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Pyrrolizidine Alkaloids
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
As PA clivorine is shown to induce apoptotic cell death and oxidative stress injury in human normal liver L-02 cells, a plant-derived flavonoid called quercetin is being trialed for preventing clivorine-induced apoptotic cell death. Through upregulation of oxidative or metabolic stress-related genes (e.g., Fmo5, Polr2k, Sod2, Ephx2, Sod1, Hmox2, Hmox1, Cyp2b10, Cyp1b1, Cyp2a5, Cyp3a11, and Cyp7a1) and heat shock–related genes (e.g., Hspa5, Hspa1 l, Hspa1b, Dnaja1, and Hspe1), quercetin works to increase the level of liver GSH (which is an important endogenous antioxidant), and to ameliorate clivorine-induced oxidative stress [34].
Intoxication as a Risk Factor
Published in Burkhard Madea, Asphyxiation, Suffocation,and Neck Pressure Deaths, 2020
Chest compression may also be a factor in sudden deaths associated with subdual of violent persons by the police, guards, paramedics or healthcare professionals. The actions taken may involve both restraint and chest compression. In many cases, positional asphyxia has also been suggested to have played an important role in these deaths. A large number of violent persons resisting arrest or emergency care are under the influence of alcohol, yet sudden deaths during apprehension and subdual of drunk subjects is rare. It was observed relatively early that many of the sudden deaths in custody comprised subjects with an altered mental status, and Wetli and Fishbain in 1985 [45] linked many of these deaths with cocaine-induced psychosis, today called ‘excited delirium’. A large number of case reports and case series were subsequently published. In parallel, many reports dealt with positional asphyxia as a competing cause for these in-custody deaths, and a number of experimental studies on human subjects were performed to evaluate the effects of various restraint measures and body positions on respiratory and circulatory parameters [7,8,33]. However, the limitation of these studies was that all volunteers were healthy subjects and were not under the influence of drugs. During the last two decades, a fairly large number of papers have been published reporting on sudden in-custody deaths associated with excited delirium. Most commonly, the excited delirium cases have been associated with cocaine abuse, but the syndrome has also been described in association with use of methamphetamine, MDMA, alpha-PVP, methylone and ephedrine [22,23,29]. Virtually all drugs associated with excited delirium are psychostimulants that result in an increase in extracellular dopamine levels in critical brain regions. The main pathophysiological explanation for the clinical symptoms is a dopaminergic overdrive, due to a failure of the affected person to upregulate the dopamine transporter protein [22], although a general depression of the cholinergic system in the brain probably contributes to the delirious state. The severity of this acute condition is well recognized today. In the acute phase, death may be caused by cardiac ischaemia due to a tremendous increase in energy demand during extraordinary exertion and sympatico-mimetic overdrive. Hyperthermia is almost always recorded, and may cause death after a while, if unrecognized, or left uncontrolled. Subjects surviving these phases may die later due to massive rhabdomyolysis. The problem is that many of these deaths occur early and unexpectedly during a violent fight, and hence before any medical examination is possible. Postmortem examination of the dopamine transporter protein in ventral striatum and expression of the HSPA1B gene and its product HSP70 in the temporal cortex has been suggested as with markers of excited delirium [23]. However, even if this condition has been observed to cause death in the absence of any intervention [36], in most cases restraints, chest compression and abnormal body position are factors that the pathologist needs to consider when evaluating the case.
Impact of copper oxide particle dissolution on lung epithelial cell toxicity: response characterization using global transcriptional analysis
Published in Nanotoxicology, 2021
Andrey Boyadzhiev, Mary-Luyza Avramescu, Dongmei Wu, Andrew Williams, Pat Rasmussen, Sabina Halappanavar
Exposure to both CuO NPs and dissolved copper ions has been shown to induce similar downstream cellular responses, such as cell cycle arrest, oxidative stress, DNA damage signaling, and apoptosis (Strauch et al. 2017). From temporal gene expression analysis conducted in the present study, observed CuO NPs mediated cellular stress responses are induced at a low concentration of 5µg/mL at 24h and involve a heat shock response, disturbances in metabolic pathways, and vesicular trafficking (‘Autophagy,’ ‘Phagosome maturation’) (Figure 4; Supplementary Table S2). However, there was no concomitant pathway induction of an oxidative stress response noted at this time point and dose. Analysis of the ‘Bag2 signaling pathway’ mediated heat shock response shows the disturbance is caused by upregulation of heat shock protein (HSP) transcripts Hspa1a (25-fold), and Hspa1b (11-fold) (Supplementary Figure S8), responsible for proper protein folding and maintenance and whose expression is increased due to cellular stress (Daugaard, Rohde, and Jäättelä 2007). Furthermore, at 24h, metallothionein (MT) transcripts Mt1 and Mt2 were both upregulated after exposure to 5–25µg/mL CuO NPs (Mt1: 6.2, 7.4, 5.3-fold respectively; Mt2: 7.0, 7.8, 4.8-fold respectively; Supplementary Figure S7), which are indicative of marked intracellular Cu accumulation (Strauch et al. 2017). Similar transcriptional responses have been reported in more advanced cells culture model systems, such as 3D cultures and air–liquid interface (ALI) exposure systems. Increases in the expression of MT1X, MT2A, and HSPA1A have been reported in A549 cells exposed for 24h to CuO NPs in an ALI system (Hufnagel et al. 2020). Increased expression of HSP and MT transcripts has also been seen in 3D human bronchial epithelial cell cultures exposed to CuO NPs for 25h in ALI (HSP90AA1, MT1M, MT2F) and in mouse lung tissue from 24h in vivo oropharyngeal CuO NP exposures (Hsp90aa1, Mt1, Mt2) (Ndika et al. 2020). These results suggest that the gene expression changes observed in the present study under the submerged exposure conditions are also observed in other cell types exposed under more complex exposure conditions as well as in vivo.