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(1) Background: The rise in electronic cigarette (E-cigarette) popularity, especially among adolescents, has prompted research to investigate potential effects on health. Although much research has been carried out on the effect on lung health, the first site exposed to vaping-the oral cavity-has received relatively little attention. The aims of this study were twofold: to examine the effects of E-liquids on the viability and hydrophobicity of oral commensal streptococci, and the effects of E-cigarette-generated aerosols on the biomass and viability of oral commensal streptococci. (2) Methods: Quantitative and confocal biofilm analysis, live-dead staining, and hydrophobicity assays were used to determine the effect on oral commensal streptococci after exposure to E-liquids and/or E-cigarette-generated aerosols. (3) Results: E-liquids and flavors have a bactericidal effect on multispecies oral commensal biofilms and increase the hydrophobicity of oral commensal streptococci. Flavorless and some flavored E-liquid aerosols have a bactericidal effect on oral commensal biofilms while having no effect on overall biomass. (4) Conclusions: These results indicate that E-liquids/E-cigarette-generated aerosols alter the chemical interactions and viability of oral commensal streptococci. Consequently, the use of E-cigarettes has the potential to alter the status of disease and health in the oral cavity and, by extension, affect systemic health.

Dicyclopentadiene (DCPD) was investigated in a 14-day oral rat toxicity study based on the OECD 407 guideline in combination with plasma metabolomics. Wistar rats received the compound daily via gavage at dose levels of 0, 50 and 150 mg/kg bw. The high dose induced transient clinical signs of toxicity and in males only reduced body weight gain. High dose liver changes were characterized by altered clinical chemistry parameters in both sexes and pathological changes in females. In high dose males an accumulation of alpha-2 u-globulin in the kidney was noted. Comparing the DCPD metabolome with previously established specific metabolome patterns in the MetaMap® Tox data base suggested that the high dose would result in liver enzyme induction leading to increased breakdown of thyroid hormones for males and females. An indication for liver toxicity in males was also noted. Metabolomics also suggested an effect on the functionality of the adrenals in high dose males, which together with published data, is suggestive of a stress related effect in this organ. The results of the present 14-day combined toxicity and metabolome investigations were qualitatively in line with literature data from subchronic oral studies in rats with DCPD. Importantly no other types of organ toxicity, or hormone dysregulation beyond the ones associated with liver enzyme induction and stress were indicated, again in line with results of published 90-day studies. It is therefore suggested that short term "smart" studies, combining classical toxicity with 'omics technologies, could be a 2 R (refine and reduce) new approach method allowing for the reduction of in vivo toxicity testing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

There is currently no suitable autologous tissue to bridge large tracheal defects. As a result, no standard of care exists for long-segment tracheal reconstruction. Tissue engineering has the potential to create a scaffold from allografts or xenografts that can support neotissue regeneration identical to the native trachea. Recent advances in tissue engineering have led to the idea of partial decellularization that allows for the creation of tracheal scaffolds that supports tracheal epithelial formation while preserving mechanical properties. However, the ability of partial decellularization to eliminate graft immunogenicity remains unknown, and understanding the immunogenic properties of partially decellularized tracheal grafts (PDTG) is a critical step toward clinical translation. Here, we determined that tracheal allograft immunogenicity results in epithelial cell sloughing and replacement with dysplastic columnar epithelium and that partial decellularization creates grafts that are able to support an epithelium without histologic signs of rejection. Moreover, allograft implantation elicits CD8+ T-cell infiltration, a mediator of rejection, while PDTG did not. Hence, we establish that partial decellularization eliminates allograft immunogenicity while creating a scaffold for implantation that can support spatially appropriate airway regeneration., Competing Interests: The authors have no conflicts of interest to disclose as described by the American Journal of Transplantation., (© 2023 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of The American Institute of Chemical Engineers.)

The diversity of microbial species in the gut has a strong influence on health and development of the host. Further, there are indications that the variation in expression of gut bacterial metabolic enzymes is less diverse than the taxonomic profile, underlying the importance of microbiome functionality, particularly from a toxicological perspective. To address these relationships, the gut bacterial composition of Wistar rats was altered by a 28 day oral treatment with the antibiotics tobramycin or colistin sulfate. On the basis of 16S marker gene sequencing data, tobramycin was found to cause a strong reduction in the diversity and relative abundance of the microbiome, whereas colistin sulfate had only a marginal impact. Associated plasma and fecal metabolomes were characterized by targeted mass spectrometry-based profiling. The fecal metabolome of tobramycin-treated animals had a high number of significant alterations in metabolite levels compared to controls, particularly in amino acids, lipids, bile acids (BAs), carbohydrates, and energy metabolites. The accumulation of primary BAs and significant reduction of secondary BAs in the feces indicated that the microbial alterations induced by tobramycin inhibit bacterial deconjugation reactions. The plasma metabolome showed less, but still many alterations in the same metabolite groups, including reductions in indole derivatives and hippuric acid, and furthermore, despite marginal effects of colistin sulfate treatment, there were nonetheless systemic alterations also in BAs. Aside from these treatment-based differences, we also uncovered interindividual differences particularly centering on the loss of Verrucomicrobiaceae in the microbiome, but with no apparent associated metabolite alterations. Finally, by comparing the data set from this study with metabolome alterations in the MetaMapTox database, key metabolite alterations were identified as plasma biomarkers indicative of altered gut microbiomes resulting from a wide activity spectrum of antibiotics.

An understanding of the changes in gut microbiome composition and its associated metabolic functions is important to assess the potential implications thereof on host health. Thus, to elucidate the connection between the gut microbiome and the fecal and plasma metabolomes, two poorly bioavailable carbapenem antibiotics (doripenem and meropenem), were administered in a 28-day oral study to male and female Wistar rats. Additionally, the recovery of the gut microbiome and metabolomes in doripenem-exposed rats were studied one and two weeks after antibiotic treatment (i.e., doripenem-recovery groups). The 16S bacterial community analysis revealed an altered microbial population in all antibiotic treatments and a recovery of bacterial diversity in the doripenem-recovery groups. A similar pattern was observed in the fecal metabolomes of treated animals. In the recovery group, particularly after one week, an over-compensation was observed in fecal metabolites, as they were significantly changed in the opposite direction compared to previously changed metabolites upon 28 days of antibiotic exposure. Key plasma metabolites known to be diagnostic of antibiotic-induced microbial shifts, including indole derivatives, hippuric acid, and bile acids were also affected by the two carbapenems. Moreover, a unique increase in the levels of indole-3-acetic acid in plasma following meropenem treatment was observed. As was observed for the fecal metabolome, an overcompensation of plasma metabolites was observed in the recovery group. The data from this study provides insights into the connectivity of the microbiome and fecal and plasma metabolomes and demonstrates restoration post-antibiotic treatment not only for the microbiome but also for the metabolomes. The importance of overcompensation reactions for health needs further studies.

To elucidate if artificial sweeteners modify fecal bacterial composition and the fecal and plasma metabolomes, Wistar rats from both sexes were treated for 28 days with acesulfame potassium (40 and 120 mg/kg body weight) and saccharin (20 and 100 mg/kg body weight). Targeted MS-based metabolome profiling (plasma and feces) and fecal 16S gene sequencing were conducted. Both sweeteners exhibited only minor effects on the fecal metabolome and microbiota. Saccharin treatment significantly altered amino acids, lipids, energy metabolism and specifically, bile acids in the plasma metabolome. Additionally, sex-specific differences were observed for conjugated primary and secondary bile acids. Acesulfame potassium treated male rats showed larger alterations in glycine conjugated primary and secondary bile-acids than females. Other changes in the plasma metabolome were more profound for saccharin than acesulfame potassium, for both sexes. Changes in conjugated bile-acids in plasma, which are often associated with microbiome changes, and the absence of similarly large changes in microbiota suggest an adaptative change of the latter, rather than toxicity. Further studies with a high resolution 16S sequencing data and/or metagenomics approach, with particular emphasis on bile acids, will be required to explore the mechanisms driving this metabolic outcome of saccharin in Wistar rats., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The oral uptake of nanoparticles is an important route of human exposure and requires solid models for hazard assessment. While the systemic availability is generally low, ingestion may not only affect gastrointestinal tissues but also intestinal microbes. The gut microbiota contributes essentially to human health, whereas gut microbial dysbiosis is known to promote several intestinal and extra-intestinal diseases. Gut microbiota-derived metabolites, which are found in the blood stream, serve as key molecular mediators of host metabolism and immunity., Results: Gut microbiota and the plasma metabolome were analyzed in male Wistar rats receiving either SiO 2 (1000 mg/kg body weight/day) or Ag nanoparticles (100 mg/kg body weight/day) during a 28-day oral gavage study. Comprehensive clinical, histopathological and hematological examinations showed no signs of nanoparticle-induced toxicity. In contrast, the gut microbiota was affected by both nanoparticles, with significant alterations at all analyzed taxonomical levels. Treatments with each of the nanoparticles led to an increased abundance of Prevotellaceae, a family with gut species known to be correlated with intestinal inflammation. Only in Ag nanoparticle-exposed animals, Akkermansia, a genus known for its protective impact on the intestinal barrier was depleted to hardly detectable levels. In SiO 2 nanoparticles-treated animals, several genera were significantly reduced, including probiotics such as Enterococcus. From the analysis of 231 plasma metabolites, we found 18 metabolites to be significantly altered in Ag-or SiO 2 nanoparticles-treated rats. For most of these metabolites, an association with gut microbiota has been reported previously. Strikingly, both nanoparticle-treatments led to a significant reduction of gut microbiota-derived indole-3-acetic acid in plasma. This ligand of the arylhydrocarbon receptor is critical for regulating immunity, stem cell maintenance, cellular differentiation and xenobiotic-metabolizing enzymes., Conclusions: The combined profiling of intestinal microbiome and plasma metabolome may serve as an early and sensitive indicator of gut microbiome changes induced by orally administered nanoparticles; this will help to recognize potential adverse effects of these changes to the host., (© 2022. The Author(s).)

Perceptual adaptation is often studied within a single sense. However, our experience of the world is naturally multisensory. Here, we investigated cross-sensory (visual-vestibular) adaptation of self-motion perception. It was previously found that relatively long visual self-motion stimuli (≳15 sec) are required to adapt subsequent vestibular perception, and that shorter duration stimuli do not elicit cross-sensory (visual↔vestibular) adaptation. However, it is not known whether several discrete short-duration stimuli may lead to cross-sensory adaptation (even when their sum, if presented together, would be too short to elicit cross-sensory adaptation). This would suggest that the brain monitors and adapts to supra-modal statistics of events in the environment. Here we investigated whether cross-sensory (visual↔vestibular) adaptation occurs after experiencing several short (1 sec) self-motion stimuli. Forty-five participants discriminated the headings of a series of self-motion stimuli. To expose adaptation effects, the trials were grouped in 140 batches, each comprising three 'prior' trials, with headings biased to the right or left, followed by a single unbiased 'test' trial. Right, and left-biased batches were interleaved pseudo-randomly. We found significant adaptation in both cross-sensory conditions (visual prior and vestibular test trials, and vice versa), as well as both unisensory conditions (when prior and test trials were of the same modality - either visual or vestibular). Fitting the data with a logistic regression model revealed that adaptation was elicited by the prior stimuli (not prior choices). These results suggest that the brain monitors supra-modal statistics of events in the environment, even for short-duration stimuli, leading to functional (supra-modal) adaptation of perception., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We describe a strategy using an in vitro metabolomics assay with tubular rat NRK-52E cells to investigate the Modes of Action (MoAs) of nephrotoxic compounds. Chemicals were selected according to their MoAs based on literature information: acetaminophen, 4-aminophenol and S-(trichlorovinyl-)L-cysteine (TCVC), (covalent protein binding); gentamycin, vancomycin, polymycin B and CdCl 2 (lysosomal overload) and tenofovir and cidofovir (mitochondrial DNA-interaction). After treatment and harvesting of the cells, intracellular endogenous metabolites were quantified relative to vehicle control. Metabolite patterns were evaluated in a purely data-driven pattern generation process excluding published information. This strategy confirmed the assignment of the chemicals to the respective MoA except for TCVC and CdCl 2 . Finally, TCVC was defined as unidentified and CdCl 2 was reclassified to the MoA "covalent protein binding". Hierarchical cluster analysis of 58 distinct metabolites from the patterns enabled a clear visual separation of chemicals in each MoA. The assay reproducibility was very good and metabolic responses were consistent. These results support the use of metabolome analysis in NRK-52E cells as a suitable tool for understanding and investigating the MoA of nephrotoxicants. This assay could enable the early identification of nephrotoxic compounds and finally reduce animal testing., Competing Interests: Declaration of Competing Interest BASF SE might use this approach also in the future for registration of their products., (Copyright © 2021 Elsevier B.V. All rights reserved.)