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A growing number of epidemiological studies has linked exposure to traffic-related air pollution (TRAP) to neurological and neurodegenerative diseases. In a previous study, we showed that subchronic inhalation exposure to diesel engine exhaust, as a model of TRAP, aggravates amyloid-β plaque formation and motor function impairment in the 5xFAD transgenic mouse model of Alzheimer’s disease (AD). To further strengthen the epidemiological association between TRAP and AD we exposed 5xFAD and wildtype littermate mice for 5 h/day, 5 days/week during 2 or 4 consecutive weeks at a representative urban traffic-dominated location to: (I) concentrated ambient particles, (II) particle filtered ambient air or (III) clean air (control). Our study revealed that repeated inhalation exposure to TRAP accelerates plaque formation in the 5xFAD mice. Data also indicated that the gaseous fraction of the air pollutant mixture probably plays only a minor role in this effect. The major outcome of this study substantiates the role of air pollution in AD and suggests that long-term exposure to traffic-related air pollution particles is a risk factor for this debilitating disease. Acknowledgements: The work leading to these results has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 814978 (TUBE) and a cross-border grant awarded by the Alzheimer Forschung Initiative (AFI, Germany) and Alzheimer Nederland.

Lipoproteins are biodegradable and biocompatible natural carriers that can be utilized for the transport of hydrophobic drugs, such as cyclosporin A (CycloA), a calcineurin inhibitor utilized for the inflammatory bowel disease, such as ulcerative colitis. A major limitation in the drug treatment of inflammatory bowel disease is the inability to deliver the drug selectively toward the inflamed tissues. Nanotechnology-based drug delivery systems have led to an amelioration of the therapeutic selectivity, but still the majority of the entrapped drug is eliminated without exercising a therapeutic effect. The present study aimed to prepare three lipoprotein formulations (HDL-, LDL-, and VLDL-based) loaded with cyclosporin A for the treatment of colitis in a murine model. After an intravenous injection of a drug dose of 2 mg/kg, clinical activity (colon weight/length ratio) and therapeutic effects (evaluated by the inflammatory markers MPO and TNF-α) were compared with those of the untreated colitis control group. All CycloA-containing lipoproteins reduced clinical activity, with a significant decrease in the case of LDL-CycloA formulation, which also led to the higher therapeutic effect.

Fe-based materials are currently considered for manufacturing biodegradable coronary stents. Here we show that Fe has a strong potential to generate hydroxyl radicals (HO·) during corrosion. This HO· generation, but not corrosion, can be inhibited by catalase. Oxidative stress was observed (increased HO-1 expression) in aortic rings after direct exposure to Fe, but not in the presence of catalase or after indirect exposure. This oxidative stress response induced an uncoupling of eNOS in, and a consequent reduced NO production by endothelial cells exposed to Fe. In isolated rat aortic rings NO production was also reduced by HO· generated during Fe corrosion, as indicated by the protective role of catalase. Finally, all these mechanisms contributed to impaired endothelium- dependent relaxation in aortic rings caused by HO· generated during the direct contact with Fe. This deleterious impact of Fe corrosion on the endothelial function should be integrated when considering the use of biodegradable Fe-based alloys for vascular implants.

Background Nanotechnologies provide new opportunities for improving the safety, quality, shelf life, flavor and appearance of foods. The most common nanoparticles (NPs) in human diet are silver metal, mainly present in food packaging and appliances, and silicon and titanium dioxides used as additives. The rapid development and commercialization of consumer products containing these engineered NPs is, however, not well supported by appropriate toxicological studies and risk assessment. Local and systemic toxicity and/or disruption of the gut microbiota (GM) have already been observed after oral administration of NPs in experimental animals, but results are not consistent and doses used were often much higher than the estimated human intakes. In view of the strong evidence linking alterations of the GM to cardiometabolic (CM) diseases, we hypothesized that dietary NPs might disturb this GM-CM axis. Materials and methods We exposed male C57BL/6JRj mice (n = 13 per dose group) to dietary NPs mixed in food pellets at doses relevant for human exposure: Ag (0, 4, 40 or 400 μg/kg pellet), SiO2 (0, 0.8, 8 and 80 mg/kg pellet) or TiO2 (0, 0.4, 4 or 40 mg/kg pellet). After 24 weeks of exposure, we assessed effects on the GM and CM health (n = 8 per dose group). The reversibility of the effects was examined after 8 additional weeks without NPs exposure (recovery period, n ≤ -5 per dose group). Results No overt toxicity was recorded. The GM β-diversity was dose-dependently disrupted by the three NPs, and the bacterial short chain fatty acids (SCFAs) were dose-dependently reduced after the administration of SiO2 and TiO2 NPs. These effects disappeared completely or partly after the recovery period, strengthening the association with dietary NPs. We did not observe atheromatous disease or glucose intolerance after NP exposure. Instead, dose-dependent decreases in the expression of IL-6 in the liver, circulating triglycerides (TG) and urea nitrogen (BUN) were recorded after administration of the NPs. Conclusion We found that long-term oral exposure to dietary NPs at doses relevant for estimated human intakes disrupts the GM composition and function. These modifications did not appear associated with atheromatous or deleterious metabolic outcomes.

Fe-based materials have increasingly been considered for the development of biodegradable cardiovascular stents. A wide range of in vitro and in vivo studies should be done to fully evaluate their biocompatibility. In this review, we summarized and analyzed the findings and the methodologies used to assess the biocompatibility of Fe materials. The majority of investigators drew conclusions about in vitro Fe toxicity based on indirect contact results. The setup applied in these tests seems to overlook the possible effects of Fe corrosion and does not allow for understanding of the complexity of released chemical forms and their possible impact on tissue. It is in particular important to ensure that test setups or interpretations of in vitro results do not hide some important mechanisms, leading to inappropriate subsequent in vivo experiments. On the other hand, the sample size of existing in vivo implantations is often limited, and effects such as local toxicity or endothelial function are not deeply scrutinized. The main advantages and limitations of in vitro design strategies applied in the development of Fe-based alloys and the correlation with in vivo studies are discussed. It is evident from this literature review that we are not yet ready to define an Fe-based material as safe or biocompatible.

The WST-1 assay is the most common test to assess the in vitro cytotoxicity of chemicals. Tetrazolium-based assays can, however, be affected by the interference of tested chemicals, including carbon nanotubes or Mg particles. Here, we report a new interference of Mn materials with the WST-1 assay. Endothelial cells exposed to Mn particles (Mn alone or Fe-Mn alloy from 50 to 1600 μg/ml) were severely damaged according to the WST-1 assay, but not the ATP content assay. Subsequent experiments revealed that Mn particles interfere with the reduction of the tetrazolium salt to formazan. Therefore, the WST-1 assay is not suitable to evaluate the in vitro cytotoxicity of Mn-containing materials, and luminescence-based assays such as CellTiter-Glo® appear more appropriate.

Fe-based materials are considered for the manufacture of temporary implants that degrade through the corrosion of Fe by oxygen. Here we document the generation of hydroxyl radicals (HO˙) during this corrosion process, and their deleterious impacts on human endothelial (ECs) and smooth muscle cells (SMCs) in vitro. The generation of HO˙ was documented by two independent acellular assays, terephtalic acid hydroxylation (fluorescence) and spin trapping technique coupled with electron paramagnetic resonance spectroscopy. All Fe-based materials tested exhibited a strong potential to generate HO˙. The addition of catalase prevented the formation of HO˙. Cellular responses were assessed in two ECs and SMCs lines using different cytotoxicity assays (WST-1 and CellTiter-Glo). Cells were exposed directly to Fe powder in the presence/absence of catalase, or to extracts obtained from the corrosion of Fe. Cell viability was dose-dependently affected by the direct contact with Fe materials, but not in the presence of catalase or after indirect exposure to cell extracts. The deleterious effect of HO˙ on ECs and SMCs was confirmed by the dose-dependent increase of the transcripts of the oxidative stress gene heme oxygenase-1 4 h or 6 h after direct exposure to the particles, but not in presence of catalase or after indirect exposure. The demonstration of HO˙production during corrosion and consequent oxidative stress on human ECs and SMCs newly reveals a deleterious consequence of Fe-corrosion that should be integrated in the assessment of the biocompatibility of Fe-based alloys.

Introduction Bioresorbable polymer stents have been used to provide a transient scaffold after coronary angioplasty. However, an increase in stent thrombosis has been observed. A current challenge is thus to develop new bioresorbable stents combining optimised mechanical and biodegradation properties together with limited thrombogenicity. Fe-based alloys are amongst the good candidates. Objective Blood compatibility of a new Fe-based alloy was studied in vitro via assessment of haemolysis and platelet activation. Methods Human whole blood was incubated for 60 min with either the Fe-based alloy or the cobalt-chromium (Co-Cr) alloy composing bare metal stents. After centrifugation, optical density of the supernatant was measured at 540 nm and the amount of haemolysis was calculated. For platelet activation assays, human or rat washed platelets were incubated for 60 min with both alloys before measuring their reactivity to platelet agonists by flow cytometry, using CD62P and activated α2bβ3 antibodies. In addition, phosphorylation of PKC substrates was evaluated by western blot. Results No significant red cells haemolysis was induced by both alloys (0.5 and 0.3% respectively). In addition, Co-Cr alloy did not affect CD62P exposure and α2bβ3 activation at platelet surface upon thrombin (0.03 to 0.3 U/ml) stimulation. In contrast, Fe alloy completely abolished their response to the agonist. A drastic inhibition of the phosphorylation state of PKC substrates was also observed after activation with thrombin, collagen (1.25 to 5 μg/ml) and ADP (0.1 to 10 μM). Since similar inhibitory effects were obtained when using a conditioned-reaction medium previously incubated with this Fe alloy, we postulate that its biocorrosion might release components counteracting platelet activation. Conclusion The Fe-based resorbable scaffold displays anti-thrombogenic properties and is a promising platform for next-generation stent technologies.

Introduction Based on their good mechanical properties, bioresorbable Fe-based materials have been proposed during the last decade as candidate alloys for coronary stents. Previous investigations on the biocompatibility of metallic materials often overlooked the complexity of the biodegradation phenomenon. Objective We document, for the first time, the generation of reactive oxygen species (ROS) during Fe-based materials corrosion and their deleterious impacts on endothelial function. Method ROS generation was evaluated by the terephtalic acid (TA) hydroxylation assay. The endothelium of rat aortic rings was directly exposed (6 h) by inserting an iron wire into the lumen in the presence/absence of catalase. Indirect exposure to iron wire was included to assess the potential role of solubilized iron ions. Nitric oxide (NO) production by rings was measured by EPR spin-trapping, and endothelium-dependent relaxation was assessed with the organ-bath method. Induction of oxidative stress in rings was assessed via the mRNA expression of the oxidative stress response gene heme oxygenase-1 (HO-1). Results Iron exhibited a strong potential to generate ROS in the TA assay. ROS generation, but not corrosion, was inhibited by catalase. Direct contact with iron significantly impaired endothelium-dependent relaxation of aortic rings. Direct contact with the material in the presence of catalase, or indirect contact did not affect endothelium function. NO production by isolated rat aortic rings was inhibited by ROS generated by the corrosion of iron, as indicated by the protective role of catalase. Expression of HO-1 was increased after direct exposure to iron, not to indirect exposure or in the presence of catalase. Conclusion The demonstration of ROS production during corrosion, induction of oxidative stress, inhibition of NO production and consequent endothelium dysfunction raise concern about the biocompatibility of biodegradable Fe-based alloys for vascular implants.