RESUMEN

At room temperature, the title salt, C7H10NO+·Cl-, is ortho-rhom-bic, space group Pbca with Z' = 1, as previously reported [Zhao (2009 ▸). Acta Cryst. E65, o2378]. Between 250 and 200 K, there is a solid-state phase transition to a twinned monoclinic P21/c structure with Z' = 2. We report the high temperature structure at 250 K and the low-temperature structure at 100 K. In the low-temperature structure, the -NH3 hydrogen atoms are ordered and this group has a different orientation in each independent mol-ecule, in keeping with optimizing N-H⋯Cl hydrogen bonding, some of which are bifurcated: these hydrogen bonds have N⋯Cl distances in the range 3.1201 (8)-3.4047 (8) Å. In the single cation of the high-temperature structure, the NH hydrogen atoms are disordered into the average of the two low-temperature positions and the N⋯Cl hydrogen bond distances are in the range 3.1570 (15)-3.3323 (18) Å. At both temperatures, the meth-oxy group is nearly coplanar with the rest of the mol-ecule, with the C-C-O-C torsion angles being -7.0 (2)° at 250 K and -6.94 (12) and -9.35 (12)° at 100 K. In the extended ortho-rhom-bic structure, (001) hydrogen-bonded sheets occur; in the monoclinic structure, the sheets propagate in the (010) plane.

RESUMEN

Cyclosporine A (CsA) is a model drug that has caused great concern due to its widespread use and abuse in the environment. However, the potential harm of CsA to organisms also remains largely unknown, and this issue is exceptionally important for the health risk assessment of antibiotics. To address this concern, the crosstalk between CsA stress and cellular metabolism at the proteomic level in Escherichia coli was investigated and dissected in this study. The results showed that CsA inhibited E. coli growth in a time-dependent manner. CsA induced reactive oxygen species (ROS) overproduction in a dose- and time-dependent manner, leading to membrane depolarization followed by cell apoptosis. In addition, translation, the citric acid cycle, amino acid biosynthesis, glycolysis and responses to oxidative stress and heat were the central metabolic pathways induced by CsA stress. The upregulated proteins, including PotD, PotF and PotG, controlled cell growth. The downregulated proteins, including SspA, SspB, CstA and DpS, were regulators of self-feedback during the starvation process. And the up- and downregulated proteins, including AtpD, Adk, GroS, GroL and DnaK, controlled energy production. These results provide an important reference for the environmental health risk assessment of CsA.

Asunto(s)

Proteínas de Escherichia coli , Proteínas de Unión Periplasmáticas , Ciclosporina/farmacología , Ciclosporina/metabolismo , Inmunosupresores/toxicidad , Escherichia coli/metabolismo , Proteómica , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo , Redes y Vías Metabólicas , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Unión Periplasmáticas/metabolismo

RESUMEN

Bisphenols A (BPA) and S (BPS) are endocrine-disrupting chemicals that affect energy metabolism, leading to impairment of glucose and lipid homeostasis. We aimed at identifying metabolic pathways regulated by both compounds in human liver cells and rat pancreatic ß-cells that could impair energy homeostasis regulation. We assessed the effects on growth, proliferation, and viability of hepatocarcinoma (HepG2) and insulinoma (INS-1E) cells exposed to either BPA or BPS in a full range concentration between 0.001 and 100 µM. Both the dose and duration of exposure caused a differential response on growth and viability of both cells. Effects were more pronounced on HepG2, as these cells exhibited non-linear dose-responses following exposure to xenobiotics. For INS-1E, effect was observed only at the highest concentration. In addition, we profiled their intracellular state by untargeted metabolomics at 24, 48, and 72 h of exposure. This analysis revealed time- and dose-dependently molecular changes for HepG2 and INS-1E that were similar between BPA and BPS. Both increased levels of inflammatory mediators, such as metabolites pertaining to linolenic and linoleic acid metabolic pathway. In summary, this study shows that BPS also disrupts molecular functions in cells that regulate energy homeostasis, displaying similar but less pronounced responses than BPA.

Asunto(s)

Disruptores Endocrinos , Plastificantes , Animales , Compuestos de Bencidrilo/química , Compuestos de Bencidrilo/toxicidad , Disruptores Endocrinos/química , Disruptores Endocrinos/toxicidad , Glucosa , Humanos , Metabolómica , Ratas , Sulfonas

RESUMEN

The main aim of the study is to evaluate the effects of the pharmaceutical diphenhydramine (DPH) on embryo-larvae Danio rerio across distinct levels of organization - individual and subcellular - and correlate those effects with the DPH mode of action (MoA) assessed by in silico analysis. An embryos heartbeat rate reduction was observed at 10 mg/L DPH, but 0.001 to 10 mg/L did not significantly affect the zebrafish survival, hatching and morphology. Larvae swimming distance decreased (hypoactivity) at 1 and 10 mg/L DPH. Moreover, the straightforward movements decrease and the increase in the zigzag movements or movements with direction changes, shown an erratic swimming behavior. Energy budgets decreased for lipid (0.01 mg/L DPH) and carbohydrate (10 mg/L DPH) contents. Cholinesterase (neural function) and glutathione S-transferase (Phase II biotransformation/antioxidant processes) increased their activities at 10 mg/L DPH, where a decrease in the total glutathione content (antioxidant system) was observed. DNA damage was found at 0.01 and 10 mg/L DPH. However, a DNA repair occurred after subsequent 72 h in clean media. The in silico study revealed a relevant conservation between human and zebrafish DPH target molecules. These data provide a valuable ecotoxicological information about the DPH effects and MoA to non-target organisms.

Asunto(s)

Difenhidramina , Contaminantes Químicos del Agua , Pez Cebra , Animales , Antioxidantes , Difenhidramina/toxicidad , Embrión no Mamífero , Humanos , Larva , Contaminantes Químicos del Agua/toxicidad

RESUMEN

The ovary is a highly important organ for female reproduction. The main functions include sex steroid hormone synthesis, follicular development, and achievement of oocyte meiotic and development competence for proper fertilization. Nanoparticle (NP) exposure is becoming unavoidable because of its wide use in different products, including cosmetics, food, health, and personal care products. Studies examining different nonreproductive tissues or systems have shown that characteristics such as the size, shape, core material, agglomeration, and dissolution influence the effects of NPs. However, most studies evaluating NP-mediated reproductive toxicity have paid little or no attention to the influence of the physicochemical characteristics of NP on the observed effects. As accumulating evidence indicates that NP may reach the ovary to impair proper functions, this review summarizes the available data on NP accumulation in ovarian tissue, as well as data describing toxicity to ovarian functions, including sex steroid hormone production, follicular development, oocyte quality, and fertility. Due to their toxicological relevance, this review also describes the main physicochemical characteristics involved in NP toxicity and the importance of considering NP physicochemical characteristics as factors influencing the ovarian toxicity of NPs. Finally, this review summarizes the main mechanisms of toxicity described in ovarian cells.

Asunto(s)

Sustancias Peligrosas/toxicidad , Nanopartículas/toxicidad , Ovario/efectos de los fármacos , Animales , Femenino , Fertilidad , Humanos , Oocitos , Reproducción

RESUMEN

Cardiotoxicity, defined as toxicity that affects the heart, is one of the most common adverse drug effects. Numerous drugs have been shown to have the potential to induce lethal arrhythmias by affecting cardiac electrophysiology, which is the focus of current preclinical testing. However, a substantial number of drugs can also affect cardiac function beyond electrophysiology. Within this broader sense of cardiotoxicity, this review discusses the key drug-protein interactions known to be involved in cardiotoxic drug response. We cover adverse effects of anticancer, central nervous system, genitourinary system, gastrointestinal, antihistaminic, anti-inflammatory, and anti-infective agents, illustrating that many share mechanisms of cardiotoxicity, including contractility, mitochondrial function, and cellular signaling.

Asunto(s)

Arritmias Cardíacas/inducido químicamente , Cardiotoxicidad/etiología , Fármacos Cardiovasculares/efectos adversos , Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Retirada de Medicamento por Seguridad/estadística & datos numéricos , Antiinfecciosos/efectos adversos , Antiinflamatorios/efectos adversos , Antineoplásicos/efectos adversos , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patología , Arritmias Cardíacas/prevención & control , Cardiotoxicidad/metabolismo , Cardiotoxicidad/patología , Cardiotoxicidad/prevención & control , Desarrollo de Medicamentos , Fármacos Gastrointestinales/efectos adversos , Agentes Genitourinarios/efectos adversos , Antagonistas de los Receptores Histamínicos/efectos adversos , Humanos , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Contracción Miocárdica/efectos de los fármacos , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fármacos Neuroprotectores/efectos adversos , Transducción de Señal

RESUMEN

Acetaldehyde (AA) has been classified as a probable human carcinogen by the International Agency for Research on Cancer (IARC, WHO) and by the US Environmental Protection Agency due to its ability to cause tumours following inhalation or alcohol consumption in animals. Humans are constantly exposed to AA through inhalation from the environment through cigarette smoke, vehicle fumes and industrial emissions as well as by persistent alcohol ingestion. Individuals with deficiencies in the enzymes that are involved in the metabolism of AA are more susceptible to its toxicity and constitute a vulnerable human population. Studies have shown that AA induces DNA damage and cytogenetic abnormalities. A study was undertaken to elucidate the clastogenic effects induced by AA and any preceding DNA damage that occurs in normal human lung fibroblasts as this will further validate the detrimental effects of inhalation exposure to AA. AA exposure induced DNA damage, involving DNA double strand breaks, which could possibly occur at the telomeric regions as well, resulting in a clastogenic effect and subsequent genomic instability, which contributed to the cell cycle arrest. The clastogenic effect induced by AA in human lung fibroblasts was evidenced by micronuclei induction and chromosomal aberrations, including those at the telomeric regions. Co-localisation between the DNA double strand breaks and telomeric regions was observed, suggesting possible induction of DNA double strand breaks due to AA exposure at the telomeric regions as a new mechanism beyond the clastogenic effect of AA. From the cell cycle profile following AA exposure, a G2/M phase arrest and a decrease in cell viability were also detected. Therefore, these effects due to AA exposure via inhalation may have implications in the development of carcinogenesis in humans.

Asunto(s)

Acetaldehído/efectos adversos , Aberraciones Cromosómicas/inducido químicamente , Daño del ADN , Fibroblastos/patología , Inestabilidad Genómica , Pulmón/patología , Mutágenos/efectos adversos , Supervivencia Celular , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fase G2 , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Telómero

RESUMEN

Fusion of biologic therapeutics to hyaluronic acid binding proteins, such as the link domain (LD) of Tumor necrosis factor (TNF)-Stimulated Gene-6 (TSG-6), is expected to increase vitreous residence time following intravitreal injection and provide for long-acting delivery. The toxicity of a single intravitreal dose of free TSG-6-LD and fusion proteins of TSG-6-LD and a nonbinding rabbit antibody fragment (RabFab) were assessed in New Zealand White rabbits. Animals administered free TSG-6-LD exhibited extensive lens opacities and variable retinal vascular attenuation, correlated with microscopic findings of lens and retinal degeneration. Similar but less severe findings were present in animals dosed with the RabFab-TSG-6-LD fusion proteins. In-life ocular inflammation was noted in all animals from 7-days postdose and was associated with high anti-RabFab antibody titers in animals administered fusion proteins. Inflammation and retinal degeneration were multifocally associated with evidence of retinal detachment, and hypertrophy and migration of vimentin, glial fibrillary acidic protein, and glutamine synthetase positive Müller cells to the outer nuclear layer. Further assessment of alternative hyaluronic acid binding protein fusions should consider the potential for retinal degeneration and enhanced immune responses early in development.

Asunto(s)

Retina , Degeneración Retiniana , Animales , Proteína Ácida Fibrilar de la Glía , Inyecciones Intravítreas , Conejos , Degeneración Retiniana/inducido químicamente

RESUMEN

Diarrhetic shellfish toxins (DSTs) are among the most prevalent marine toxins in Europe's and in other temperate coastal regions. These toxins are produced by several dinoflagellate species; however, the contamination of the marine trophic chain is often attributed to species of the genus Dinophysis. This group of toxins, constituted by okadaic acid (OA) and analogous molecules (dinophysistoxins, DTXs), are highly harmful to humans, causing severe poisoning symptoms caused by the ingestion of contaminated seafood. Knowledge on the mode of action and toxicology of OA and the chemical characterization and accumulation of DSTs in seafood species (bivalves, gastropods and crustaceans) has significantly contributed to understand the impacts of these toxins in humans. Considerable information is however missing, particularly at the molecular and metabolic levels involving toxin uptake, distribution, compartmentalization and biotransformation and the interaction of DSTs with aquatic organisms. Recent contributions to the knowledge of DSTs arise from transcriptomics and proteomics research. Indeed, OMICs constitute a research field dedicated to the systematic analysis on the organisms' metabolisms. The methodologies used in OMICs are also highly effective to identify critical metabolic pathways affecting the physiology of the organisms. In this review, we analyze the main contributions provided so far by OMICs to DSTs research and discuss the prospects of OMICs with regard to the DSTs toxicology and the significance of these toxins to public health, food safety and aquaculture.

Asunto(s)

Toxinas Marinas/toxicidad , Animales , Biomarcadores , Biotransformación , Inocuidad de los Alimentos , Genómica , Humanos , Proteómica , Mariscos , Intoxicación por Mariscos/etiología , Intoxicación por Mariscos/metabolismo

RESUMEN

To develop and evaluate scientifically robust and innovative approaches for the safety assessment of chemicals across multiple regulatory sectors, the EU Reference Laboratory for alternatives to animal testing (EURL ECVAM) has started a project to explore how to better use the available information, including that from existing animal studies. The aim is to minimize reliance on in vivo testing to avoid redundancy and to facilitate the integration of novel non-animal methods in the regulatory setting with the ultimate goal of designing sustainable testing strategies. In this thought-starter paper, we present a number of examples to illustrate and trigger further discussions within the scientific and regulatory communities on ways to extrapolate useful information for predicting toxicity from one toxicity endpoint to another or across endpoints based on mechanistic information.

RESUMEN

Human exposure to fine particulate matter (PM2.5) in various environment could lead to a number of adverse health effects. Little is known about the toxic mechanism and the further response caused by PM2.5 exposure. In this study, a metabolomics approach using gas chromatography-mass spectrometry (GC-MS) was adopted to evaluate the liver toxicity induced by different gradient concentrations of PM2.5. A multivariate statistical analysis had shown, a total of 12 endogenous metabolites including amino acids and organic acids were identified as potential biomarkers of PM2.5 and most of them were down-regulated. By analyzing the metabolic pathways using the identified biomarkers, the significantly interfered metabolic pathways when mice were exposed to PM2.5 were found as: glycine, serine and threonine metabolism, aminoacyl-tRNA biosynthesis, cysteine and methionine metabolism, alanine, aspartate and glutamate metabolism, methane metabolism, linoleic acid metabolism and valine, and leucine and isoleucine biosynthesis, all of which were closely related to liver metabolism. The findings of this study reveal detailed toxic metabolic effects of PM2.5 in liver tissues, provide ways for assessing the health risk of PM2.5 at molecular level, and further offer insights on the potential mechanism of its toxicity.

Asunto(s)

Contaminantes Atmosféricos/toxicidad , Metaboloma/efectos de los fármacos , Material Particulado/toxicidad , Animales , Biomarcadores , Metabolismo de los Lípidos , Hígado/metabolismo , Redes y Vías Metabólicas , Metabolómica , Ratones

RESUMEN

Zebrafish (Danio rerio) larvae are a uniquely powerful model system which investigate the effects of toxicant exposure on liver development and function. Manufacturing processes and development of new synthetic compounds increased rapidly since the middle of the twentieth century, resulting in widespread exposure to environmental toxicants. This is compounded by the shift in the global burden of disease from infectious agents to chronic disease, particularly in industrialized nations, which increases the need to investigate the long-term and transgenerational effects of environmental exposures on human health. Zebrafish provide an excellent model to investigate the mechanisms of action of environmental pollutants given their large-scale embryo production and rapid development, which allow for short-term assessment of toxicity in a whole animal system. Here we describe methods for the use of zebrafish to study hepatotoxicity and liver disease induced by chemical toxicants. Many of the genetic, molecular, and cellular processes are conserved between zebrafish and mammals, enabling translation to human populations and diseases.

Asunto(s)

Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Exposición a Riesgos Ambientales/efectos adversos , Larva/crecimiento & desarrollo , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Larva/efectos de los fármacos , Larva/metabolismo , Análisis de Secuencia de ARN , Pez Cebra

RESUMEN

Heavy metals are naturally existing elements that have relatively high atomic weight and a minimum density five times the density of water. Heavy metals have extensive applications in industries, homes, agriculture and medicine, leading to their wide distribution in the environment. Most heavy metals are reported to be highly toxic. They also have numerous exposure routes, including ingestion, inhalation, and dermal absorption, subsequently inducing some health effects resulting from human and heavy metals contact. The implications of heavy metals with regards to children's health have been noted to be more severe compared to adults. The element's harmful consequences on children health include mental retardation, neurocognitive disorders, behavioral disorders, respiratory problems, cancer and cardiovascular diseases. Much attention should be given to heavy metals because of their high toxicity potential, widespread use, and prevalence. This review therefore examines the exposure routes and health effects of mercury (Hg), lead (Pb), chromium (Cr), cadmium (Cd), and barium (Ba) on children. In addition, their toxic mechanisms are elucidated.

Asunto(s)

Bario/toxicidad , Cadmio/toxicidad , Cromo/toxicidad , Plomo/toxicidad , Metales Pesados/toxicidad , Humanos

RESUMEN

As a consequence of their increase in annual production and widespread distribution in the environment, nanoparticles potentially pose a significant public health risk. The sought-after catalytic activity granted by their physiochemical properties doubles as a hazard to physiological processes following exposure through inhalation, oral, transdermal, subcutaneous, and intravenous uptake. Upon uptake into the body, their size, morphology, surface charge, coating, and chemical composition augment the response of biological systems to the materials and enhance their toxicity. Identification of each property is necessary to predict the harm imposed by foreign nanomaterials in the body. Assay methods ranging from endotoxin and lactate dehydrogenase (LDH) signaling to apoptosis and oxidative stress detection supply valuable techniques for exposing biomarkers of nanoparticle-induced cellular damage. Spectroscopic investigation of epithelial barrier permeation and distribution within living cells reveals the proclivity of nanoparticles to penetrate the body's natural defensive boundaries and deposit themselves in cytotoxic locations. Combination of the various characterization methodologies and assays is required for every new nanoparticulate system despite preexisting data for similar systems due to the lack of deterministic trends among investigated nanoparticles. The propensity of nanomaterials to denature proteins and oxidize substrates in their local environment generates significant concern for the applicability of several traditional in vitro assays, and the modification of susceptible approaches into novel methods suitable for the evaluation of nanoparticles comprises the focus of future work centered on nanoparticle toxicity analysis.

Asunto(s)

Bioensayo/métodos , Técnicas In Vitro/métodos , Nanopartículas/toxicidad , Pruebas de Toxicidad/métodos , Animales , Humanos , Nanopartículas/química , Análisis Espectral/métodos

RESUMEN

Designer drugs are synthetically formulated to mimic the psychostimulatory effects of an original controlled/illegal drug of abuse. Designer drugs have similar chemical structure or functional analog as compared to existing controlled psychostimulatory drugs. There is a substantial rise in the production and use of designer drugs globally. Piperazine designer drugs were synthesized as an alternative to MDMA and have shown to induce numerous toxic effects leading to huge health, safety, law enforcement & monetary problems, and lethality. Currently, there are very few studies on the dopaminergic neurotoxicity of 1-(3-trifluoromethylphenyl) piperazine (3-TFMPP) and its derivatives (structural congeners). N27 rat dopaminergic neurons are valid cells to investigate the neurotoxic effects and establish the neurotoxic mechanisms of various substances. In the current study, we studied the time and dose-dependent neurotoxicity mechanisms of dopaminergic neurotoxicity of 3-TFMPP (parent compound) and its derivatives (2-TFMPP, 4-TFMPP). TFMPP derivatives-induced significant neurotoxicity (induced dopaminergic neuronal death. TFMPP derivatives-induced oxidative stress, mitochondrial dysfunction, apoptosis and decreased tyrosine hydroxylase expression. If the use of designer drugs are not strictly regulated and restricted around the world, this can lead to numerous central and peripheral disorders leading to a liability to the current and future society.

Asunto(s)

Apoptosis/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Mitocondrias/patología , Síndromes de Neurotoxicidad/patología , Estrés Oxidativo/efectos de los fármacos , Piperazinas/química , Piperazinas/toxicidad , Animales , Células Cultivadas , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/metabolismo , Ratas , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/toxicidad , Tirosina 3-Monooxigenasa/metabolismo

RESUMEN

The past decade has seen an increase in the development and clinical use of biomarkers associated with histological features of liver disease. Here, we conduct a comparative histological and global proteomics analysis to identify coregulated modules of proteins in the progression of hepatic steatosis or fibrosis. We orally administered the reference chemicals bromobenzene (BB) or 4,4'-methylenedianiline (4,4'-MDA) to male Sprague-Dawley rats for either 1 single administration or 5 consecutive daily doses. Livers were preserved for histopathology and global proteomics assessment. Analysis of liver sections confirmed a dose- and time-dependent increase in frequency and severity of histopathological features indicative of lipid accumulation after BB or fibrosis after 4,4'-MDA. BB administration resulted in a dose-dependent increase in the frequency and severity of inflammation and vacuolation. 4,4'-MDA administration resulted in a dose-dependent increase in the frequency and severity of periportal collagen accumulation and inflammation. Pathway analysis identified a time-dependent enrichment of biological processes associated with steatogenic or fibrogenic initiating events, cellular functions, and toxicological states. Differentially expressed protein modules were consistent with the observed histology, placing physiologically linked protein networks into context of the disease process. This study demonstrates the potential for protein modules to provide mechanistic links between initiating events and histopathological outcomes.

Asunto(s)

Biomarcadores/análisis , Hígado Graso/metabolismo , Cirrosis Hepática/metabolismo , Proteómica/métodos , Administración Oral , Compuestos de Anilina/toxicidad , Animales , Bromobencenos/toxicidad , Hígado Graso/inducido químicamente , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática/inducido químicamente , Masculino , Ratas , Ratas Sprague-Dawley

RESUMEN

BACKGROUND: Nanosafety aims for a solution through the safer design (and re-design) of nanostructured materials, optimizing both performance and safety, by resolving which structural features lead to the desired properties and modifying them to avoid their detrimental effects without losing their desired nanoscale properties in the process. Starting with known toxic NPs, the final aim should be the re-design of such detrimental specific NP characteristics and to redefine the way they should be manipulated from the beginning to the end of their life cycle. METHODS: The researchers reviewed literature in the area of novel nanosafety strategies addressing the "safe-by-design" paradigm. RESULTS: The potential hazards of engineered NPs are not only determined by the physicochemical properties of the engineered NPs per se but also on the interactions of these NPs with immediate surrounding environments. The aim of promoting the timely and safe development of NPs cannot be achieved via traditional studies as they address one material at one time. The development of a safer design strategy of engineered NPs requires an understanding of both intrinsic (synthetic) properties together with their extrinsic responses to external stimuli. CONCLUSIONS: We have summarized recent developments of novel nanosafety strategies addressing the "safe-by-design" paradigm for optimizing both performance and safety, allowing the comparison of results of different studies and ultimately providing guidelines for the re-design of safer NPs. The resulting discussion is intended to provide guidelines for synthetic nanochemists on how to design NPs to be safe during their full life cycle while maintaining their parental desired properties.

Asunto(s)

Diseño de Fármacos , Nanopartículas/química , Membrana Celular/química , Membrana Celular/metabolismo , Humanos , Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/metabolismo , Inflamasomas/efectos de los fármacos , Inflamasomas/metabolismo , Nanopartículas/metabolismo , Nanopartículas/toxicidad , Corona de Proteínas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Seguridad

RESUMEN

Most toxic physeal changes are characterized microscopically by altered chondrocyte development, proliferation, or maturation in the growth plate and eventually result in disordered appositional bone growth. Many therapeutic drugs directly or indirectly target proteins involved in chondrocytic differentiation and maturation pathways, so toxic physeal injury has become increasingly common in preclinical toxicologic pathology. While physeal dysplasia has been associated with several different drug classes including bisphosphonates, vascular endothelial growth factor receptor inhibitors, fibroblast growth factor receptor inhibitors, transforming growth factor beta receptor inhibitors, and vascular targeting agents, physeal changes often share similar morphologic features including thickening and disorganization of the hypertrophic layer, increased numbers of hypertrophic chondrocytes, altered mineralization of endochondral ossification, and/or increased thickness of subphyseal bone. Knowledge of genetic and nutritional diseases affecting bone growth has been important in helping to determine which specific target drugs may be affecting that could result in toxic physeal lesions. A pathophysiologic mechanism for most physeal toxicants has been determined in detail using a variety of investigative techniques. However, due to the signaling cross talk and the tight regulation required for chondrocyte maturation in the physis, several growth factor pathways are likely to be affected simultaneously with pharmacologic disruption of physeal homeostasis and inhibition of one factor necessary for chondrocyte function often affects others.

Asunto(s)

Desarrollo Óseo/efectos de los fármacos , Enfermedades Óseas/inducido químicamente , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Placa de Crecimiento/efectos de los fármacos , Animales , Enfermedades Óseas/fisiopatología , Huesos/efectos de los fármacos , Huesos/fisiopatología , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Difosfonatos/efectos adversos , Modelos Animales de Enfermedad , Placa de Crecimiento/patología , Humanos , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores

RESUMEN

OBJECTIVES: Much research has been performed on the field of identifying the roles of adenosine and adenosinergic signalling, but a relatively low number of marketing authorizations have been granted for adenosine receptor (AdR) ligands. In part, this could be related to their safety issues; therefore, our aim was to examine the toxicological and adverse effects data of different compounds acting on adenosinergic signalling, including different AdR ligands and compounds resembling the structure of adenosine. We also wanted to present recent pharmaceutical developments of experimental compounds that showed promising results in clinical trial setting. KEY FINDINGS: Safety issues of compounds modulating adenosinergic signalling were investigated, and different mechanisms were presented. Structurally different classes of compounds act on AdRs, the most important being adenosine, adenosine derivatives and other non-nucleoside compounds. Many of them are either not selective enough or are targeting other targets of adenosinergic signalling such as metabolizing enzymes that regulate adenosine levels. Many other targets are also involved that are not part of adenosinergic signalling system such as GABA receptors, different channels, enzymes and others. Some synthetic AdR ligands even showed to be genotoxic. SUMMARY: Current review presents safety data of adenosine, adenosine derivatives and other non-nucleoside compounds that modulate adenosinergic signalling. We have presented different mechanisms that participate to an adverse effect or toxic outcome. A separate section also deals with possible organ-specific toxic effects on different in-vitro and in-vivo models.

Asunto(s)

Adenosina/metabolismo , Diseño de Fármacos , Receptores Purinérgicos P1/efectos de los fármacos , Adenosina/química , Animales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Humanos , Ligandos , Agonistas del Receptor Purinérgico P1/efectos adversos , Agonistas del Receptor Purinérgico P1/farmacología , Antagonistas de Receptores Purinérgicos P1/efectos adversos , Antagonistas de Receptores Purinérgicos P1/farmacología , Receptores Purinérgicos P1/metabolismo , Transducción de Señal/efectos de los fármacos

RESUMEN

Gold nanoparticles (AuNP) adsorb macromolecules to form a protein corona (PC) after systemic delivery, to which the kidney as the primary excretory organ is constantly exposed. The role of the PC on AuNP cell uptake and toxicity was investigated in vitro in human proximal tubule cells (HPTC) using 40 and 80nm branched polyethylenimine (BPEI), lipoic acid (LA) and polyethylene glycol (PEG) coated AuNP with or without (bare) PCs composed of human plasma (HP) or human serum albumin (HSA) for 0.25 to 24h. Time-dependent intracellular uptake, assessed by ICP-MS showed PC modulated cell uptake and cytotoxicity; with bare 40nm BPEI-AuNP showing the greatest responses. All AuNP showed minimal to no cytokine release. At the nontoxic dose, 40nm bare BPEI-AuNP significantly modified gene expression related to immunotoxicity, steatosis, and mitochondrial metabolism; while at the high dose, pathways of DNA damage and repair, apoptosis, fatty acid metabolism and heat shock response were modulated. HP corona BPEI-AuNP response was comparable to control. These studies clearly showed reduced uptake and cytotoxicity, as well as differentiated gene expression of AuNP with PCs, questioning the utility of in vitro studies using bare NP to assess in vivo effects. Significantly, only cationic bare BPEI-AuNP had HPTC uptake or cytotoxicity suggesting the relative safety of PEG and LA-AuNP as nanomedicine constructs.

Asunto(s)

Oro , Túbulos Renales Proximales/citología , Nanopartículas del Metal , Corona de Proteínas/química , Albúmina Sérica/química , Células Cultivadas , Citocinas/metabolismo , Expresión Génica/efectos de los fármacos , Oro/administración & dosificación , Oro/química , Oro/toxicidad , Humanos , Nanopartículas del Metal/administración & dosificación , Nanopartículas del Metal/química , Nanopartículas del Metal/toxicidad , Plasma/química , Polietilenglicoles/química , Polietileneimina/química , Ácido Tióctico/química