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•The effects of polymethylmethacrylate nanoplastics (PMMA-NPs) were evaluated in fish.•Parameters both at the molecular and biochemical levels were modulated by PMMA-NPs.•A short-term ...exposure to PMMA-NPs increased the expression of antioxidant genes.•An increase in both total antioxidant capacity and total oxidative status was found.•PMMA-NPs induced an increase in the frequency of erythrocyte nuclear abnormalities.
This study evaluated the effect of a short-term exposure to 45 nm polymethylmethacrylate nanoplastics (PMMA-NPs) on the gilthead seabream (Sparus aurata), by assessing biomarkers at different levels of biological organization in liver and plasma. Fish were exposed via water to PMMA-NPs (0, 0.001, 0.01, 0.1, 1 and 10 mg L−1) and sampled after 24 and 96 h. Results showed a general up-regulation of mRNA levels of key genes associated with lipid metabolism (e.g. apolipoprotein A1 and retinoid X receptor). Together with the modulation of the lipid pathway genes we also found a global increase in cholesterol and triglycerides in plasma. Antioxidant-related genes (e.g. glutathione peroxidase 1) were also up-regulated after 24 h of exposure, but their expression levels returned to control afterwards. Total antioxidant capacity (TAC) was increased throughout the experiment, however at 96 h the antioxidant capacity became less efficient, reflected by an increase in the total oxidative status (TOS). Concomitantly, we found an increase in the erythrocytic nuclear abnormalities (ENAs) throughout the trial. Altogether, PMMA-NPs activated the organism’s antioxidant defenses and induced alterations in lipid metabolism pathways and genotoxicity in the blood cells of gilthead seabream.
Granulomas are complex cellular structures composed predominantly of macrophages and lymphocytes that function to contain and kill invading pathogens. Here, we investigated the single-cell phenotypes ...associated with antimicrobial responses in human leprosy granulomas by applying single-cell and spatial sequencing to leprosy biopsy specimens. We focused on reversal reactions (RRs), a dynamic process whereby some patients with disseminated lepromatous leprosy (L-lep) transition toward self-limiting tuberculoid leprosy (T-lep), mounting effective antimicrobial responses. We identified a set of genes encoding proteins involved in antimicrobial responses that are differentially expressed in RR versus L-lep lesions and regulated by interferon-γ and interleukin-1β. By integrating the spatial coordinates of the key cell types and antimicrobial gene expression in RR and T-lep lesions, we constructed a map revealing the organized architecture of granulomas depicting compositional and functional layers by which macrophages, T cells, keratinocytes and fibroblasts can each contribute to the antimicrobial response.
Plastic pollution is a worldwide problem, highlighted by the fact that plastic materials degrade into nano-size particles (<100 nm), potentially becoming more bioavailable as well as a source of ...entry of other contaminants into organisms. The present study aimed to assess the effects of polystyrene nanoplastics (PS), individually or combined with carbamazepine (Cbz), on the Mediterranean mussel, Mytilus galloprovincialis. For this purpose, mussels were exposed for 96 h to a concentration range of PS (from 0.05 up to 50 mg L−1), to Cbz (6.3 μg L−1) alone and to the mixture of PS + Cbz (0.05 mg L−1+ 6.3 μg L−1). Molecular and biochemical biomarkers were assessed in the digestive glands, gills and haemolymph. The abundance of mRNA in the digestive glands and gills revealed significant alterations in the expression of genes associated with biotransformation, DNA repair, cell stress-response and innate immunity. Combined exposure of PS + Cbz induced significant downregulation in gene expression (e.g., hsp70) when compared to individual exposure. Total oxidant status increased in digestive glands after exposure to 0.5 mg L−1 PS. Moreover, increased total antioxidant capacity and esterase activity were observed for PS 50 mg L−1, in digestive glands and gills, respectively. The PS induced effects on neurotransmission, measured as inhibition of cholinesterase activity in haemolymph. Genotoxicity was found in haemocytes after exposure to PS, Cbz and their mixture. Moreover, lipid peroxidation was observed for 0.05 mg L−1 PS exposure, showing that nanoplastics can induce oxidative damage. The present study demonstrated that PS, even at low concentrations, led to alterations on the assessed mussels' endpoints.
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•Effects of polystyrene nanoplastics (PS) were assessed at molecular and biochemical levels.•PS induced changes in the expression of biotransformation and immune related genes.•PS exposure inhibits cholinesterase activity in haemolymph.•DNA integrity decreased after exposure to PS, carbamazepine (Cbz) and PS + Cbz.•PS (0.05 mg L−1) induced lipid peroxidation (LPO) in the digestive gland.
Leishmaniasis is a group of infectious neglected tropical diseases caused by more than 20 pathogenic species of Leishmania sp. Due to the limitations of the current treatments available, chalcone ...moiety has been drawn with a lot of attention due to the simple chemistry and synthesis, being reported with antileishmanial activity in particular against amastigote form. This review aims to provide an overview towards antileishmanial activity of chalcones derivatives against amastigote form for Leishmania major, L. amazonensis, L. panamensis, L. donovani and L. infantum as well as their structure-activity relationship (SAR), molecular targets and in silico ADMET evaluation. In this way, it is expected that this review may support the research and development of new promising chalcones candidates a leishmanicidal drugs.
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•Chalcones derivatives against Leishmania sp.•Different patterns of substitutions on chalcone rings.•Application of medicinal chemistry strategies.•In silico ADMET were performed.
The present study aimed to evaluate the effects of ~45 nm nanoplastics (NPs) on the marine fish Dicentrarchus labrax after a short-term exposure. Animals were exposed to a concentration range of NPs ...for 96 h and liver, plasma and skin mucus were sampled. Assessed endpoints included biochemical biomarkers and expression of genes related to lipid metabolism, immune system and general cell stress. Abundance of mRNA transcripts related to lipid metabolism, pparα and pparγ, were significantly increased after exposure to NPs. Biochemical endpoints revealed decreased esterase activity levels in plasma, suggesting that the immune system of fish might be compromised by exposure to NPs. Moreover, significantly lower levels of alkaline phosphatase were found in the skin mucus of animals exposed to NPs. The present results suggest that NPs may represent a hazard to this marine fish, potentially interfering with the metabolism of lipids and the correct function of the immune response.
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•Plastic materials in the environment degrade into nano-size particles•Effects of nanoplastics (NPs) on D. labrax after short-term exposure were assessed•Molecular signaling pathways related to lipid metabolism were altered in liver•NPs might interfere with the D.labrax's immune response
Type I interferons (IFN-α and IFN-β) are important for protection against many viral infections, whereas type II interferon (IFN-γ) is essential for host defense against some bacterial and parasitic ...pathogens. Study of IFN responses in human leprosy revealed an inverse correlation between IFN-β and IFN-γ gene expression programs. IFN-γ and its downstream vitamin D—dependent antimicrobial genes were preferentially expressed in self-healing tuberculoid lesions and mediated antimicrobial activity against the pathogen Mycobacterium leprae in vitro. In contrast, IFN-β and its downstream genes, including interleukin-10 (IL-10), were induced in monocytes by M. leprae in vitro and preferentially expressed in disseminated and progressive lepromatous lesions. The IFN-γ—induced macrophage vitamin D—dependent antimicrobial peptide response was inhibited by IFN-β and by IL-10, suggesting that the differential production of IFNs contributes to protection versus pathogenesis in some human bacterial infections.
Cancer patients are at risk for severe complications related to the underlying malignancy or its treatment and, therefore, usually require admission to intensive care units (ICU). Here, we evaluated ...the clinical characteristics and outcomes in this subgroup of patients.
Secondary analysis of two prospective cohorts of cancer patients admitted to ICUs. We used multivariable logistic regression to identify variables associated with hospital mortality.
Out of 2,028 patients, 456 (23%) had cancer-related complications. Compared to those without cancer-related complications, they more frequently had worse performance status (PS) (57% vs 36% with PS≥2), active malignancy (95% vs 58%), need for vasopressors (45% vs 34%), mechanical ventilation (70% vs 51%) and dialysis (12% vs 8%) (P<0.001 for all analyses). ICU (47% vs. 27%) and hospital (63% vs. 38%) mortality rates were also higher in patients with cancer-related complications (P<0.001). Chemo/radiation therapy-induced toxicity (6%), venous thromboembolism (5%), respiratory failure (4%), gastrointestinal involvement (3%) and vena cava syndrome (VCS) (2%) were the most frequent cancer-related complications. In multivariable analysis, the presence of cancer-related complications per se was not associated with mortality odds ratio (OR) = 1.25 (95% confidence interval, 0.94-1.66), P = 0.131. However, among the individual cancer-related complications, VCS OR = 3.79 (1.11-12.92), P = 0.033, gastrointestinal involvement OR = 3.05 (1.57-5.91), P = <0.001 and respiratory failure OR = 1.96(1.04-3.71), P = 0.038 were independently associated with in-hospital mortality.
The prognostic impact of cancer-related complications was variable. Although some complications were associated with worse outcomes, the presence of an acute cancer-related complication per se should not guide decisions to admit a patient to ICU.
Aging is a major risk factor for many neurological diseases and is associated with mild cognitive decline. Previous studies suggest that aging is accompanied by reduced synapse number and synaptic ...plasticity in specific brain regions. However, most studies, to date, used either postmortem or ex vivo preparations and lacked key in vivo evidence. Thus, whether neuronal arbors and synaptic structures remain dynamic in the intact aged brain and whether specific synaptic deficits arise during aging remains unknown. Here we used in vivo two-photon imaging and a unique analysis method to rigorously measure and track the size and location of axonal boutons in aged mice. Unexpectedly, the aged cortex shows circuit-specific increased rates of axonal bouton formation, elimination, and destabilization. Compared with the young adult brain, large (i.e., strong) boutons show 10-fold higher rates of destabilization and 20-fold higher turnover in the aged cortex. Size fluctuations of persistent boutons, believed to encode long-term memories, also are larger in the aged brain, whereas bouton size and density are not affected. Our data uncover a striking and unexpected increase in axonal bouton dynamics in the aged cortex. The increased turnover and destabilization rates of large boutons indicate that learning and memory deficits in the aged brain arise not through an inability to form new synapses but rather through decreased synaptic tenacity. Overall our study suggests that increased synaptic structural dynamics in specific cortical circuits may be a mechanism for age-related cognitive decline.
The extent of the widespread, planetary contamination by plastic waste is difficult to fully capture. Nanoplastics (NPs) are currently in the center of research concerning plastic litter, both for ...the analytical challenges they pose and for their potential to provoke hazardous effects in organisms. However, there are still many unanswered questions in this multidisciplinary field, with a crucial missing piece being the quantification of NPs in fish tissues after in vivo exposures. Another relevant question that is still greatly unexplored is how a chronic exposure to NPs will affect fish health. This study aims to provide answers to both of these relevant knowledge gaps. To this end, goldfish (Carassius auratus) were exposed to 44 nm polystyrene (PS)-NPs via water for 30 days. Following the exposure, gastrointestinal tract, liver and muscle were sampled for PS-NPs analysis by means of size exclusion chromatography coupled to high resolution mass spectrometry. PS-NPs were detected in all liver and muscle samples of exposed fish, with higher concentrations in liver than in muscle, whereas no PS-NPs were detected in the gastrointestinal tract. Nevertheless, exposure to PS-NPs did not induce changes in hematology parameters nor in cortisol and glucose levels in plasma. On the other hand, even a relatively low concentration of PS-NPs was able to cause DNA damage, measured by an increase in erythrocyte nuclear abnormalities, suggesting that PS-NPs can reach the cell nucleus and cause genotoxicity. These results show for the first time that PS-NPs find their way to fish muscle after chronic exposure, where they bioaccumulate, but do not alter fish survival nor hematological or physiological stress indicators. The accumulation of PS-NPs in fish muscle can represent a threat to human health as a possible route of exposure to small-sized plastics. The present results in a model fish species open windows for future studies in edible fish species.
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•Polystyrene nanoplastics (PS-NPs) were quantified in goldfish gut, liver and muscle.•No accumulation of PS-NPs was found in gut.•PS-NPs levels where higher in the liver than in the muscle.•A chronic exposure to PS-NPs caused chromosomal damage in fish erythrocytes.•No changes in haematological and stress indicators were found after PS-NPs exposure.
As circulating monocytes enter the site of disease, the local microenvironment instructs their differentiation into tissue macrophages (MΦ). To identify mechanisms that regulate MΦ differentiation, ...we studied human leprosy as a model, since M1-type antimicrobial MΦ predominate in lesions in the self-limited form, whereas M2-type phagocytic MΦ are characteristic of the lesions in the progressive form. Using a heterotypic co-culture model, we found that unstimulated endothelial cells (EC) trigger monocytes to become M2 MΦ. However, biochemical screens identified that IFN-γ and two families of small molecules activated EC to induce monocytes to differentiate into M1 MΦ. The gene expression profiles induced in these activated EC, when overlapped with the transcriptomes of human leprosy lesions, identified Jagged1 (JAG1) as a potential regulator of MΦ differentiation. JAG1 protein was preferentially expressed in the lesions from the self-limited form of leprosy, and localized to the vascular endothelium. The ability of activated EC to induce M1 MΦ was JAG1-dependent and the addition of JAG1 to quiescent EC facilitated monocyte differentiation into M1 MΦ with antimicrobial activity against M. leprae. Our findings indicate a potential role for the IFN-γ-JAG1 axis in instructing MΦ differentiation as part of the host defense response at the site of disease in human leprosy.
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