing any acceptance limits for CB units to be banked. There were no differences in CB with in utero or ex utero collections.     

Sedentary behavior and physical activity in cardiac rehabilitation participants

Background

There is a deleterious association between sedentary behavior and mortality risk factors. Elevated sedentary time has been reported in several studies that involved cardiac rehabilitation (CR) participants.