Epigenetic mechanisms in metal carcinogenesis.

Many metals exhibit genotoxic and/or carcinogenic effects. These toxic metals can be found ubiquitously - in drinking water, food, air, general use products, in everyday and occupational settings. Exposure to such carcinogenic metals can result in serious health disorders, including cancer. Arsenic, cadmium, chromium, nickel, and their compounds have already been recognized as carcinogens by the International Agency for Research on Cancer. This review summarizes a wide range of epigenetic mechanisms contributing to carcinogenesis induced by these metals, primarily including, but not limited to, DNA methylation, miRNA regulation, and histone posttranslational modifications. The mechanisms are described and discussed both from a metal-centric and a mechanism-centric standpoint. The review takes a broad perspective, putting the mechanisms in the context of real-life exposure, and aims to assist in guiding future research, particularly with respect to the assessment and control of exposure to carcinogenic metals and novel therapy development.

Toxic-Metal-Induced Alteration in miRNA Expression Profile as a Proposed Mechanism for Disease Development.

Toxic metals are extensively found in the environment, households, and workplaces and contaminate food and drinking water. The crosstalk between environmental exposure to toxic metals and human diseases has been frequently described. The toxic mechanism of action was classically viewed as the ability to dysregulate the redox status, production of inflammatory mediators and alteration of mitochondrial function. Recently, growing evidence showed that heavy metals might exert their toxicity through microRNAs (miRNA)-short, single-stranded, noncoding molecules that function as positive/negative regulators of gene expression. Aberrant alteration of the endogenous miRNA has been directly implicated in various pathophysiological conditions and signaling pathways, consequently leading to different types of cancer and human diseases. Additionally, the gene-regulatory capacity of miRNAs is particularly valuable in the brain-a complex organ with neurons demonstrating a significant ability to adapt following environmental stimuli. Accordingly, dysregulated miRNAs identified in patients suffering from neurological diseases might serve as biomarkers for the earlier diagnosis and monitoring of disease progression. This review will greatly emphasize the effect of the toxic metals on human miRNA activities and how this contributes to progression of diseases such as cancer and neurodegenerative disorders (NDDs).

Safety and Security in International Humanitarian Missions - Assessing the Stress Level of Responders in Critical Situations during a Realistic Full-Scale Training.

INTRODUCTION: Crises, wars, and disasters are remarkably increasing across the world. Responders are frequently tackled with an ever-greater number of challenges, and undoubtedly, they are physically and mentally affected during and after their missions, during which posttraumatic stress disorder (PTSD) is considered high-risk. To the authors' knowledge, no studies have addressed which type of incident has the greatest influence to trigger stress, and consequently, to cause PTSD for the responders after their missions. METHODS: A prospective longitudinal study was conducted with 69 participants of the "Safety and Security" course at the Federal Office for Civil Protection and Disaster Aid of the Federal Ministry of Interior Affairs (Berlin, Germany). The course is certified by the Hostile Environment Awareness Training (HEAT) guidelines of Europe's New Training Initiative for Civilian Crisis Management (ENTRi; Center for International Peace Operations; Berlin, Germany). Four incidents were evaluated: hostage-taking, carjacking, evacuation, and border-crossing. The participants completed the Positive and Negative Affect Schedule (PANAS) before and after each incident. For each incident, the delta of the PANAS scores was calculated. The differences between the described incidents, as well as the differences between novice and experienced responders, were evaluated. RESULTS: The hostage-taking incident had the greatest influence on the participants' temper, followed by carjacking and evacuation. Ultimately, the border-crossing event had the least effect on the responders. Novices were more affected by hostage-taking than experienced responders; however, no significant difference had been demonstrated between novices and experienced responders for the other evaluated incidents. CONCLUSION: Different incidents have big psychological impacts on humanitarian responders, in which consequences vary from short-term effects to PTSD. Therefore, humanitarian responders should be selected very carefully. They should also have more specific preparation for their missions. Mental after-care should be obligatory. Further studies are needed to understand and avoid reasons for the development of PTSD or other potential problems of responders.

Animal Model for Leigh Syndrome.

Leigh syndrome (LS) is a common neurodegenerative disease affecting neonates with devastating sequences. One of the characteristic features for LS is the phenotypic polymorphism, which-in part-can be dedicated to variety of genetic causes. A strong correlation with mitochondrial dysfunction has been assumed as the main cause of LS. This was based on the fact that most genetic causes are related to mitochondrial complex I genome. The first animal LS model was designed based on NDUFS4 knockdown. Interestingly, however, this one or others could not recapitulate the whole spectrum of manifestations encountered in different cases of LS. We show in this chapter a new animal model for LS based on silencing of one gene that is reported previously in clinical cases, FOXRED1. The new model carries some differences from previous models in the fact that more histopathological degeneration in dopaminergic system is seen and more behavioral changes can be recognized. FOXRED1 is an interesting gene that is related to complex I assembly, hence, plays important role in different neurodegenerative disorders leading to different clinical manifestations.

Mechanisms of disordered neurodegenerative function: concepts and facts about the different roles of the protein kinase RNA-like endoplasmic reticulum kinase (PERK).

Neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, prion disease, and amyotrophic lateral sclerosis, are a dissimilar group of disorders that share a hallmark feature of accumulation of abnormal intraneuronal or extraneuronal misfolded/unfolded protein and are classified as protein misfolding disorders. Cellular and endoplasmic reticulum (ER) stress activates multiple signaling cascades of the unfolded protein response (UPR). Consequently, translational and transcriptional alterations in target gene expression occur in response directed toward restoring the ER capacity of proteostasis and reestablishing the cellular homeostasis. Evidences from in vitro and in vivo disease models indicate that disruption of ER homeostasis causes abnormal protein aggregation that leads to synaptic and neuronal dysfunction. However, the exact mechanism by which it contributes to disease progression and pathophysiological changes remains vague. Downstream signaling pathways of UPR are fully integrated, yet with diverse unexpected outcomes in different disease models. Three well-identified ER stress sensors have been implicated in UPR, namely, inositol requiring enzyme 1, protein kinase RNA-activated-like ER kinase (PERK), and activating transcription factor 6. Although it cannot be denied that each of the involved stress sensor initiates a distinct downstream signaling pathway, it becomes increasingly clear that shared pathways are crucial in determining whether or not the UPR will guide the cells toward adaptive prosurvival or proapoptotic responses. We review a body of work on the mechanism of neurodegenerative diseases based on oxidative stress and cell death pathways with emphasis on the role of PERK.