Hazard assessment of engineered nanomaterials - impacts on hepatic and renal models

This study was conducted as part of a large consortium (FP7 project – ENPRA) to investigate the potential hazard of a wide range of nanomaterials (one Ag, two ZnO, two MWCNTs and five TiO2) on the liver and the kidneys for the purpose of risk assessment. The in vitro C3A hepatocyte model demonstrated that Ag and ZnO NMs were consistently more potent with respect to cytotoxicity and cytokine production. In comparison the MWCNT and TiO2 nanomaterials investigated revealed relatively lower toxicity. The cytotoxicity of ZnO may be related to its solubility, but this is less likely for the Ag NMs. Urea and albumin production were measured as indicators of hepatic function. These markers were only altered by the coated and uncoated ZnO, which significantly decreased albumin production. The C3A model also showed that the NM which induced a low cytotoxicity (TiO2 and MWCNTs) generated intracellular ROS, induced oxidative stress (GSH depletion) and that an oxidative mechanism was involved in both the induction of IL8 protein production and genotoxicity. The C3A cells were demonstrated to be a very good model to investigate nanomaterial induced effects on hepatocytes when compared to primary human hepatocytes. The results also suggested that biotransformation enzymes in hepatocytes are not important in terms of determining nanotoxicology. In vivo mice models demonstrated that the instilled Ag, ZnO and positively charged TiO2 result in distal effects on the liver in the form of oxidative stress. While all NMs with the exception of the two MWCNTs instilled via the lungs caused changes in gene expression in the liver in varying degrees. The intravenous exposure of mice to the NMs resulted in a neutrophil influx into the liver. These leukocytes play an important in the initiation of the immune response to the NMs. However the NMs were not sufficient to cause any long term neutrophil mediated inflammation or damage to the liver tissue. Any changes that were observed after 24 hr post exposure in terms of leukocyte infiltration into the tissue, antioxidants status and changes in gene expression related to inflammation, oxidative stress and apoptosis had resolved 72 hr post exposure. Next, we show that Kupffer cells are very important in the liver immune response to the NMs with a significant change in the cytokine profile following the enrichment of the macrophage population. Finally, investigations using the HK-2 renal model demonstrated that ZnO and Ag NMs were consistently more potent with respect to cytotoxicity, cytokine production (IL6 and IL8) and intracellular reactive oxygen species production. These results were consistent with those observed in the hepatocyte models. We noted that short term sub-lethal exposure to the Ag and two of the TiO2 NMs (positively charged and the 94 nm TiO2) resulted in most evident DNA damage

AIMS: An Automatic Semantic Machine Learning Microservice Framework to Support Biomedical and Bioengineering Research

The fusion of machine learning and biomedical research offers novel ways to understand, diagnose, and treat various health conditions. However, the complexities of biomedical data, coupled with the intricate process of developing and deploying machine learning solutions, often pose significant challenges to researchers in these fields. Our pivotal achievement in this research is the introduction of the Automatic Semantic Machine Learning Microservice Framework (AIMS). AIMS addresses these challenges by automating various stages of the machine learning pipeline, with a particular emphasis on the ontology of machine learning services tailored for the biomedical domain. This ontology encompasses everything from task representation, service modeling, and knowledge acquisition to knowledge reasoning and the establishment of a self-supervised learning policy. Our framework has been crafted to prioritize model interpretability, integrate domain knowledge effortlessly, and handle biomedical data with efficiency. Additionally, AIMS boasts a distinctive feature: it leverages self-supervised knowledge learning through reinforcement learning techniques, paired with an ontology-based policy recording schema. This enables it to autonomously generate, fine-tune, and continually adapt to machine learning models, especially when faced with new tasks and data. Our work has two standout contributions of demonstrating that machine learning processes in the biomedical domain can be automated, while integrating a rich domain knowledge base and providing a way for machines to have a self-learning ability, ensuring they handle new tasks effectively. To showcase AIMS in action, we've highlighted its prowess in three case studies from biomedical tasks. These examples emphasize how our framework can simplify research routines, uplift the caliber of scientific exploration, and set the stage for notable advances

A review of hepatic nanotoxicology - summation of recent findings and considerations for the next generation of study designs

The liver is one of the most important multi-functional organs in the human body. Amongst various crucial functions, it is the main detoxification center and predominantly implicated in the clearance of xenobiotics potentially including particulates that reach this organ. It is now well established that a significant quantity of injected, ingested or inhaled nanomaterials (NMs) translocate from primary exposure sites and accumulate in liver. This review aimed to summarize and discuss the progress made in the field of hepatic nanotoxicology, and crucially highlight knowledge gaps that still exist. Key considerations include In vivo studies clearly demonstrate that low-solubility NMs predominantly accumulate in the liver macrophages the Kupffer cells (KC), rather than hepatocytes. KCs lining the liver sinusoids are the first cell type that comes in contact with NMs in vivo. Further, these macrophages govern overall inflammatory responses in a healthy liver. Therefore, interaction with of NM with KCs in vitro appears to be very important. Many acute in vivo studies demonstrated signs of toxicity induced by a variety of NMs. However, acute studies may not be that meaningful due to liver’s unique and unparalleled ability to regenerate. In almost all investigations where a recovery period was included, the healthy liver was able to recover from NM challenge. This organ’s ability to regenerate cannot be reproduced in vitro. However, recommendations and evidence is offered for the design of more physiologically relevant in vitro models. Models of hepatic disease enhance the NM-induced hepatotoxicity. The review offers a number of important suggestions for the future of hepatic nanotoxicology study design. This is of great significance as its findings are highly relevant due to the development of more advanced in vitro, and in silico models aiming to improve physiologically relevant toxicological testing strategies and bridging the gap between in vitro and in vivo experimentation

The role of mast cells during experimental Schistosomiasis mansoni in mice

Mast cells are important immune cells which reside in crucial sites in all organs of the body. The large number of potentially active substances which are released from the mast cell upon cell degranulation play a central role in the pathology of parasitic infections, allergic and other chronic inflammatory disorders. The influence of mast cell-derived mediators may well be important factors in atherosclerosis, anaesthesia, arthritis, angiogenesis, lipid metabolism, fibroblast interactions and other events. The association between mast cells, eosinophils and IgE antibody (three hallmarks of helminth infections and some other diseases) is of great interest. An increase in our knowledge of the processes in this association would be beneficial for the treatment and prevention of those diseases. Development of reliable methods for better investigation of mast cells and eosinophils both separately and together in tissues and body fluids was the first target of the study and a prolonged investigation resulted in the development of improved methods for fixation and staining of mast cells and eosinophils simultaneously in internal organ and skin tissues. The investigation also resulted in improving the fixation and staining of those cells separately in internal tissue. The common method of counting the cells in intestinal tissues suffers from various limitations. A new simple counting method, which could be applied to counting of the cells in the intestine and any other diffuse tissue, was developed during this investigation. The kinetics of mast cell populations in the anterior, middle and posterior portions of the small intestine and the kinetics of the mast cells and eosinophils in the liver granuloma and the association and the effect of mast cells and eosinophils on egg destruction and granuloma production were studied during a 16 week experimental Schistosoma mansoni-infection. The distribution of mast cells was always greater in the anterior than posterior portion of intestine and the number of the mast cells was greater in the intestine than in the liver (with relatively equal numbers of granulomas). On the basis of these observations and information obtained from a review literature, the possibility of mast cell attraction to nerve-derived material was proposed. The notion is that continuous stimulation of the nerve receptors or damage and degeneration of the nerve fibres by rough foreign particles (stimulants) are terminats in the release of chemoattractant material (s) from irritated nerve cells. Consequently mast cells migrate toward the injured tissue as a result of nerve-induced chemotaxis. This hypothesis not only explains the unequal distribution of mast cells in inflamed tissues but also gives a reasonable framework for consideration of possible influences on T helper cell activation. In this way mast cells which are attracted to inflamed tissues are triggered through cross-linking of high affinity IgE receptors on their surface plasma membranes. Degranulation and release of a collection of Th-1 down-regulating and Th-2 up-regulating cytokines from mast cells would lead to Th-2 type helper cell activation. For a test of this hypothesis, in vitro and in vivo experiments were designed. Pure mast cells were prepared by bone marrow culture and in vitro chemotaxis assays (culture, micro-pore and polarisation) were carried out. Promising results were achieved from polarisation assays, but because of time limitations the investigation had to be curtailed. Continuation of the in vitro and the in vivo experiments are believed to be worth considering

Hepatic toxicity assessment of cationic liposome exposure in healthy and chronic alcohol fed mice

The utilisation of nanoparticles as the means of targeted delivery of therapeutics and/or imaging agents could greatly enhance the specific transport of biologically active payloads to target tissues while avoiding or reducing undesired side-effects. To allow for this to become a reality, the question of potential toxicological effects needs to be addressed. In the present investigation, a cationic liposome with prospective for medical applications was constructed and thoroughly assessed for any material-induced hepatic adverse effects in vivo − in healthy and alcoholic hepatic disease models and in vitro − (HepG2 cells). The data demonstrated that intravenous injection of liposomes did not cause any significant in vivo hepatic toxicity (inflammation, alterations in blood parameters, anti-oxidant depletion, acute phase response and histopathology) at doses of 200 μg per mouse in either healthy or chronically alcohol fed mice. Additionally, the in vitro material-induced adverse effects (cytotoxicity, inflammation or albumin secretion) were all also minimal. The data from this study demonstrated that the intravenous injection of cationic liposomes does not cause hepatic toxicity. This investigation is important as it investigates the toxicity of a nano-sized material in a model of alcoholic hepatic disease in vitro and in vivo. This is an area of research in the field of nanotoxicology that is currently almost entirely overlooked. Keywords: Toxicology, Nanoparticles, Pharmaceutical scienc

Nanotoxicology

As the production and use of nanomaterials (NMs) in medicine and many other applications develops, so the need to understand the potential risks posed by NMs to human health (and the environment) increases (Aitken et al. 2006). At the nanoscale (1-100 nm), materials exhibit properties that are different to larger or bulk materials. These new properties are exploited by researchers and industry to generate new products; however, the same properties can also inuence how the NM behaves in biological systems, including affecting toxicity. Nanotoxicology is a relatively new eld of research that aims to assess the human and environmental hazard of nanomaterials. In recent years, this new discipline has seen a rapid expansion in the number of studies concerned with assessing the safety of engineered NMs (Figure 20.1)

Hepatic oxidative stress, genotoxicity and vascular dysfunction in lean or obese zucker rats

Metabolic syndrome is associated with increased risk of cardiovascular disease, which could be related to oxidative stress. Here, we investigated the associations between hepatic oxidative stress and vascular function in pressurized mesenteric arteries from lean and obese Zucker rats at 14, 24 and 37 weeks of age. Obese Zucker rats had more hepatic fat accumulation than their lean counterparts. Nevertheless, the obese rats had unaltered age-related level of hepatic oxidatively damaged DNA in terms of formamidopyrimidine DNA glycosylase (FPG) or human oxoguanine DNA glycosylase (hOGG1) sensitive sites as measured by the comet assay. There were decreasing levels of oxidatively damaged DNA with age in the liver of lean rats, which occurred concurrently with increased expression of Ogg1. The 37 week old lean rats also had higher expression level of Hmox1 and elevated levels of DNA strand breaks in the liver. Still, both strain of rats had increased protein level of HMOX-1 in the liver at 37 weeks. The external and lumen diameters of mesenteric arteries increased with age in obese Zucker rats with no change in media cross-sectional area, indicating outward re-modelling without hypertrophy of the vascular wall. There was increased maximal response to acetylcholine-mediated endothelium-dependent vasodilatation in both strains of rats. Collectively, the results indicate that obese Zucker rats only displayed a modest mesenteric vascular dysfunction, with no increase in hepatic oxidative stress-generated DNA damage despite substantial hepatic steatosis

Substantial modification of the gene expression profile following exposure of macrophages to welding-related nanoparticles

International audienceAnthropic nanoparticles (NP) are increasingly produced and emitted, with accompanying concerns for human health. Currently there is no global understanding as to the exact mechanistics of NP toxicity, as the traditional nanotoxicological approaches only provide a restricted overview. To address this issue, we performed an in-depth transcriptomic analysis of human macrophages exposed to a panel of welding-related metal oxide NP that we previously identified in welders lungs (Fe 2 O 3 , Fe 3 O 4 , MnFe 2 O 4 and CrOOH NP). Utilizing the specified analysis criteria (|fold change|≥1.5, p≤0.001), a total of 2164 genes were identified to be differentially expressed after THP-1 macrophage exposure to the different NP. Performing Gene Ontology enrichment analysis, for cellular content, biological processes and Swiss-Prot/Protein Information Resource keywords the data show for the first time a profound modification of gene differential expression in response to the different NP, among which MnFe 2 O 4 NP were the most potent to induce THP-1 macrophage activation. The transcriptomic analysis utilized in the study, provides novel insights into mechanisms that could contribute to NP-induced adverse effects and support the need for widened approaches to supplement existing knowledge of the processes underlying NP toxicity which would have not been possible using traditional nanotoxicological studies

Engineered Nanomaterial Impact in the Liver following Exposure via an Intravenous Route–The Role of Polymorphonuclear Leukocytes and Gene Expression in the Organ

Background and methods: Following exposure via a number of routes (inhalation, ingestion or injection), someNanomaterials (NMs) translocate to secondary tissues, prominently the liver. This study investigated the effects of anarray of NMs, varying in their physicochemical characteristics, consisting of two types of Zinc Oxide (ZnO), two MultiwalledCarbon Nanotubes (MWCNT), one silver (Ag) and one titanium dioxide (TiO2) on the liver, following Intravenous(IV) exposure of C57/BL6 mice. The animals were exposed to either a single dose of NM (128 μg/ml–100 μl) or threedoses of (64 μg/ml–100 μl), every 24 hr. Animals were dissected 6, 24, 48 and 72 hr after the single IV injection, or 72hr after the triple injection regime.Results and conclusions: A Myeloperoxidase (MPO) assay was utilised to quantify neutrophil influx into thetissue. However, as MPO is also found in other granulocytes in smaller quantities, the neutrophils in the liver tissue werealso labelled, using a specific neutrophil cell surface marker (Ly-6B.2). A wide array of NMs (including ZnO, Ag, TiO2and MWCNT) induced a neutrophil influx into the liver, as early as 6 hr post IV exposure. However, the neutrophils wereonly involved in the initial phases of the immune response against the NMs, as the leukocyte numbers had returned tocontrol levels after 48 hr. Finally, analysis of mRNA expression in mice livers showed alterations in levels of C3, IL6,IL10, CXCL2 and ICAM-1