Fühner-Wieland's Sammlung von Vergiftungsfällen

Es wird eine Übersicht über die im Aufsichtsbezirk des Staatlichen Gewerbearztes von Nordrhein vorgekommenen gewerblichen Vergiftungen durch Phosphorverbindungen gegeben. Es werden die Entstehungsweise und das klinische Bild der beobachteten Intoxikationen durch Phosphoroxyde, Phosphorwasserstoff und organische Phosphorsäureester geschildert.

Results of long-term toxicity studies of methylmercury (MeHg) in monkeys have been reported. The aim of this study was to estimate the threshold body burden, blood level and threshold daily intake (TDI) of MeHg for monkey and human. The concepts of this study stood on that body burden of MeHg would follow the accumulation theory, and that the more intake of MeHg, the earlier the neurotoxicity appeared, vice versa. The threshold blood level (TBL) of monkey was estimated to be 0.71 as Hg mg/L and the body burden was estimated to be 4.83 as Hg mg/kg. The TDI was estimated to be 0.025 as Hg mg/kg day. In human, the TBL was estimated with compensation by elimination constants of human and monkey. The blood threshold limit and TDI of human were estimated to be 0.33 as Hg mg/L and 0.0046 as Hg mg/kg day, respectively. The estimated body burden was 0.46 as Hg mg/kg.

Tens of thousands of long non-coding RNAs (lncRNAs) have been identified through RNA-seq analysis, but the biological and pathological significance remains unclear. By integrating the genome-wide lncRNA data with a cross-ancestry meta-analysis of PDAC GWASs, we depicted a comprehensive atlas of pancreatic ductal adenocarcinoma (PDAC)-associated lncRNAs, containing 1,204 lncRNA (445 novel lncRNAs and 759 GENCODE annotated lncRNAs) and 4,368 variants. Furthermore, we found that PDAC-associated lncRNAs could function by altering chromatin activity, transcription factors, and RNA-binding proteins binding affinity. Importantly, genetic variants linked to PDAC are preferentially found at PDAC-associated lncRNA regions, supporting the biological and clinical relevance of PDAC-associated lncRNAs. Finally, we prioritized a novel transcript (MICT00000110172.1) of RP11-638I2.4 as a potential tumor promoter. MICT00000110172.1 is able to reinforce the interaction with YY1, which could reverse the effect of YY1 on pancreatic cancer cell cycle arrest to promote the pancreatic cancer growth. G > A change at rs2757535 in the second exon of MICT00000110172.1 induces a spatial structural change and creates a target region for YY1 binding, which enforces the effect of MICT00000110172.1 in an allele-specific manner, and thus confers susceptibility to tumorigenesis. In summary, our results extend the repertoire of PDAC-associated lncRNAs that could act as a starting point for future functional explorations, and the identification of lncRNA‐based target therapy.

Monolayer cultures of primary hepatocytes, isolated from freshly removed livers, represent widely used in vitro tools in the area of liver physiology and pathology, pharmacology and toxicology. However, a major shortcoming of these systems is that they cope with dedifferentiation, which is accompanied by spontaneous cell death. The goal of the present study was to elucidate the mechanisms that drive the process of self-generated cell demise in primary hepatocyte cultures. For this purpose, isolated rat hepatocytes were cultivated under conventional conditions, and the occurrence of apoptosis and necrosis was monitored during 4 days by performing a set of acknowledged cell death assays. These included examination of cell morphology by light microscopy, quantification of apoptotic and necrotic cell populations by Hoechst 33342 and propidium iodide in situ staining, assessment of apoptotic and necrotic activities by measuring caspase 3-like activity and extracellular leakage of lactate dehydrogenase, and studying the expression of apoptosis regulators through immunoblot analysis. In essence, two cell death peaks were observed, namely shortly after cell seeding and in the final stages of the cultivation period, both involving apoptotic and necrotic actions. The outcome of this study not only sheds new light onto the molecular processes that underlie spontaneous cell death in primary hepatocyte cultures, but also opens perspectives for the establishment of strategies to increase cell survival in these popular in vitro systems.

Icaritin (ICT), a prenylflavonoid derivative extracted from the Epimedium genus, has exhibited antitumor effects in hepatocellular carcinoma (HCC) cells and safety and tolerance in clinical settings. However, ICT exhibits low blood concentration and the in vivo dominant plasma species of ICT is glucuronides [icaritin-3-glucuronide (G1), icaritin-7-glucuronide (G2) and icaritin-3, 7-diglucuronide (DIG)]. Therefore, how ICT reaches the liver and exerts its effect with low toxicity remains unknown. Therefore, pharmacokinetic experiments (p.o. 5 mg/kg with/out 50 mg/kg inhibitor combo), intestinal perfusion (2 μM ICT), portal vein infusion (1.6 μM ICT, 7.1 μM G1, 6.8 μM G2 and 4.4 μM DIG), and in vitro studies (the concentration range of substrates: 0.3–10 μM) were conducted in the present study. Ultimately, ICT was shown to undergo glucuronidation by the intestine and subsequent uptake by hepatocytes via organic anion transporting peptides (OATPs) as conjugates, followed by biliary excretion mainly as diglucuronide. In conclusion, we found for the first time that the intestine is considered as the major metabolic organ, liver as the main recycling organ for the enterohepatic recycling (EHR) of ICT. Moreover, DIG is the main species in the systemic circulation following oral administration of ICT which explains the low toxicity of ICT in clinical settings.

Organ-on-chip (OoC) technology is full of engineering and biological challenges, but it has the potential to revolutionize the Next-Generation Risk Assessment of novel ingredients for consumer products and chemicals. A successful incorporation of OoC technology into the Next-Generation Risk Assessment toolbox depends on the robustness of the microfluidic devices and the organ tissue models used. Recent advances in standardized device manufacturing, organ tissue cultivation and growth protocols offer the ability to bridge the gaps towards the implementation of organ-on-chip technology. Next-Generation Risk Assessment is an exposure-led and hypothesis-driven tiered approach to risk assessment using detailed human exposure information and the application of appropriate new (non-animal) toxicological testing approaches. Organ-on-chip presents a promising in vitro approach by combining human cell culturing with dynamic microfluidics to improve physiological emulation. Here, we critically review commercial organ-on-chip devices, as well as recent tissue culture model studies of the skin, intestinal barrier and liver as the main metabolic organ to be used on-chip for Next-Generation Risk Assessment. Finally, microfluidically linked tissue combinations such as skin–liver and intestine–liver in organ-on-chip devices are reviewed as they form a relevant aspect for advancing toxicokinetic and toxicodynamic studies. We point to recent achievements and challenges to overcome, to advance non-animal, human-relevant safety studies.