Search Results (7)

Background: Polluted soils represent a major problem in many industrialized countries that urgently requires appropriate health risk assessment. The One Health concept that considers a close relationship between human and animal health and ecosystems relies, among other techniques, on continuous monitoring through the use of animal species as bioindicators. In this context, terrestrial gastropods, already recognized as relevant indicators due to their anatomo-physiology, provide a reliable model to study the pneumotoxic effects of pollutants. On the other hand, risk assessment is based on multi-biomarker studies. Therefore, omic approaches seem particularly useful since they can simultaneously detect numerous early biological changes. Methods: In this study, Helix aspersa maxima was exposed to naphthalene, a highly volatile aromatic hydrocarbon responsible for numerous respiratory disorders. Pulmonary membrane extracts and hemolymph samples were analyzed by ¹H-NMR spectroscopy after single or repeated exposures to naphthalene. Results: Numerous metabolic changes were observed, which could be related to membrane lesions, energy, anti-inflammatory, and tumorigenesis pathways. Conclusions: Our findings highlight the potential of combining animal indicator and omics techniques to predict respiratory health risks in cases of exposure to polluted soils. Full article

Monocrotaline (MCT) has well-characterized hepatotoxic and pneumotoxic effects attributed to its active pyrrole metabolites. Studies have previously shown that astrocytes and neurons are targets of MCT, and that toxicity is attributed to astrocyte P450 metabolism to reactive metabolites. However, little is known about MCT toxicity and metabolism by brain endothelial cells (BECs), cells that, together with astrocytes, are specialized in xenobiotic metabolism and neuroprotection. Therefore, in the present study, we evaluated the toxicity of MCT in BECs, and the effects on astrocyte reactivity and neuronal viability in vitro. MCT was purified from Crotalaria retusa seeds. BECs, obtained from the brain of adult Wistar rats, were treated with MCT (1–500 µM), and cell viability and morphology were analyzed after 24–72 h of treatment. Astrocyte/neuron co-cultures were prepared from the cortex of neonatal and embryonic Wistar rats, and the cultures were exposed to conditioned medium (secretome) derived from BECs previously treated with MCT (100–500 µM, SBECM100/500). MCT was not toxic to BECs at the concentrations used and induced a concentration-dependent increase in cell dehydrogenase after 72 h of treatment, suggesting resistance to damage and drug metabolism. However, exposure of astrocyte/neuron co-cultures to the SBECM for 24 h induced changes in the cell morphology, vacuolization, and overexpression of GFAP in astrocytes, characterizing astrogliosis, and neurotoxicity with a reduction in the length of neurites labeled for β-III-tubulin, effects that were MCT concentration-dependent. These results support the hypothesis that MCT neurotoxicity may be due to products of its metabolism by components of the BBB such as BECs and astrocytes, which may be responsible for the brain lesions and symptoms observed after intoxication. Full article

Crofton weed (Ageratina adenophora) is a global and highly invasive weed, with ingestion causing severe respiratory disease in horses, leading to irreversible and untreatable pulmonary fibrosis and oedema. While reports of equine pneumotoxicity remain common in Australia and New Zealand, equine pneumotoxicity may be underdiagnosed in other countries where Crofton weed is endemic but poorly differentiated. The pathogenesis of Crofton weed toxicity following ingestion has been well described in a number of different animal models, including rodents, rabbits, and goats. However, induced toxicity is organ-selective across different animal species, and these vastly differ from the pathogenesis described in horses, both clinically and after experimental exposure. Sources of variation may include species-specific susceptibility to different toxins present in the plant, different mechanistic processes of toxicity, and species differences in toxin biotransformation and bioactivation across different organs. Considering disease severity and Crofton weed’s invasiveness globally, assessing published toxicological and exposure data is necessary to advance research, identify specific toxins for horses, and possible prophylactic and therapeutic strategies. This review presents an overview of the available literature on equine toxicity, parallels between toxicity in horses and other animal species, and important aspects to be included in the future research agenda. Full article

This study tested whether a medicinal plant, Vasaka, typically consumed as a tea to treat respiratory malaise, could protect airway epithelial cells (AECs) from wood smoke particle-induced damage and prevent pathological mucus production. Wood/biomass smoke is a pneumotoxic air pollutant. Mucus normally protects the airways, but excessive production can obstruct airflow and cause respiratory distress. Vasaka tea pre- and co-treatment dose-dependently inhibited mucin 5AC (MUC5AC) mRNA induction by AECs treated with wood smoke particles. This correlated with transient receptor potential ankyrin-1 (TRPA1) inhibition, an attenuation of endoplasmic reticulum (ER) stress, and AEC damage/death. Induction of mRNA for anterior gradient 2, an ER chaperone/disulfide isomerase required for MUC5AC production, and TRP vanilloid-3, a gene that suppresses ER stress and wood smoke particle-induced cell death, was also attenuated. Variable inhibition of TRPA1, ER stress, and MUC5AC mRNA induction was observed using selected chemicals identified in Vasaka tea including vasicine, vasicinone, apigenin, vitexin, isovitexin, isoorientin, 9-oxoODE, and 9,10-EpOME. Apigenin and 9,10-EpOME were the most cytoprotective and mucosuppressive. Cytochrome P450 1A1 (CYP1A1) mRNA was also induced by Vasaka tea and wood smoke particles. Inhibition of CYP1A1 enhanced ER stress and MUC5AC mRNA expression, suggesting a possible role in producing protective oxylipins in stressed cells. The results provide mechanistic insights and support for the purported benefits of Vasaka tea in treating lung inflammatory conditions, raising the possibility of further development as a preventative and/or restorative therapy. Full article

High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is an option to consolidate remission in Waldenstrom’s macroglobulinemia (WM), particularly in selected younger patients with chemosensitive disease. BEAM, consisting of BCNU, etoposide, cytarabine, and melphalan, is often used as a conditioning regimen. However, problems with BCNU, including pneumotoxicity, tolerance, and availability, necessitate the search for alternatives. In this pilot study, we investigated high-dose chemotherapy with BeEAM, in which BCNU is replaced with high-dose bendamustine as an alternative conditioning regimen in six subsequent patients with WM. Bendamustine treatment was well tolerated without unexpected toxicities. The overall response rate was 6/6 patients (2 very good partial responses (VGPR) and 4 PR). After a median follow-up of 72 months, two (33%) patients relapsed. Median progression-free and overall survivals were not reached, and no severe late-onset toxicities were observed so far. In this pilot study, BeEAM conditioning before ASCT seems feasible, safe, and effective in patients with WM. Full article

Phytochemicals like pyrrolizidine alkaloids (PAs) can affect the health of humans and animals. PAs can occur for example in tea, honey or herbs. Some PAs are known to be cytotoxic, genotoxic, and carcinogenic. Upon intake of high amounts, hepatotoxic and pneumotoxic effects were observed in humans. This study aims to elucidate different toxicokinetic parameters like the uptake of PAs and their metabolism with in vitro models. We examined the transport rates of differently structured PAs (monoester, open-chained diester, cyclic diester) over a model of the intestinal barrier. After passing the intestinal barrier, PAs reach the liver, where they are metabolized into partially instable electrophilic metabolites interacting with nucleophilic centers. We investigated this process by the usage of human liver, intestinal, and lung microsomal preparations for incubation with different PAs. These results are completed with the detection of apoptosis as indicator for bioactivation of the PAs. Our results show a structure-dependent passage of PAs over the intestinal barrier. PAs are structure-dependently metabolized by liver microsomes and, to a smaller extent, by lung microsomes. The detection of apoptosis of A549 cells treated with lasiocarpine and monocrotaline following bioactivation by human liver or lung microsomes underlines this result. Conclusively, our results help to shape the picture of PA toxicokinetics which could further improve the knowledge of molecular processes leading to observed effects of PAs in vivo. Full article

Tramadol and tapentadol, two structurally related synthetic opioid analgesics, are widely prescribed due to the enhanced therapeutic profiles resulting from the synergistic combination between μ-opioid receptor (MOR) activation and monoamine reuptake inhibition. However, the number of adverse reactions has been growing along with their increasing use and misuse. The potential toxicological mechanisms for these drugs are not completely understood, especially for tapentadol, owing to its shorter market history. Therefore, in the present study, we aimed to comparatively assess the putative lung, cardiac, and brain cortex toxicological damage elicited by the repeated exposure to therapeutic doses of both prescription opioids. To this purpose, male Wistar rats were intraperitoneally injected with single daily doses of 10, 25, and 50 mg/kg tramadol or tapentadol, corresponding to a standard analgesic dose, an intermediate dose, and the maximum recommended daily dose, respectively, for 14 consecutive days. Such treatment was found to lead mainly to lipid peroxidation and inflammation in lung and brain cortex tissues, as shown through augmented thiobarbituric acid reactive substances (TBARS), as well as to increased serum inflammation biomarkers, such as C reactive protein (CRP) and tumor necrosis factor-α (TNF-α). Cardiomyocyte integrity was also shown to be affected, since both opioids incremented serum lactate dehydrogenase (LDH) and α-hydroxybutyrate dehydrogenase (α-HBDH) activities, while tapentadol was associated with increased serum creatine kinase muscle brain (CK-MB) isoform activity. In turn, the analysis of metabolic parameters in brain cortex tissue revealed increased lactate concentration upon exposure to both drugs, as well as augmented LDH and creatine kinase (CK) activities following tapentadol treatment. In addition, pneumo- and cardiotoxicity biomarkers were quantified at the gene level, while neurotoxicity biomarkers were quantified both at the gene and protein levels; changes in their expression correlate with the oxidative stress, inflammatory, metabolic, and histopathological changes that were detected. Hematoxylin and eosin (H & E) staining revealed several histopathological alterations, including alveolar collapse and destruction in lung sections, inflammatory infiltrates, altered cardiomyocytes and loss of striation in heart sections, degenerated neurons, and accumulation of glial and microglial cells in brain cortex sections. In turn, Masson’s trichrome staining confirmed fibrous tissue deposition in cardiac tissue. Taken as a whole, these results show that the repeated administration of both prescription opioids extends the dose range for which toxicological injury is observed to lower therapeutic doses. They also reinforce previous assumptions that tramadol and tapentadol are not devoid of toxicological risk even at clinical doses. Full article