No abstract

Antimicrobial resistance (AMR) represents one of the most important human- and animal health-threatening issues worldwide. Bacterial capability to face antimicrobial compounds is an ancient feature, enabling bacterial survival over time and the dynamic surrounding. Moreover, bacteria make use of their evolutionary machinery to adapt to the selective pressure exerted by antibiotic treatments, resulting in reduced efficacy of the therapeutic intervention against human and animal infections. The mechanisms responsible for both innate and acquired AMR are thoroughly investigated. Commonly, AMR traits are included in mobilizable genetic elements enabling the homogeneous diffusion of the AMR traits pool between the ecosystems of diverse sectors, such as human medicine, veterinary medicine, and the environment. Thus, a coordinated multisectoral approach, such as One-Health, provides a detailed comprehensive picture of the AMR onset and diffusion. Following a general revision of the molecular mechanisms responsible for both innate and acquired AMR, the present manuscript focuses on reviewing the contribution of veterinary medicine to the overall issue of AMR. The main sources of AMR amenable to veterinary medicine are described, driving the attention towards the indissoluble cross-talk existing between the diverse ecosystems and sectors and their cumulative cooperation to this warning phenomenon.

The maintenance of physiological levels of nitric oxide (NO) produced by eNOS represents a key element for vascular endothelial homeostasis. On the other hand, NO overproduction, due to the activation of iNOS under different stress conditions, leads to endothelial dysfunction and, in the late stages, to the development of atherosclerosis. Oxidized LDLs (oxLDLs) represent the major candidates to trigger biomolecular processes accompanying endothelial dysfunction and vascular inflammation leading to atherosclerosis, though the pathophysiological mechanism still remains to be elucidated. Here, we summarize recent evidence suggesting that oxLDLs produce significant impairment in the modulation of the eNOS/iNOS machinery, downregulating eNOS via the HMGB1-TLR4-Caveolin-1 pathway. On the other hand, increased oxLDLs lead to sustained activation of the scavenger receptor LOX-1 and, subsequently, to NFkB activation, which, in turn, increases iNOS, leading to EC oxidative stress. Finally, these events are associated with reduced protective autophagic response and accelerated apoptotic EC death, which activates atherosclerotic development. Taken together, this information sheds new light on the pathophysiological mechanisms of oxLDL-related impairment of EC functionality and opens new perspectives in atherothrombosis prevention.

Background The use of biopolymers is increasing in drug delivery, thanks to the peculiar properties of these compounds such as their biodegradability, availability, and the possibility of modulating their physico-chemical characteristics. In particular, protein-based systems such as albumin are able to interact with many active compounds, modulating their biopharmaceutical properties. Zein is a protein of 20–40 kDa made up of many hydrophobic amino acids, generally regarded as safe (GRAS) and used as a coating material. Methods In this investigation, zein was combined with various surfactants in order to obtain stable nanosystems by means of the nanoprecipitation technique. Specific parameters, eg, temperature, pH value, Turbiscan Stability Index, serum stability, in vitro cytotoxicity and entrapment efficiency of various model compounds were investigated, in order to identify the nanoformulation most useful for a systemic drug delivery application. Results The use of non-ionic and ionic surfactants such as Tween 80, poloxamer 188, and sodium deoxycholate allowed us to obtain nanoparticles characterized by a mean diameter of 100–200 nm when a protein concentration of 2 mg/mL was used. The surface charge was modulated by means of the protein concentration and the nature of the stabilizer. The most suitable nanoparticle formulation to be proposed as a colloidal drug delivery system was obtained using sodium deoxycholate (1.25% w/v) because it was characterized by a narrow size distribution, a good storage stability after freeze-drying and significant feature of retaining lipophilic and hydrophilic compounds. Conclusion The sodium deoxycholate-coated zein nanoparticles are stable biocompatible colloidal carriers to be used as useful drug delivery systems.

BACKGROUND AND PURPOSEThe mechanisms of paraquat (PQ)-induced toxicity are poorly understood and PQ poisoning is often fatal due to a lack of effective antidotes. In this study we report the effects of N-[2-(2-methoxy-6H-dipyrido{2,3-a:3,2-e}pyrrolizin-11-yl)ethyl]-2-furamide (NMDPEF), a melatonin-related inhibitor of quinone oxidoreductase2 (QR2) on the toxicity of PQ in vitro & in vivo. EXPERIMENTAL APPROACHPrevention of PQ-induced toxicity was tested in different cells, including primary pneumocytes and astroglial U373 cells. Cell death and reactive oxygen species (ROS) were analysed by flow cytometry and fluorescent probes. QR2 silencing was achieved by lentiviral shRNAs. PQ (30 mg·kg -1 ) and NMDPEF were administered i.p. to Wistar rats and animals were monitored for 28 days. PQ toxicity in the substantia nigra (SN) was tested by a localized microinfusion and electrocorticography. QR2 activity was measured by fluorimetry of N-benzyldihydronicotinamide oxidation. KEY RESULTSNMDPEF potently antagonized non-apoptotic PQ-induced cell death, ROS generation and inhibited cellular QR2 activity. In contrast, the cytoprotective effect of melatonin and apocynin was limited and transient compared with NMDPEF. Silencing of QR2 attenuated PQ-induced cell death and reduced the efficacy of NMDPEF. Significantly, NMDPEF (4.5 mg·kg -1 ) potently antagonized PQ-induced systemic toxicity and animal mortality. Microinfusion of NMDPEF into SN prevented severe behavioural and electrocortical effects of PQ which correlated with inhibition of malondialdehyde accumulation in cells and tissues. CONCLUSIONS AND IMPLICATIONSNMDPEF protected against PQ-induced toxicity in vitro and in vivo, suggesting a key role for QR2 in the regulation of oxidative stress. LINKED ARTICLEThis article is commented on by Baltazar et al.,