Showing papers in "Archives of Toxicology in 2015"

Compromised MAPK signaling in human diseases: an update

Abstract: The mitogen-activated protein kinases (MAPKs) in mammals include c-Jun NH2-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK). These enzymes are serine-threonine protein kinases that regulate various cellular activities including proliferation, differentiation, apoptosis or survival, inflammation, and innate immunity. The compromised MAPK signaling pathways contribute to the pathology of diverse human diseases including cancer and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The JNK and p38 MAPK signaling pathways are activated by various types of cellular stress such as oxidative, genotoxic, and osmotic stress as well as by proinflammatory cytokines such as tumor necrosis factor-α and interleukin 1β. The Ras-Raf-MEK-ERK signaling pathway plays a key role in cancer development through the stimulation of cell proliferation and metastasis. The p38 MAPK pathway contributes to neuroinflammation mediated by glial cells including microglia and astrocytes, and it has also been associated with anticancer drug resistance in colon and liver cancer. We here summarize recent research on the roles of MAPK signaling pathways in human diseases, with a focus on cancer and neurodegenerative conditions.

The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update.

Abstract: Apoptosis is a critically important biological process that plays an essential role in cell fate and homeostasis. An important component of the apoptotic pathway is the family of proteins commonly known as the B cell lymphoma-2 (Bcl-2). The primary role of Bcl-2 family members is the regulation of apoptosis. Although the structure of Bcl-2 family of proteins was reported nearly 10 years ago, however, it still surprises us with its structural and functional complexity and diversity. A number of studies have demonstrated that Bcl-2 family influences many other cellular processes beyond apoptosis which are generally independent of the regulation of apoptosis, suggesting additional roles for Bcl-2. The disruption of the regulation of apoptosis is a causative event in many diseases. Since the Bcl-2 family of proteins is the key regulator of apoptosis, the abnormalities in its function have been implicated in many diseases including cancer, neurodegenerative disorders, ischemia and autoimmune diseases. In the past few years, our understanding of the mechanism of action of Bcl-2 family of proteins and its implications in various pathological conditions has enhanced significantly. The focus of this review is to summarize the current knowledge on the structure and function of Bcl-2 family of proteins in apoptotic cellular processes. A number of drugs have been developed in the past few years that target different Bcl-2 members. The role of Bcl-2 proteins in the pathogenesis of various diseases and their pharmacological significance as effective molecular therapeutic targets is also discussed.

Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets.

Abstract: The onset of heart failure is typically preceded by cardiac hypertrophy, a response of the heart to increased workload, a cardiac insult such as a heart attack or genetic mutation. Cardiac hypertrophy is usually characterized by an increase in cardiomyocyte size and thickening of ventricular walls. Initially, such growth is an adaptive response to maintain cardiac function; however, in settings of sustained stress and as time progresses, these changes become maladaptive and the heart ultimately fails. In this review, we discuss the key features of pathological cardiac hypertrophy and the numerous mediators that have been found to be involved in the pathogenesis of cardiac hypertrophy affecting gene transcription, calcium handling, protein synthesis, metabolism, autophagy, oxidative stress and inflammation. We also discuss new mediators including signaling proteins, microRNAs, long noncoding RNAs and new findings related to the role of calcineurin and calcium-/calmodulin-dependent protein kinases. We also highlight mediators and processes which contribute to the transition from adaptive cardiac remodeling to maladaptive remodeling and heart failure. Treatment strategies for heart failure commonly include diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and β-blockers; however, mortality rates remain high. Here, we discuss new therapeutic approaches (e.g., RNA-based therapies, dietary supplementation, small molecules) either entering clinical trials or in preclinical development. Finally, we address the challenges that remain in translating these discoveries to new and approved therapies for heart failure.

Human exposure to PBDE and critical evaluation of health hazards

Abstract: Polybrominated diphenyl ethers (PBDEs) are used in large quantities as flame-retardant additives in a number of commercial products. Biomonitoring data show that, in recent years, PBDE concentrations have increased rapidly in the bodies of wildlife and humans. Usually, PBDE levels in North America have been reported to be higher than those in Europe and Asia. Moreover, body burden of PBDEs is three- to ninefold higher in infants and toddlers than in adults, showing these last two age groups the highest levels of these compounds, due to exposure via maternal milk and through dust. Tetra-, Penta-, and Hexa-BDEs are the isomers most commonly found in humans. Based on studies on experimental animals, the toxicological endpoints of exposure to PBDEs are likely to be thyroid homeostasis disruption, neurodevelopmental deficits, reproductive changes, and even cancer. Experimental studies in animals and epidemiological observations in humans suggest that PBDEs may be developmental neurotoxicants. Pre- and/or postnatal exposure to PBDEs may cause long-lasting behavioral abnormalities, particularly on motor activity and cognition. This paper is focused on reviewing the current status of PBDEs in the environment, as well as the critical adverse health effects based on the recent studies on the toxic effects of PBDEs.

Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism

Abstract: Mitochondrial reactive oxygen species (ROS) production and detoxification are tightly balanced. Shifting this balance enables ROS to activate intracellular signaling and/or induce cellular damage and cell death. Increased mitochondrial ROS production is observed in a number of pathological conditions characterized by mitochondrial dysfunction. One important hallmark of these diseases is enhanced glycolytic activity and low or impaired oxidative phosphorylation. This suggests that ROS is involved in glycolysis (dys)regulation and vice versa. Here we focus on the bidirectional link between ROS and the regulation of glucose metabolism. To this end, we provide a basic introduction into mitochondrial energy metabolism, ROS generation and redox homeostasis. Next, we discuss the interactions between cellular glucose metabolism and ROS. ROS-stimulated cellular glucose uptake can stimulate both ROS production and scavenging. When glucose-stimulated ROS production, leading to further glucose uptake, is not adequately counterbalanced by (glucose-stimulated) ROS scavenging systems, a toxic cycle is triggered, ultimately leading to cell death. Here we inventoried the various cellular regulatory mechanisms and negative feedback loops that prevent this cycle from occurring. It is concluded that more insight in these processes is required to understand why they are (un)able to prevent excessive ROS production during various pathological conditions in humans.

Acetaminophen hepatotoxicity: an updated review.

Abstract: As the most common cause of acute liver failure (ALF) in the USA and UK, acetaminophen-induced hepatotoxicity remains a significant public health concern and common indication for emergent liver transplantation. This problem is largely attributable to acetaminophen combination products frequently prescribed by physicians and other healthcare professionals, with unintentional and chronic overdose accounting for over 50 % of cases of acetaminophen-related ALF. Treatment with N-acetylcysteine can effectively reduce progression to ALF if given early after an acute overdose; however, liver transplantation is the only routinely used life-saving therapy once ALF has developed. With the rapid course of acetaminophen-related ALF and limited supply of donor livers, early and accurate diagnosis of patients that will require transplantation for survival is crucial. Efforts in developing novel treatments for acetaminophen-induced ALF are directed toward bridging patients to recovery. These include auxiliary, artificial, and bioartificial support systems. This review outlines the most recent developments in diagnosis and management of acetaminophen-induced ALF.

The hallucinogenic world of tryptamines: an updated review

Abstract: In the area of psychotropic drugs, tryptamines are known to be a broad class of classical or serotonergic hallucinogens. These drugs are capable of producing profound changes in sensory perception, mood and thought in humans and act primarily as agonists of the 5-HT2A receptor. Well-known tryptamines such as psilocybin contained in Aztec sacred mushrooms and N,N-dimethyltryptamine (DMT), present in South American psychoactive beverage ayahuasca, have been restrictedly used since ancient times in sociocultural and ritual contexts. However, with the discovery of hallucinogenic properties of lysergic acid diethylamide (LSD) in mid-1900s, tryptamines began to be used recreationally among young people. More recently, new synthetically produced tryptamine hallucinogens, such as alpha-methyltryptamine (AMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), emerged in the recreational drug market, which have been claimed as the next-generation designer drugs to replace LSD (‘legal’ alternatives to LSD). Tryptamine derivatives are widely accessible over the Internet through companies selling them as ‘research chemicals’, but can also be sold in ‘headshops’ and street dealers. Reports of intoxication and deaths related to the use of new tryptamines have been described over the last years, raising international concern over tryptamines. However, the lack of literature pertaining to pharmacological and toxicological properties of new tryptamine hallucinogens hampers the assessment of their actual potential harm to general public health. This review provides a comprehensive update on tryptamine hallucinogens, concerning their historical background, prevalence, patterns of use and legal status, chemistry, toxicokinetics, toxicodynamics and their physiological and toxicological effects on animals and humans.

Microsatellite instability: an update

Abstract: Deficient DNA mismatch repair (MMR) results in a strong mutator phenotype known as microsatellite instability (MSI), which is a hallmark of Lynch syndrome-associated cancers. MSI is characterized by length alterations within simple repeated sequences that are called microsatellites. Lynch syndrome is primarily caused by mutations in the MMR genes, mainly MLH1 and MSH2, and less frequently in MSH6, and rarely PMS2, and large genomic rearrangements account for 5–20 % of all mutations. Germ line hemiallelic methylations of MLH1 or MSH2 are termed as epimutations and have been identified as causative of Lynch syndrome. Moreover, germ line 3′ deletions of EPCAM gene is involved in MSH2 methylation. MSI is also observed in about 15 % of sporadic colorectal cancer (CRC), gastric cancer (GC), and endometrial cancer (EC), and at lower frequencies in other cancers, often in association with hypermethylation of the MLH1 gene. Trimethylation of histone H3 on Lys36 (H3K36 me3) is an epigenetic histone mark that was required for DNA MMR in vivo. Thus, mutations in the H3K36 trimethyltransferase SETD2 have been reported as a potential cause of MSI. Genetic, epigenetic, and transcriptomic differences have been identified between cancers with and without MSI. Recent comprehensive molecular characterizations of CRC, EC, and GC by The Cancer Genome Atlas indicate that MSI+ cancers are distinct biological entities. The BRAF V600E mutation is specifically associated with sporadic MSI+ CRCs with methylated MLH1, but is not associated with Lynch syndrome-related CRCs. Accumulating evidence indicates a role of interactions between MSI and microRNA (miRNA) in the pathogenesis of MSI-positive (MSI+) cancer. As another new mechanism underlying MSI, overexpression of miR-155 or miR-21 has been shown to downregulate the expression of the MMR genes. Gene targets of frameshift mutations caused by MSI are involved in various cellular functions, including DNA repair (MSH3 and MSH6), cell signaling (TGFBR2 and ACVR2A), apoptosis (BAX), epigenetic regulation (HDAC2 and ARID1A), and miRNA processing (TARBP2 and XPO5), and a subset of MSI+ CRCs reportedly shows the mutated miRNA machinery phenotype. Moreover, microsatellite repeats in miRNA genes, such as hsa-miR-1273c, may be novel MSI targets for CRC, and mutations in noncoding regulatory regions of MRE11, BAX (BaxΔ2), and HSP110 (HSP110ΔE9) may affect the efficiency of chemotherapy. Thus, analyses of MSI and its related molecular alterations in cancers are increasingly relevant in clinical settings, and MSI is a useful screening marker for identifying patients with Lynch syndrome and a prognostic factor for chemotherapeutic interventions. In this review, we summarize recent advances in the pathogenesis of MSI and focus on genome-wide analyses that indicate the potential use of MSI and related alterations as biomarkers and novel therapeutic targets.

NF‑κB in cancer therapy

Abstract: The transcription factor nuclear factor kappa B (NF-κB) has attracted increasing attention in the field of cancer research from last few decades. Aberrant activation of this transcription factor is frequently encountered in a variety of solid tumors and hematological malignancies. NF-κB family members and their regulated genes have been linked to malignant transformation, tumor cell proliferation, survival, angiogenesis, invasion/metastasis, and therapeutic resistance. In this review, we highlight the diverse molecular mechanism(s) by which the NF-κB pathway is constitutively activated in different types of human cancers, and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. Additionally, various pharmacological approaches employed to target the deregulated NF-κB signaling pathway, and their possible therapeutic potential in cancer therapy is also discussed briefly.

Biology of the cell cycle inhibitor p21(CDKN1A): molecular mechanisms and relevance in chemical toxicology.

Abstract: The cell cycle inhibitor p21CDKN1A is a protein playing multiple roles not only in the DNA damage response, but also in many cellular processes during unperturbed cell growth. The main, well-known function of p21 is to arrest cell cycle progression by inhibiting the activity of cyclin-dependent kinases. In addition, p21 is involved in the regulation of transcription, apoptosis, DNA repair, as well as cell motility. However, p21 appears to a have a dual-face behavior because, in addition to its tumor suppressor functions, it may act as an oncogene, depending on the cell type and on the cellular localization. As a biomarker of the cell response to different toxic stimuli, p21 expression and functions have been analyzed in an impressive number of studies investigating the activity of several types of chemicals, in order to determine their possible harmful effects on human cells. Here, we review these studies in order to highlight the different roles p21 may play in the cell response to chemical exposure and to better evaluate the information provided by this biomarker.

Oxidative stress in Alzheimer disease and mild cognitive impairment: evidence from human data provided by redox proteomics

Abstract: Alzheimer disease (AD) is a neurodegenerative disease with many known pathological features, yet there is still much debate into the exact cause and mechanisms for progression of this degenerative disorder. The amyloid-beta (Aβ)-induced oxidative stress hypothesis postulates that it is the oligomeric Aβ that inserts into membrane systems to initiate much of the oxidative stress observed in brain during the progression of the disease. In order to study the effects of oxidative stress on tissue from patients with AD and amnestic mild cognitive impairment (MCI), we have developed a method called redox proteomics that identifies specific brain proteins found to be selectively oxidized. Here, we discuss experimental findings of oxidatively modified proteins involved in three key cellular processes implicated in the pathogenesis of AD progression: energy metabolism, cell signaling and neurotransmission, as well as the proteasomal degradation pathways and antioxidant response systems. These proteomics studies conducted by our laboratory and others in the field shed light on the molecular changes imposed on the cells of AD and MCI brain, through the deregulated increase in oxidative/nitrosative stress inflicted by Aβ and mitochondrial dysfunction.

Towards understanding of nanoparticle–protein corona

Abstract: With the rapid developments of nanotechnology, chances of exposing nanoscale particles to humans (e.g., workers and consumers) also increase correspondingly, which raises serious concerns on their biosafety. Entrance of nanoparticles into diverse biological environment endows them with new and dynamic biological identities as the so-called nanoparticle–protein corona. Therefore, understanding the role of these nanoparticle–protein coronas and resulting biological responses is crucial, as it helps to clarify the biological mechanism and prevent the potential adverse effects of nanoparticles. In this review, we summarize the latest developments relating to the nanoparticle–protein interaction and corresponding biological responses, with an emphasis on the characterization methods, induced biological effects and possible molecular mechanisms. In addition, we overview both the challenges and opportunities (particularly in nanomedicine) raised by this entrance of nanoparticles into the living creatures, especially human beings, with some future perspectives based on our understanding.

Hepatotoxicity of green tea: an update

Abstract: Green tea (GT), obtained from the leaves of Camellia sinensis (L.) Kuntze (Fam. Theaceae), is largely used for its potential health benefits such as reduction in risk of cardiovascular diseases and weight loss. Nevertheless, it is suspected to induce liver damage. Present work reviews the hepatic adverse reactions associated with GT-based herbal supplements, published by the end of 2008 to March 2015. A systematic research was carried out on PubMed, MedlinePlus, Scopus and Google Scholar databases, without any language restriction. Moreover, some accessible databases on pharmacovigilance or phytovigilance were consulted. The causality assessment was performed using the CIOMS/RUCAM score. Nineteen cases of hepatotoxicity related to the consumption of herbal products containing GT were identified. The hepatic reactions involved mostly women (16/19); the kind of liver damage was generally classified as hepatocellular (16/19). The causality assessment between consumption of herbal preparation and hepatic reaction resulted as probable in eight cases and as possible in eleven cases. In seven cases, patients used preparations containing only GT, while twelve reactions involved patients who took multicomponent preparations (MC). The reactions induced by GT had a generally long latency (179.1 ± 58.95 days), and the outcome was always resolution, with recovery time of 64.6 ± 17.78 days. On the contrary, liver injury associated with MC had a shorter latency (44.7 ± 13.85 days) and was more serious in four cases that required liver transplantation and, when resolution occurred, the recovery time was longer (118.9 ± 38.79). MC preparations contained numerous other components, many of which are suspected to induce liver damage, so it is difficult to ascribe the toxicity to one specific component, e.g., GT. Present data confirm a certain safety concern with GT, even if the number of hepatic reactions reported is low considering the great extent of use of this supplement. The mechanism of GT hepatotoxicity remains unclear, but factors related to the patient are becoming predominant. A major safety concern exists when GT is associated with other ingredients that can interact between them and with GT, enhancing the risk of liver damage. Patients should be discouraged from using herbal or dietary supplements containing complex mixtures and should be encouraged to use herbal and dietary supplement possibly under supervision of healthcare professionals.

The role of DNA damage responses in p53 biology

Abstract: The tumour suppressor p53 is a central player in cellular DNA damage responses P53 is upregulated and activated by genotoxic stress and induces a transcriptional programme with effectors promoting apoptosis, cell cycle arrest, senescence and DNA repair For the best part of the last three decades, these DNA damage-related programmes triggered by p53 were unequivocally regarded as the major if not sole mechanism by which p53 exerts its tumour suppressor function However, this interpretation has been challenged by a number of recent in vivo studies, demonstrating that mice which are defective in inducing p53-dependent apoptosis, cell cycle arrest and senescence suppress thymic lymphoma as well as wild-type p53 expressing animals Consequently, the importance of DNA damage responses for p53-mediated tumour suppression has been questioned In this review, I summarize current knowledge on p53-controlled DNA damage responses and argue that these activities, while their role has certainly changed, remain an important feature of p53 biology with relevance for cancer therapy and tumour suppression

International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes

Abstract: A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23–24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.

DNA damage response in cisplatin-induced nephrotoxicity.

Abstract: Cisplatin and its derivatives are widely used chemotherapeutic drugs for cancer treatment. However, they have debilitating side effects in normal tissues and induce ototoxicity, neurotoxicity, and nephrotoxicity. In kidneys, cisplatin preferentially accumulates in renal tubular cells causing tubular cell injury and death, resulting in acute kidney injury (AKI). Recent studies have suggested that DNA damage and the associated DNA damage response (DDR) are an important pathogenic mechanism of AKI following cisplatin treatment. Activation of DDR may lead to cell cycle arrest and DNA repair for cell survival or, in the presence of severe injury, kidney cell death. Modulation of DDR may provide novel renoprotective strategies for cancer patients undergoing cisplatin chemotherapy.

Bayesian integrated testing strategy (ITS) for skin sensitization potency assessment: a decision support system for quantitative weight of evidence and adaptive testing strategy

Abstract: The presented Bayesian network Integrated Testing Strategy (ITS-3) for skin sensitization potency assessment is a decision support system for a risk assessor that provides quantitative weight of evidence, leading to a mechanistically interpretable potency hypothesis, and formulates adaptive testing strategy for a chemical. The system was constructed with an aim to improve precision and accuracy for predicting LLNA potency beyond ITS-2 (Jaworska et al., J Appl Toxicol 33(11):1353-1364, 2013) by improving representation of chemistry and biology. Among novel elements are corrections for bioavailability both in vivo and in vitro as well as consideration of the individual assays' applicability domains in the prediction process. In ITS-3 structure, three validated alternative assays, DPRA, KeratinoSens and h-CLAT, represent first three key events of the adverse outcome pathway for skin sensitization. The skin sensitization potency prediction is provided as a probability distribution over four potency classes. The probability distribution is converted to Bayes factors to: 1) remove prediction bias introduced by the training set potency distribution and 2) express uncertainty in a quantitative manner, allowing transparent and consistent criteria to accept a prediction. The novel ITS-3 database includes 207 chemicals with a full set of in vivo and in vitro data. The accuracy for predicting LLNA outcomes on the external test set (n = 60) was as follows: hazard (two classes)-100 %, GHS potency classification (three classes)-96 %, potency (four classes)-89 %. This work demonstrates that skin sensitization potency prediction based on data from three key events, and often less, is possible, reliable over broad chemical classes and ready for practical applications.

Biomarkers of lipid peroxidation in Alzheimer disease (AD): an update.

Abstract: Increasing evidence suggests that free radical-mediated oxidation of biological substrates is a key feature of Alzheimer's disease (AD) pathogenesis. While it has long been established that biomarkers of lipid peroxidation (LPO) are elevated in AD brain as well as ventricular CSF postmortem, more recent studies have demonstrated increased LPO biomarkers in postmortem brain from subjects with mild cognitive impairment, the earliest clinically detectable phase of dementia and preclinical AD, the earliest detectable pathological phase. Furthermore, multiple LPO biomarkers are elevated in readily accessible biological fluids throughout disease progression. Collectively, these studies demonstrate that LPO is an early feature during disease progression and may be considered a key pathway for targeted therapeutics as well as an enhancer of diagnostic accuracy for early detection of subjects during the prodromal phase.

Toxicological interactions between the mycotoxins deoxynivalenol, nivalenol and their acetylated derivatives in intestinal epithelial cells.

Abstract: combinations were synergistic, with magnitude of synergy for 10 % cytotoxicity ranging from 2 to 7. The association between DON and 3-ADON also demonstrated a synergy but only at high doses, at lower doses antagonism was noted. Additivity was observed between NIV and FX, and antagonism between DON and FX. These results indicate that the simultaneous presence of mycotoxins in food commodities and diet may be more toxic than predicted from the mycotoxins alone. This synergy should be taken into account considering the frequent co-occurrence of TCTB in the diet.

Hepatotoxicity of herbal and dietary supplements: an update

Abstract: Herbal and dietary supplements (HDS) have been used for health-related purposes since more than 5000 years, and their application is firmly anchored in all societies worldwide. Over last decades, a remarkable renaissance in the use of HDS can be noticed in affluent societies for manifold reasons. HDS are forms of complementary and alternative medicines commonly used to prevent or treat diseases, or simply as a health tonic. Another growing indication for HDS is their alleged benefit for weight loss or to increase physical fitness. Access is easy via internet and mail-order pharmacies, and their turnover reaches billions of dollars in the USA and Europe alone. However, HDS are generally not categorized as drugs and thus less strictly regulated in most countries. As a result, scientific evidence proving their beneficial effects is mostly lacking, although some HDS may have purported benefits. However, the majority lacks such proof of value, and their use is predominantly based on belief and hope. In addition to missing scientific evidence supporting their use, HDS are typically prone to batch-to-batch variability in composition and concentration, contamination, and purposeful adulteration. Moreover, numerous examples of preparations emerged which have been linked to significant liver injury. These include single ingredients, such as kava, germander, and several Chinese herbals. Other HDS products associated with liver toxicity consist of multiple, often ill-defined ingredients, such as Hydroxycut and Herbalife. Affirmative diagnostic tests are not available, and the assessment of liver injury ascribed to HDS depends on a thorough and proactive medical history, careful exclusion of other causes, and a search for available reports on similar events linked to the intake of the suspected preparation or ingredients contained therein.

Effect of particle agglomeration in nanotoxicology.

Abstract: The emission of engineered nanoparticles (ENPs) into the environment in increasing quantity and variety raises a general concern regarding potential effects on human health. Compared with soluble substances, ENPs exhibit additional dimensions of complexity, that is, they exist not only in various sizes, shapes and chemical compositions but also in different degrees of agglomeration. The effect of the latter is the topic of this review in which we explore and discuss the role of agglomeration on toxicity, including the fate of nanomaterials after their release and the biological effects they may induce. In-depth investigations of the effect of ENP agglomeration on human health are still rare, but it may be stated that outside the body ENP agglomeration greatly reduces human exposure. After uptake, agglomeration of ENPs reduces translocation across primary barriers such as lungs, skin or the gastrointestinal tract, preventing exposure of “secondary” organs. In analogy, also cellular ENP uptake and intracellular distribution are affected by agglomeration. However, agglomeration may represent a risk factor if it occurs after translocation across the primary barriers, and ENPs are able to accumulate within the tissue and thus reduce clearance efficiency.

Progress and future of in vitro models to study translocation of nanoparticles.

Abstract: The increasing use of nanoparticles in products likely results in increased exposure of both workers and consumers. Because of their small size, there are concerns that nanoparticles unintentionally cross the barriers of the human body. Several in vivo rodent studies show that, dependent on the exposure route, time, and concentration, and their characteristics, nanoparticles can cross the lung, gut, skin, and placental barrier. This review aims to evaluate the performance of in vitro models that mimic the barriers of the human body, with a focus on the lung, gut, skin, and placental barrier. For these barriers, in vitro models of varying complexity are available, ranging from single-cell-type monolayer to multi-cell (3D) models. Only a few studies are available that allow comparison of the in vitro translocation to in vivo data. This situation could change since the availability of analytical detection techniques is no longer a limiting factor for this comparison. We conclude that to further develop in vitro models to be used in risk assessment, the current strategy to improve the models to more closely mimic the human situation by using co-cultures of different cell types and microfluidic approaches to better control the tissue microenvironments are essential. At the current state of the art, the in vitro models do not yet allow prediction of absolute transfer rates but they do support the definition of relative transfer rates and can thus help to reduce animal testing by setting priorities for subsequent in vivo testing.

Drug-induced liver injury: an overview over the most critical compounds

Abstract: There has been a substantial interest in drug-induced liver injury (DILI) recently. National Institutes of Health has sponsored a multicenter study in the USA for the last 10 years, which has collected valuable information in this context. Idiosyncratic DILI is like other adverse effects of drugs underestimated and underreported in most epidemiological studies. A recent prospective population-based study from Iceland found a crude incidence of approximately 19 cases per 100,000 and year. Antibiotic is the class of drugs most commonly implicated in patients with DILI. Amoxicillin–clavulanate continues to be the most commonly implicated agent occurring in approximately 1 out of 2,300 users. Drugs with the highest risk of DILI in the Icelandic study were azathioprine and infliximab. Although rare, statin-induced hepatotoxicity has been well documented. Liver injury associated with the use of herbal medicines and dietary supplements seems to be increasing. Information on the documented hepatotoxicity of drugs has recently been made easier by a website available in the public domain: LiverTox ( http://livertox.nlm.nih.gov ). Unfortunately, at the current time, pre-therapy risk assessment for DILI in the individual patient is difficult but previous well-documented hepatotoxicity is usually a contraindication for a subsequent treatment with the same drug.

Toxicology of nanosized titanium dioxide: an update

Abstract: Nanosized titanium dioxide (nano-TiO2) has tremendous potential for a host of applications, and TiO2 nanoparticles (NP) possess different physicochemical properties compared to their fine particle analogs, which might alter their bioactivity. Their adverse effects on living cells have raised serious concerns recently for their use in health care and consumer sectors such as sunscreens, cosmetics, pharmaceutical additives and implanted biomaterials. Many researches have demonstrated that the physicochemical properties including shape, size, surface characteristics and inner structure of nano-TiO2 particles have different degrees of toxicity to different organism groups under different conditions. Some former reports have demonstrated that nano-TiO2 materials could enter into human body through different routes such as inhalation, dermal penetration and ingestion. After being taken by human body, NP might induce oxidative stress, cytotoxicity, genotoxicity, inflammation and cell apoptosis ultimately in mammal organs and systems. Here, we summarized the update about toxicity of nano-TiO2 and aimed to supply a safety usage guideline of this nanomaterial.

Developmental neurotoxicity of persistent organic pollutants: an update on childhood outcome

Abstract: Organohalogens are persistent organic pollutants that have a wide range of chemical application. There is growing evidence that several of these chemical compounds interfere with human development in various ways. The aim of this review is to provide an update on the relationship between various persistent organic pollutants and childhood neurodevelopmental outcome from studies from the past 10 years. This review focuses on exposure to polychlorinated biphenyls (PCBs), hydroxylated PCBs (OH-PCBs), polybrominated diphenyl ethers (PBDEs) and dichlorodiphenyldichloroethylene (DDE), and in addition on exposure to phthalates, bisphenol A, and perfluorinated compounds and their associations with neurodevelopmental outcome in childhood, up to 18 years of age. This review shows that exposure to environmental chemicals affects neurodevelopmental outcome in children. Regarding exposure to PCBs and OH-PCBs, most studies report no or inverse associations with neurodevelopmental outcomes. Regarding exposure to PBDEs, lower mental development, psychomotor development and IQ were found at preschool age, and poorer attention at school age. Regarding exposure to DDE, most studies reported inverse associations with outcome, while others found no associations. Significant relations were particularly found at early infancy on psychomotor development, on attention and ADHD, whereas at school age, no adverse relationships were described. Additionally, several studies report gender-related vulnerability. Future research should focus on the long-term effects of prenatal and childhood exposure to these environmental chemicals, on sex-specific and combined exposure effects of environmental chemicals, and on possible mechanisms by which these chemicals have their effects on neurodevelopmental and behavioral outcomes.

The Hedgehog pathway: role in cell differentiation, polarity and proliferation

Abstract: Hedgehog (Hh) is first described as a genetic mutation that has “spiked” phenotype in the cuticles of Drosophila in later 1970s. Since then, Hh signaling has been implicated in regulation of differentiation, proliferation, tissue polarity, stem cell population and carcinogenesis. The first link of Hh signaling to cancer was established through discovery of genetic mutations of Hh receptor gene PTCH1 being responsible for Gorlin syndrome in 1996. It was later shown that Hh signaling is associated with many types of cancer, including skin, leukemia, lung, brain and gastrointestinal cancers. Another important milestone for the Hh research field is the FDA approval for the clinical use of Hh inhibitor Erivedge/Vismodegib for treatment of locally advanced and metastatic basal cell carcinomas. However, recent clinical trials of Hh signaling inhibitors in pancreatic, colon and ovarian cancer all failed, indicating a real need for further understanding of Hh signaling in cancer. In this review, we will summarize recent progress in the Hh signaling mechanism and its role in human cancer.

Perspectives of CD44 targeting therapies

Abstract: CD44 is a family of single-span transmembrane glycoproteins. Members of this family differ in the extracellular domain where ten variant exons are either excluded or included in various combinations. CD44 isoforms participate in many physiological processes including hematopoiesis, regeneration, lymphocyte homing and inflammation. Most importantly, they are involved in pathological processes and in particular in cancer. In several types of tumors, CD44 together with other antigens specifies for cancer stem cell populations. Mechanistically, CD44 proteins act as receptors for hyaluronan, co-receptor for receptor tyrosine kinases (RTKs) or G-protein-coupled receptors or provide a platform for metalloproteinases. For all these reasons, targeting CD44 may be a successful approach in cancer therapy. In this review, we discuss the various possibilities of targeting CD44. Among these are the production of CD44 ectodomains, antibodies, peptides or aptamers. Also inhibition of CD44 expression has been proposed. Finally, the function of CD44 as a hyaluronan receptor was also taken advantage of. We are convinced that the success of these therapies will depend on an increased understanding of the molecular functions of specific CD44 isoforms in particular in cancer stem cells.

Glutathione and mitochondria determine acute defense responses and adaptive processes in cadmium-induced oxidative stress and toxicity of the kidney

Abstract: Cadmium (Cd(2+)) induces oxidative stress that ultimately defines cell fate and pathology. Mitochondria are the main energy-producing organelles in mammalian cells, but they also have a central role in formation of reactive oxygen species, cell injury, and death signaling. As the kidney is the major target in Cd(2+) toxicity, the roles of oxidative signature and mitochondrial function and biogenesis in Cd(2+)-related stress outcomes were investigated in vitro in cultured rat kidney proximal tubule cells (PTCs) (WKPT-0293 Cl.2) for acute Cd(2+) toxicity (1-30 µM, 24 h) and in vivo in Fischer 344 rats for sub-chronic Cd(2+) toxicity (1 mg/kg CdCl2 subcutaneously, 13 days). Whereas 30 µM Cd(2+) caused ~50 % decrease in cell viability, apoptosis peaked at 10 µM Cd(2+) in PTCs. A steep, dose-dependent decline in reduced glutathione (GSH) content occurred after acute exposure and an increase of the oxidized glutathione (GSSG)/GSH ratio. Quantitative PCR analyses evidenced increased antioxidative enzymes (Sod1, Gclc, Gclm), proapoptotic Bax, metallothioneins 1A/2A, and decreased antiapoptotic proteins (Bcl-xL, Bcl-w). The positive regulator of mitochondrial biogenesis Pparγ and mitochondrial DNA was increased, and cellular ATP was unaffected with Cd(2+) (1-10 µM). In vivo, active caspase-3, and hence apoptosis, was detected by FLIVO injection in the kidney cortex of Cd(2+)-treated rats together with an increase in Bax mRNA. However, antiapoptotic genes (Bcl-2, Bcl-xL, Bcl-w) were also upregulated. Both GSSG and GSH increased with chronic Cd(2+) exposure with no change in GSSG/GSH ratio and augmented expression of antioxidative enzymes (Gpx4, Prdx2). Mitochondrial DNA, mitofusin 2, and Pparα were increased indicating enhanced mitochondrial biogenesis and fusion. Hence, these results demonstrate a clear involvement of higher mitochondria copy numbers or mass and mitochondrial function in acute defense against oxidative stress induced by Cd(2+) in renal PTCs as well as in adaptive processes associated with chronic renal Cd(2+) toxicity.

Quercetin induces mitochondrial-derived apoptosis via reactive oxygen species-mediated ERK activation in HL-60 leukemia cells and xenograft

Abstract: Quercetin is a plant-derived bioflavonoid that was recently shown to have multiple anticancer activities in various solid tumors. Here, novel molecular mechanisms through which quercetin exerts its anticancer effects in acute myeloid leukemia (AML) cells were investigated. Results from Western blot and flow cytometric assays revealed that quercetin significantly induced caspase-8, caspase-9, and caspase-3 activation, poly ADP-ribose polymerase (PARP) cleavage, and mitochondrial membrane depolarization in HL-60 AML cells. The induction of PARP cleavage by quercetin was also observed in other AML cell lines: THP-1, MV4-11, and U937. Moreover, treatment of HL-60 cells with quercetin induced sustained activation of extracellular signal-regulated kinase (ERK), and inhibition of ERK by an ERK inhibitor significantly abolished quercetin-induced cell apoptosis. MitoSOX red and 2',7'-dichlorofluorescin fluorescence, respectively, showed that mitochondrial superoxide and intracellular peroxide levels were higher in quercetin-treated HL-60 cells compared with the control group. Moreover, both N-acetylcysteine and the superoxide dismutase mimetic, MnTBAP, reversed quercetin-induced intracellular reactive oxygen species production, ERK activation, and subsequent cell death. The in vivo xenograft mice experiments revealed that quercetin significantly reduced tumor growth through inducing intratumoral oxidative stress while activating the ERK pathway and subsequent cell apoptosis in mice with HL-60 tumor xenografts. In conclusions, our results indicated that quercetin induced cell death of HL-60 cells in vitro and in vivo through induction of intracellular oxidative stress following activation of an ERK-mediated apoptosis pathway.

Raising awareness of new psychoactive substances: chemical analysis and in vitro toxicity screening of 'legal high' packages containing synthetic cathinones.

Abstract: The world's status quo on recreational drugs has dramatically changed in recent years due to the rapid emergence of new psychoactive substances (NPS), represented by new narcotic or psychotropic drugs, in pure form or in preparation, which are not controlled by international conventions, but that may pose a public health threat comparable with that posed by substances listed in these conventions. These NPS, also known as 'legal highs' or 'smart drugs', are typically sold via Internet or 'smartshops' as legal alternatives to controlled substances, being announced as 'bath salts' and 'plant feeders' and is often sought after for consumption especially among young people. Although NPS have the biased reputation of being safe, the vast majority has hitherto not been tested and several fatal cases have been reported, namely for synthetic cathinones, with pathological patterns comparable with amphetamines. Additionally, the unprecedented speed of appearance and distribution of the NPS worldwide brings technical difficulties in the development of analytical procedures and risk assessment in real time. In this study, 27 products commercialized as 'plant feeders' were chemically characterized by gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. It was also evaluated, for the first time, the in vitro hepatotoxic effects of individual synthetic cathinones, namely methylone, pentedrone, 4-methylethcathinone (4-MEC) and 3,4-methylenedioxypyrovalerone (MDPV). Two commercial mixtures ('Bloom' and 'Blow') containing mainly cathinone derivatives were also tested, and 3,4-methylenedioxymethamphetamine (MDMA) was used as the reference drug. The study allowed the identification of 19 compounds, showing that synthetic cathinones are the main active compounds present in these products. Qualitative and quantitative variability was found in products sold with the same trade name in matching or different 'smartshops'. In the toxicity studies performed in primary cultured rat hepatocytes, pentedrone and MDPV proved to be the most potent individual agents, with EC50 values of 0.664 and 0.742 mM, respectively, followed by MDMA (EC50 = 0.754 mM). 4-MEC and methylone were the least potent substances, with EC50 values significantly higher (1.29 and 1.18 mM, respectively; p < 0.05 vs. MDMA). 'Bloom' and 'Blow' showed hepatotoxic effects similar to MDMA (EC50 = 0.788 and 0.870 mM, respectively), with cathinones present in these mixtures contributing additively to the overall toxicological effect. Our results show a miscellany of psychoactive compounds present in 'legal high' products with evident hepatotoxic effects. These data contribute to increase the awareness on the real composition of 'legal high' packages and unveil the health risks posed by NPS.