Multi-drug-resistant
tuberculosis (TB) is a major public health
problem, concerning about half a million cases each year. Patients
hardly adhere to the current strict treatment consisting of more than
10 000 tablets over a 2-year period. There is a clear need
for efficient and better formulated medications. We have previously
shown that nanoparticles made of cross-linked poly-β-cyclodextrins
(pβCD) are efficient vehicles for pulmonary delivery of powerful
combinations of anti-TB drugs. Here, we report that in addition to
being efficient drug carriers, pβCD nanoparticles are endowed
with intrinsic antibacterial properties. Empty pβCD nanoparticles
are able to impair
Mycobacterium tuberculosis
(Mtb)
establishment after pulmonary administration in mice. pβCD hamper
colonization of macrophages by Mtb by interfering with lipid rafts,
without inducing toxicity. Moreover, pβCD provoke macrophage
apoptosis, leading to depletion of infected cells, thus creating a
lung microenvironment detrimental to Mtb persistence. Taken together,
our results suggest that pβCD nanoparticles loaded or not with
antibiotics have an antibacterial action on their own and could be
used as a carrier in drug regimen formulations effective against TB.
Nivalenol (NIV) and deoxynivalenol (DON) are structurally related mycotoxins produced by Fusarium fungi. These fungi typically infest cereal crops such as wheat, maize, barley, oats and rye, and NIV and DON are regularly found in cereal grains, food and feed. Recent risk assessments identified possible data gaps for both DON and NIV in particular with respect to genotoxicity and carcinogenicity. The overall objective of the project was to assess the genotoxicity of DON and NIV, including the identification of potential modes of action. A battery of in vivo genotoxicity tests was performed in mice: Comet assay with and without fpg in seven organs (duodenum, colon, blood, liver, spleen, kidney, bone marrow), micronucleus assay in bone marrow and colon, and Pig-a assay in peripheral blood. In addition, to clarify the genotoxic mode of action of both mycotoxins, we performed in vitro Comet assay studies in TK6 cells to investigate potential genotoxic oxidative stress induced by mycotoxins. The response in all the genotoxicity assays with NIV after three oral doses at 5, 10 and 20 mg/kg, were uniformly negative. In the case of DON, we found that DON failed to induce micronuclei formation in bone marrow and colon and failed to induce DNA damage in all organs observed by the Comet assay with and without fpg at 4, 8 and 16 mg/kg. The Pig-a assay with DON after three oral gavage doses at 2, 4 and 8 mg/kg, did not show any mutagenic effect at day 28 and 45 after the last dose. In vitro studies indicated that both mycotoxins did not induce DNA damage in the Comet assay with or without fpg in TK6 cells even after GSH depletion. It was concluded that NIV and DON could be considered as devoid of genotoxic potential and pose no genotoxic or mutagenic risk.
Graphene-based materials (GBMs) are promising nanomaterials, and several innovations depend on their use. However, the assessment of their potential hazard must be carefully explored before entering any market. GBMs are indeed well-known to induce various biological impacts, including oxidative stress, which can potentially lead to DNA damage. Genotoxicity is a major endpoint for hazard assessment and has been explored for GBMs, but the available literature shows conflicting results. In this study, we assessed the genotoxicity of 13 various GBMs, one carbon black and one amorphous silica through a DNA damage response assay (using a human respiratory cell model, BEAS-2B).Concurrently, oxidative stress was assessed through a ROS production quantification (DCFH-DA assay using a murine macrophage model, RAW 264.7). We also performed a full physicochemical characterization of our samples to explore potential structureactivity relationships involving genotoxicity. We observed that surface oxidation appears linked to genotoxicity response and were able to distinguish several groups within our studied GBMs showing different genotoxicity results. Our findings highlight the necessity to individually consider each nanoform of GBMs since the tested samples showed various results and modes of action. We propose this study as a genotoxicity assessment using a high-throughput screening method and suggest few hypotheses concerning the genotoxicity mode of action of GBMs.
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