ABSTRACT
Exposure to acrylic amide (AD) has garnered worldwide attention due to its potential adverse health effects, prompting calls from the World Health Organization for intensified research into associated risks. Despite this, the relationship between oral acrylic amide (acrylamide) (AD) exposure and pulmonary dysfunction remains poorly understood. Our study aimed to investigate the correlation between internal oral exposure to AD and the decline in lung function, while exploring potential mediating factors such as tissue inflammation, oxidative stress, pyroptosis, and apoptosis. Additionally, we aimed to evaluate the potential protective effect of zinc oxide nanoparticles green-synthesized moringa extract (ZNO-MONPs) (10â¯mg/kg b.wt) against ACR toxicity and conducted comprehensive miRNA expression profiling to uncover novel targets and mechanisms of AD toxicity (miRNA 223-3â¯P and miRNA 325-3â¯P). Furthermore, we employed computational techniques to predict the interactions between acrylic amide and/or MO-extract components and tissue proteins. Using a rat model, we exposed animals to oral acrylamide (20â¯mg/kg b.wt for 2 months). Our findings revealed that AD significantly downregulated the expression of miRNA 223-3â¯P and miRNA 325-3â¯P, targeting NLRP-3 & GSDMD, respectively, indicating the induction of pyroptosis in pulmonary tissue via an inflammasome activating pathway. Moreover, AD exposure resulted in lipid peroxidative damage and reduced levels of GPX, CAT, GSH, and GSSG. Notably, AD exposure upregulated apoptotic, pyroptotic, and inflammatory genes, accompanied by histopathological damage in lung tissue. Immunohistochemical and immunofluorescence techniques detected elevated levels of indicative harmful proteins including vimentin and 4HNE. Conversely, concurrent administration of ZNO-MONPs with AD significantly elevated the expression of miRNA 223-3â¯P and miRNA 325-3â¯P, protecting against oxidative stress, apoptosis, pyroptosis, inflammation, and fibrosis in rat lungs. In conclusion, our study highlights the efficacy of ZNO-MONPs NPs in protecting pulmonary tissue against the detrimental impacts of foodborne toxin AD.
Subject(s)
Inflammasomes , MicroRNAs , Plant Extracts , Pyroptosis , Rats, Sprague-Dawley , Signal Transduction , Animals , MicroRNAs/genetics , MicroRNAs/metabolism , Inflammasomes/metabolism , Inflammasomes/drug effects , Inflammasomes/genetics , Rats , Male , Pyroptosis/drug effects , Signal Transduction/drug effects , Plant Extracts/pharmacology , Acrylamide/toxicity , Lung/drug effects , Lung/pathology , Lung/metabolism , Oxidative Stress/drug effects , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/metabolism , Acrylamides/toxicity , Lung Injury/chemically induced , Lung Injury/pathology , Lung Injury/genetics , Lung Injury/metabolismABSTRACT
Osimertinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used for cancer treatment, can cause significant cardiac toxicity. However, the specific mechanism of osimertinib-induced cardiotoxicity is not fully understood. In this study, we administered osimertinib to mice and neonatal rat ventricular myocytes (NRVMs). We observed significant structural and functional damage to the hearts of these mice, along with a marked increase in cardiac injury biomarkers and accompanying ultrastructural damage to mitochondria. We integrated 4D label-free protein quantification and RNA-Seq methods to analyze the sequencing data of NRVMs under osimertinib treatment (0 and 2.5⯵M). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis evidenced that differentially expressed genes (DEGs)and differentially expressed proteins (DEPs) were distinctly enriched for oxidative phosphorylation (OXPHOs). Simultaneously, osimertinib primarily affected the contents of adenosine triphosphate (ATP). Further investigations revealed that osimertinib disrupts the functions of the ATP synthase (complex V), leading to a reduction in ATP production. Taken together, our data demonstrated that osimertinib causes mitochondrial dysfunction, which in turn leads to the onset of cardiac toxicity.
Subject(s)
Acrylamides , Aniline Compounds , Cardiotoxicity , Mitochondria, Heart , Myocytes, Cardiac , Proteomics , Animals , Acrylamides/toxicity , Aniline Compounds/toxicity , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Myocytes, Cardiac/ultrastructure , Mitochondria, Heart/drug effects , Mitochondria, Heart/metabolism , Mitochondria, Heart/ultrastructure , Proteomics/methods , Mice , Rats , Male , Transcriptome/drug effects , Mice, Inbred C57BL , Protein Kinase Inhibitors/toxicity , Protein Kinase Inhibitors/pharmacology , Rats, Sprague-Dawley , Adenosine Triphosphate/metabolism , Indoles , PyrimidinesABSTRACT
We describe a case of a young male who presented to the emergency department with unilateral eye pain, blurred vision, conjunctival injection, and ocular pH of 9, one day after direct ocular exposure to palytoxin (PTX) from coral in a home saltwater fish tank. Although uncommon, ocular PTX toxicity is a potentially vision-threatening condition that requires prompt recognition. This case report documents the successful management of presumed ocular PTX exposure and suggests additional workup and treatment considerations for future patients.
Subject(s)
Anthozoa , Cnidarian Venoms , Animals , Humans , Male , Cnidarian Venoms/toxicity , Acrylamides/toxicity , FaceABSTRACT
Acrylamides are widely used industrial chemicals that cause adverse effects in humans or animals, such as carcinogenicity or neurotoxicity. The excess toxicity of these reactive electrophilic chemicals is especially interesting, as it is mostly triggered by covalent reactions with biological nucleophiles, such as DNA bases, proteins, or peptides. The cytotoxicity and activation of oxidative stress response of 10 (meth)acrylamides measured in three reporter gene cell lines occurred at similar concentrations. Most acrylamides exhibited high excess toxicity, while methacrylamides acted as baseline toxicants. The (meth)acrylamides showed no reactivity toward the hard biological nucleophile 2-deoxyguanosine (2DG) within 24 h, and only acrylamides reacted with the soft nucleophile glutathione (GSH). Second-order degradation rate constants (kGSH) were measured for all acrylamides with N,N'-methylenebis(acrylamide) (NMBA) showing the highest kGSH (134.800 M-1 h-1) and N,N-diethylacrylamide (NDA) the lowest kGSH (2.574 M-1 h-1). Liquid chromatography coupled to high-resolution mass spectrometry was used to confirm the GSH conjugates of the acrylamides with a double conjugate formed for NMBA. The differences in reactivity between acrylamides and methacrylamides could be explained by the charge density of the carbon atoms because the electron-donating inductive effect of the methyl group of the methacrylamides lowered their electrophilicity and thus their reactivity. The differences in reactivity within the group of acrylamides could be explained by the energy of the lowest unoccupied molecular orbital and steric hindrance. Cytotoxicity and activation of oxidative stress response were linearly correlated with the second-order reaction rate constants of the acrylamides with GSH. The reaction of the acrylamides with GSH is hence not only a detoxification mechanism but also leads to disturbances of the redox balance, making the cells more vulnerable to reactive oxygen species. The reactivity of acrylamides explained the oxidative stress response and cytotoxicity in the cells, and the lack of reactivity of the methacrylamides led to baseline toxicity.
Subject(s)
Acrylamide , Acrylamides , Animals , Humans , Acrylamides/toxicity , Acrylamide/toxicity , Glutathione/metabolism , Oxidative Stress , Oxidation-ReductionSubject(s)
Anthozoa , Cnidarian Venoms , Animals , Humans , Cnidarian Venoms/adverse effects , Acrylamides/toxicityABSTRACT
The frequent occurrence of marine dinoflagellates producing palytoxin (PLTX) or okadaic acid (OA) raises concern for the possible co-presence of these toxins in seafood, leading to additive or synergistic adverse effects in consumers. Thus, the acute oral toxicity of PLTX and OA association was evaluated in mice: groups of eight female CD-1 mice were administered by gavage with combined doses of PLTX (30, 90 or 270 µg/kg) and OA (370 µg/kg), or with each individual toxin, recording signs up to 24 h (five mice) and 14 days (three mice). Lethal effects occurred only after PLTX (90 or 270 µg/kg) exposure, alone or combined with OA, also during the 14-day recovery. PLTX induced scratching, piloerection, abdominal swelling, muscle spasms, paralysis and dyspnea, which increased in frequency or duration when co-administered with OA. The latter induced only diarrhea. At 24 h, PLTX (90 or 270 µg/kg) and OA caused wall redness in the small intestine or pale fluid accumulation in its lumen, respectively. These effects co-occurred in mice co-exposed to PLTX (90 or 270 µg/kg) and OA, and were associated with slight ulcers and inflammation at forestomach. PLTX (270 µg/kg alone or 90 µg/kg associated with OA) also decreased the liver/body weight ratio, reducing hepatocyte glycogen (270 µg/kg, alone or combined with OA). No alterations were recorded in surviving mice after 14 days. Overall, the study suggests additive effects of PLTX and OA that should be considered for their risk assessment as seafood contaminants.
Subject(s)
Cnidarian Venoms , Mice , Animals , Female , Okadaic Acid/toxicity , Cnidarian Venoms/toxicity , Acrylamides/toxicity , LiverABSTRACT
Ostreopsis cf. ovata is a benthic dinoflagellate known to produce palytoxin (PLTX) and its analogues. Recent investigations suggested the production of unknown toxins by a Mediterranean strain. In the present work, two new families of toxins, potentially novel in their structures, were purified from this same Mediterranean strain of Ostreopsis cf. ovata. The low amount of material isolated only allowed for acquisition of high-resolution mass spectrometry data and the evaluation of their cytotoxicity to human lung cancer cells. Based on their HRMS data, none of these new compounds appear to be close PLTX analogues, although their mass spectra suggest poly-hydroxylated long chain compounds of high molecular weight (1370-2143 Da). The cell cytotoxicity concentrations (CC50) of these new purified toxins ranged between 0.68 and 3.12 µg/mL, and this was enhanced when they were tested as mixtures, suggesting synergistic effects of Ostreopsis toxins. The two families of compounds were named the liguriatoxins (LGTX) and rivieratoxins (RVTX), with each family containing three members. Additional work on purification is needed to fully characterize the structures of these six new dinoflagellate toxins.
Subject(s)
Cnidarian Venoms , Dinoflagellida , Acrylamides/toxicity , Cnidarian Venoms/toxicity , Dinoflagellida/chemistry , Dinoflagellida/genetics , Humans , Marine Toxins/analysis , Mass SpectrometryABSTRACT
Palytoxin (PLTX) is a polyether marine toxin isolated from sea anemones. It is one of the most toxic nonprotein substances, causing many people to be poisoned every year and to die in severe cases. Despite its known impact on Na+,K+-ATPase, much still remains unclear about PLTX's mechanism of action. Here, we tested different concentrations of PLTX on HaCaT cells and studied its distributions in cells, its impact on gene expression, and the associated pathways via proteomics combined with bioinformatics tools. We found that PLTX could cause ferroptosis in HaCaT cells, a new type of programmed cell death, by up-regulating the expression of VDAC3, ACSL4 and NCOA4, which lead to the occurrence of ferroptosis. PLTX also acts on the MAPK pathway, which is related to cell apoptosis, proliferation, division and differentiation. Different from its effect on ferroptosis, PLTX down-regulates the expression of ERK, and, as a result, the expressions of MAPK1, MAP2K1 and MAP2K2 are also lower, affecting cell proliferation. The genes from these two mechanisms showed interactions, but we did not find overlap genes between the two. Both ferroptosis and MAPK pathways can be used as anticancer targets, so PLTX may become an anticancer drug with appropriate modification.
Subject(s)
Cnidarian Venoms , HaCaT Cells , Acrylamides/toxicity , Cnidarian Venoms/toxicity , Humans , ProteomicsABSTRACT
Palytoxin (PLTX) is a highly toxic polyether identified in various marine organisms, such as Palythoa soft corals, Ostreopsis dinoflagellates, and Trichodesmium cyanobacteria. In addition to adverse effects in humans, negative impacts on different marine organisms have been often described during Ostreopsis blooms and the concomitant presence of PLTX and its analogues. Considering the increasing frequency of Ostreopsis blooms due to global warming, PLTX was investigated for its effects on Artemia franciscana, a crustacean commonly used as a model organism for ecotoxicological studies. At concentrations comparable to those detected in culture media of O. cf. ovata (1.0-10.0 nM), PLTX significantly reduced cysts hatching and induced significant mortality of the organisms, both at larval and adult stages. Adults appeared to be the most sensitive developmental stage to PLTX: significant mortality was recorded after only 12 h of exposure to PLTX concentrations > 1.0 nM, with a 50% lethal concentration (LC50) of 2.3 nM (95% confidence interval = 1.2-4.7 nM). The toxic effects of PLTX toward A. franciscana adults seem to involve oxidative stress induction. Indeed, the toxin significantly increased ROS levels and altered the activity of the major antioxidant enzymes, in particular catalase and peroxidase, and marginally glutathione-S-transferase and superoxide dismutase. On the whole, these results indicate that environmentally relevant concentrations of PLTX could have a negative effect on Artemia franciscana population, suggesting its potential ecotoxicological impact at the marine level.
Subject(s)
Acrylamides/toxicity , Artemia/drug effects , Cnidarian Venoms/toxicity , Marine Toxins/toxicity , Oxidative Stress/drug effects , Acrylamides/administration & dosage , Animals , Cnidarian Venoms/administration & dosage , Dose-Response Relationship, Drug , Ecotoxicology , Lethal Dose 50 , Life Cycle Stages , Marine Toxins/administration & dosage , Reactive Oxygen Species/metabolism , Time FactorsABSTRACT
Size expansion can effectively improve tumor accumulation of nanocarriers where precise control is required. A dual-responsive nanocarrier stimulated by both endogenous pH and exogenous heat stimuli can change its size. Herein, a nanoparticle composed of poly(N,N-diethyl acrylamide) (PDEAA) and poly(2-(diisopropylamino) ethyl methacrylate) (PDPA) is developed. The antitumor drug celastrol (CLT) and the photosensitizer indocyanine green (ICG) are then loaded in it to form CIPP. ICG generates heat under near-infrared (NIR) stimulation to kill tumor cells and enhance CIPP penetration. Meanwhile, CIPP expands in response to hyperthermia and acid tumor microenvironments, preventing itself from returning to the blood flow, thus accumulating in tumor sites. Ultimately, the acidic lysosomal environment in tumor cells disintegrates CIPP to release CLT, directly inducing immunogenic cell death and sensitizing tumor cells for hyperthermia by disrupting the interaction of heat shock protein 90 and P50cdc37. Most of the tumors in B16F10-bearing mice are eradicated after single laser irradiation. The dual-responsive CIPP with multiple functions and simple design displays a synergistic antitumor effect. This study provides a basis for developing size-expandable stimulus-responsive drug delivery systems against tumors.
Subject(s)
Antineoplastic Agents/therapeutic use , Drug Carriers/chemistry , Nanoparticles/chemistry , Neoplasms/drug therapy , Photosensitizing Agents/therapeutic use , Acrylamides/chemical synthesis , Acrylamides/chemistry , Acrylamides/pharmacokinetics , Acrylamides/toxicity , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Combined Modality Therapy , Drug Carriers/chemical synthesis , Drug Carriers/pharmacokinetics , Drug Carriers/toxicity , Drug Liberation , Drug Therapy , Female , Indocyanine Green/chemistry , Indocyanine Green/radiation effects , Indocyanine Green/therapeutic use , Infrared Rays , Male , Mice, Inbred C57BL , Mice, Nude , Nanoparticles/toxicity , Pentacyclic Triterpenes/chemistry , Pentacyclic Triterpenes/therapeutic use , Photosensitizing Agents/chemistry , Photosensitizing Agents/radiation effects , Photothermal Therapy , Polymers/chemical synthesis , Polymers/chemistry , Polymers/pharmacokinetics , Polymers/toxicity , Polymethacrylic Acids/chemical synthesis , Polymethacrylic Acids/chemistry , Polymethacrylic Acids/pharmacokinetics , Polymethacrylic Acids/toxicityABSTRACT
During drug development, potential safety issues can occur at any time. Understanding the cause of a toxicity can help with deciding on how to advance the drug development program. Chemoproteomics provides a way to help understand the cause of a toxicity wherein the affected tissue is accessible and can be probed with a covalently binding compound that is analogous to the offending drug. In this case, N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (CC-292), a covalently binding Bruton's tyrosine kinase inhibitor, had produced testicular toxicity in rodents. Experiments were conducted using a CC-292 analog that could be chemically modified with biotin to probe rodent testes homogenates for potential binding sites that were subsequently recovered with avidin beads. These biotin-tagged proteins undergo trypsin digest on the avidin beads to yield peptides that are identified using mass spectrometry. Two proteins were identified from the testicular homogenates of both rats and mice, namely retinal dehydrogenase 1 (ALDH1A1) and retinal dehydrogenase 2 (ALDH1A2). Literature confirmed a link between inhibition of these enzymes and testicular toxicity. Subsequently, molecular modeling was used to demonstrate that CC-292 can be docked into both the nicotinamide adenine dinucleotide and retinal binding pockets of the analogous human ALDH1A2 enzyme. These data suggest that the off-target binding site for CC-292 on retinal dehydrogenase enzymes may provide a mechanistic explanation to the testicular toxicity observed in rodents and that there may be a potential concern for human male fertility. SIGNIFICANCE STATEMENT: Biotinylated covalently binding drug analogues are used to enrich bound proteins from tissue homogenates wherein toxicity was observed in rodents. Bound proteins were subsequently identified by mass spectroscopy. Competition of the analog binding with the parent inhibitor itself and three-dimensional molecular modeling were used to establish a likely link between the off-targets of CC-292, ALDH1A1, and ALDH1A2 with potential testicular toxicity.
Subject(s)
Acrylamides/toxicity , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/toxicity , Proteomics/methods , Pyrimidines/toxicity , Testis/drug effects , Testis/enzymology , Agammaglobulinaemia Tyrosine Kinase/genetics , Agammaglobulinaemia Tyrosine Kinase/metabolism , Amino Acid Sequence , Animals , Dose-Response Relationship, Drug , Humans , Male , Mice , Mice, Inbred C57BL , Protein Structure, Secondary , Protein Structure, Tertiary , Rats , Rats, Sprague-DawleyABSTRACT
Protein S-acylation is a dynamic lipid post-translational modification that can modulate the localization and activity of target proteins. In humans, the installation of the lipid onto target proteins is catalyzed by a family of 23 Asp-His-His-Cys domain-containing protein acyltransferases (DHHC-PATs). DHHCs are increasingly recognized as critical players in cellular signaling events and in human disease. However, progress elucidating the functions and mechanisms of DHHC "writers" has been hampered by a lack of chemical tools to perturb their activity in live cells. Herein, we report the synthesis and characterization of cyano-myracrylamide (CMA), a broad-spectrum DHHC family inhibitor with similar potency to 2-bromopalmitate (2BP), the most commonly used DHHC inhibitor in the field. Possessing an acrylamide warhead instead of 2BP's α-halo fatty acid, CMA inhibits DHHC family proteins in cellulo while demonstrating decreased toxicity and avoiding inhibition of the S-acylation eraser enzymes, two of the major weaknesses of 2BP. Our studies show that CMA engages with DHHC family proteins in cells, inhibits protein S-acylation, and disrupts DHHC-regulated cellular events. CMA represents an improved chemical scaffold for untangling the complexities of DHHC-mediated cell signaling by protein S-acylation.
Subject(s)
Acrylamides/pharmacology , Acyltransferases/antagonists & inhibitors , CD36 Antigens/metabolism , Enzyme Inhibitors/pharmacology , Acrylamides/chemical synthesis , Acrylamides/toxicity , Acylation/drug effects , Animals , Cell Line, Tumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/toxicity , ErbB Receptors/metabolism , Humans , Lipoylation/drug effects , Mice , Protein Processing, Post-Translational/drug effectsABSTRACT
EGFR tyrosine kinase inhibitors (TKIs) are mainly used to treat non-small cell lung cancer; however, adverse effects such as severe diarrhea represent a major obstacle towards the continuation of EGFR-TKIs therapy. Chloride channels, which control the fluid flow in the intestinal lumen, are proposed as an important target to remediate EGFR-TKIs-induced diarrhea, but the mechanism remains unclear. The aim of this study was to clarify the mechanism underlying EGFR-TKIs-induced diarrhea with a particular focus on the role of intestinal chloride channels. Here, we show that osimertinib-treated rats exhibit diarrhea and an increase in fecal water content without showing any severe histopathological changes. This diarrhea was attenuated by intraperitoneal treatment with the calcium-activated chloride channel (CaCC) inhibitor CaCCinh-A01. These findings were confirmed in afatinib-treated rats with diarrhea. Moreover, treatment with the Japanese traditional herbal medicine, hangeshashinto (HST), decreased fecal water content and improved fecal appearance in rats treated with EGFR-TKIs. HST inhibited the ionomycin-induced CaCC activation in HEK293 cells in patch-clamp current experiments and its active ingredients were identified. In conclusion, secretory diarrhea induced by treatment with EGFR-TKIs might be partially mediated by the activation of CaCC. Therefore, blocking the CaCC could be a potential new treatment for EGFR-TKI-induced diarrhea.
Subject(s)
Chloride Channels/antagonists & inhibitors , Chloride Channels/metabolism , Diarrhea/chemically induced , ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/toxicity , Acrylamides/toxicity , Afatinib/toxicity , Aniline Compounds/toxicity , Animals , Diarrhea/pathology , Feces/chemistry , HEK293 Cells , Humans , Male , Patch-Clamp Techniques , Rats , Rats, Sprague-Dawley , Thiophenes/pharmacology , Water/chemistryABSTRACT
Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting.
Subject(s)
Acrylamides/administration & dosage , Acrylamides/pharmacology , Aniline Compounds/administration & dosage , Aniline Compounds/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm , Lung Neoplasms/diet therapy , Quinazolinones/administration & dosage , Quinazolinones/pharmacology , Acrylamides/pharmacokinetics , Acrylamides/toxicity , Aniline Compounds/pharmacokinetics , Aniline Compounds/toxicity , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/secondary , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Cohort Studies , Computer Simulation , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , ErbB Receptors/metabolism , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Models, Statistical , Models, Theoretical , Mutation , Quinazolinones/pharmacokinetics , Quinazolinones/toxicityABSTRACT
Palytoxin (PLTX) is one of the most poisonous substances known to date and considered as an emergent toxin in Europe. Palytoxin binds to the Na+-K+ ATPase, converting the enzyme in a permeant cation channel. This toxin is known for causing human fatal intoxications associated with the consumption of contaminated fish and crustaceans such as crabs, groupers, mackerel, and parrotfish. Human intoxications by PLTX after consumption of contaminated fishery products are a serious health issue and can be fatal. Different reports have previously explored the acute oral toxicity of PLTX in mice. Although the presence of palytoxin in marine products is currently not regulated in Europe, the European Food Safety Authority expressed its opinion on PLTX and demanded assessment for chronic toxicity studies of this potent marine toxin. In this study, the chronic toxicity of palytoxin was evaluated after oral administration to mice by gavage during a 28-day period. After chronic exposure of mice to the toxin, a lethal dose 50 (LD50) of 0.44 µg/kg of PLTX and a No-Observed-Adverse-Effect Level (NOAEL) of 0.03 µg/kg for repeated daily oral administration of PLTX were determined. These results indicate a much higher chronic toxicity of PLTX and a lower NOAEL than that previously described in shorter treatment periods, pointing out the need to further reevaluate the levels of this compound in marine products.
Subject(s)
Acrylamides/toxicity , Cnidarian Venoms/toxicity , Administration, Oral , Animals , Chlorides/blood , Female , Lethal Dose 50 , Mice , No-Observed-Adverse-Effect Level , Potassium/blood , Sodium/blood , Stomach/drug effects , Stomach/pathology , Stomach/ultrastructure , Toxicity Tests, SubacuteABSTRACT
Palytoxin has been found in several soft coral species which are popular for in-home reef aquariums. Although a limited number of case reports describing acute respiratory distress after inhalational exposure to palytoxin have been reported, there have been no reports regarding the potential long-term effects of inhalational exposure to palytoxin in the literature. This case follows an aquatic specialist in the U.S. over a period of seven years after a single intense occupational exposure to the aerosolized toxin from cleaning of a residential aquarium.
Subject(s)
Acrylamides/toxicity , Cnidarian Venoms/toxicity , Inhalation Exposure , Occupational Exposure , Animals , Anthozoa , United StatesABSTRACT
Palytoxin is an emergent toxin in Europe and one of the most toxic substances know to date. The toxin disrupts the physiological functioning of the Na+/K+-ATPase converting the enzyme in a permeant cation channel. Human intoxications by PLTX after consumption of contaminated fishery products are a serious health issue and can be fatal. Several reports have previously investigated the oral and intraperitoneal toxicity of PLTX in mice. However, in all cases short observation periods (24 and 48 h) after toxin administration were evaluated. In this work, single oral or intraperitoneal doses of PLTX were administered to healthy mice and surviving animals were followed up for 96 h. The data obtained here allowed us to calculate the oral and intraperitoneal lethal doses 50 (LD50) which were in the range of the values previously described. Surprisingly, the oral NOAEL for PLTX was more than 10 times lower than that previously described, a fact that indicates the need for the reevaluation of the levels of the toxin in edible fishery products.
Subject(s)
Acrylamides/toxicity , Cnidarian Venoms/toxicity , Toxicity Tests, Acute , Animals , Humans , Lethal Dose 50 , Mice , No-Observed-Adverse-Effect Level , Sodium-Potassium-Exchanging ATPase/metabolismABSTRACT
Acrylamide (AA) constitutes an important industrial chemical agent and well-known neurotoxin. However, the mechanism underlying AA-mediated neurotoxicity is extremely complicated and controversial. In this study, we found that activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and its subsequent downstream inflammatory responses plays an important role in AA-induced neurotoxicity mechanisms. In vitro experiments revealed that AA (2.5 mM) induced BV2 microglial cytotoxicity and triggered NLRP3 inflammasome activation along with downstream proinï¬ammatory cytokine interleukin-1ß and interleukin-18 expression. Treatment with inhibitor or NLRP3 siRNA efficiently protected BV2 microglial cells against AA-induced cytotoxicity and reversed NLRP3 inflammasome activation and its mediated inflammatory reaction. Similarly, AA exposure (50 mg/kg) for 10 consecutive days caused significant activation of NLRP3 inflammasomes and neuroinflammation in C57BL/6 mice, whereas inhibiting these effects through specific NLRP3 inflammasome blocker MCC950 (5 mg/kg) intervention or NLRP3 knock-out significantly ameliorated AA-induced ataxia, cerebellar Purkinje cells degeneration, and apoptosis. Furthermore, we demonstrated that antagonism of NLRP3 could also up-regulate the Nrf2 signalling pathway and related antioxidant genes. In conclusion, our findings indicate that activation of the NLRP3 inflammasome pathway is involved in AA-induced neurotoxicity, whereas MCC950 treatment or NLRP3 knock-out could effectively protect against AA-induced neurotoxic injury through the inhibition of neuroinflammation and activation of the Nrf2 antioxidant pathway. Therefore, the NLRP3 inflammasome might serve as a promising therapeutic target, with drugs designed to specifically inhibit this pathway potentially providing new avenues for preventing or ameliorating AA poisoning.
Subject(s)
Acrylamides/toxicity , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Neurotoxicity Syndromes/prevention & control , Animals , Behavior, Animal/drug effects , Cell Line , Cytokines/metabolism , Furans , Heterocyclic Compounds, 4 or More Rings/pharmacology , Indenes , Inflammation/chemically induced , Inflammation/pathology , Inflammation Mediators/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microglia/drug effects , Microglia/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Neurotoxicity Syndromes/pathology , Neurotoxicity Syndromes/psychology , RNA, Small Interfering/pharmacology , Signal Transduction/drug effects , Sulfonamides , Sulfones/pharmacologyABSTRACT
In this study, we performed a systematic evaluation of the synthesis parameters of a multiresponsive core-shell nanoplatform (Fe3O4 nanoparticles coated by poly(N-isopropylacrylamide). These nanocomposites allow the possibility of controlling specific properties, such as particle size and morphology. The polymer coating was performed by in-situ free-radical polymerization of N-isopropylacrylamide on Fe3O4 nanoparticles to obtain a nanocomposite with a core-shell structure. We monitored the size and morphology of the nanocomposite by scanning transmission electron microscopy. Electrophoretic mobility determined the evolution of ζ-potentials during coating. We assessed the functionalization of the Fe3O4 nanoparticles by Fourier-transform infrared spectroscopy and ultraviolet-visible spectroscopy. The core-shell systems exhibited a collapsed structure when heated above the lower critical solution temperature, which was determined by dynamic light scattering. Squid based vibrating sample magnetometer tests were performed to verify superparamagnetic behavior at room temperature. The platform was approved as biocompatible for the HeLa and MDA-MB-231 cell lines by MTT assays, and it shows the desired properties for potential use in localized and controlled drug delivery.
Subject(s)
Acrylamides , Nanoparticles , Acrylamides/toxicity , Acrylic Resins , Humans , Magnetic PhenomenaABSTRACT
Marine isolates such as palytoxin (PTX) are of concern within the Caribbean region due to their toxicity. PTX for example has been described as a one of the most known potent marine toxins, known to prevent predation from larger species (e.g. vertebrates) as well as the prevention of being overgrown from other coral species. PTX is a polyhydroxylated polyether toxin with a very large and complex chemical structure that possesses both hydrophilic and lipophilic properties. Previous acute toxicity tests using brine shrimp (Artemia salina) and PTX extract had shown it to be moderately toxic. In humans, PTX has been credited to be responsible for extreme symptoms such anaphylactic shock, rapid cardiac failure and eventual death occurring within minutes. Extrapolation for human dose ranges has therefore been suggested to be between 2.3 and 31.5⯵g. This study isolates a potentially PTX-enriched extract from Palythoa caribaeorum and examines its organic extract toxicity from a biogeography perspective from a within-colony to a variety of reef sites around Trinidad and Tobago that are popular for marine visitors. This research represents an acute study with a high level of crude organic extract toxicity on A. salina whilst postulating potential factors which may contribute to its extreme toxicity and the risk posed to users of these environments.