Showing papers on "Toxicity published in 2018"

Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.

Abstract: Small interfering RNAs (siRNAs) conjugated to a trivalent N-acetylgalactosamine (GalNAc) ligand are being evaluated in investigational clinical studies for a variety of indications. The typical development candidate selection process includes evaluation of the most active compounds for toxicity in rats at pharmacologically exaggerated doses. The subset of GalNAc-siRNAs that show rat hepatotoxicity is not advanced to clinical development. Potential mechanisms of hepatotoxicity can be associated with the intracellular accumulation of oligonucleotides and their metabolites, RNA interference (RNAi)-mediated hybridization-based off-target effects, and/or perturbation of endogenous RNAi pathways. Here we show that rodent hepatotoxicity observed at supratherapeutic exposures can be largely attributed to RNAi-mediated off-target effects, but not chemical modifications or the perturbation of RNAi pathways. Furthermore, these off-target effects can be mitigated by modulating seed-pairing using a thermally destabilizing chemical modification, which significantly improves the safety profile of a GalNAc-siRNA in rat and may minimize the occurrence of hepatotoxic siRNAs across species.

Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads

Abstract: Background Antibody drug conjugates (ADCs) utilize a monoclonal antibody to deliver a cytotoxic payload specifically to tumor cells, limiting exposure to healthy tissues. Major clinical toxicities of ADCs include hematologic, hepatic, neurologic, and ophthalmic events, which are often dose-limiting. These events may be off-target effects caused by premature release of payload in circulation. A meta-analysis was performed to summarize key clinical safety data for ADCs by payload, and data permitting, establish a dose-response model for toxicity incidence as a function of payload, dose/regimen, and cancer type. Methods A literature search was performed to identify and extract data from clinical ADC studies. Toxicity incidence and severity were collected by treatment arm for anemia, neutropenia, thrombocytopenia, leukopenia, hepatic toxicity, peripheral neuropathy, and ocular toxicity. Exploratory plots, descriptive summaries, and logistic regression modelling were used to explore Grade ≥ 3 (G3/4) toxicities and assess the impact of covariates, including cancer type and dose/regimen. Results The dataset contained 70 publications; quantitative analysis included 43 studies with G3/4 toxicity information reported for the endpoints above. G3/4 anemia, neutropenia and peripheral neuropathy were consistently reported for MMAE ADCs, thrombocytopenia and hepatic toxicity for DM1, and ocular toxicity for MMAF. Safety profiles of MMAE, DM1, and DM4 ADCs differed between solid and hematologic cancers. Conclusions Published ADC clinical data is limited by non-uniform reporting for toxicity and lack of dosing information, limiting the ability to develop quantitative models relating toxicity to exposure. However, the current analysis suggests that key G3/4 toxicities of ADCs in the clinic are likely off-target and related to payload.

Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage

Abstract: Cyclophosphamide (CP) is a common chemotherapeutic agent that is effective against a wide variety of tumors. The associated hepatotoxicity and nephrotoxicity, however, limit its therapeutic use. Naringin (NG) is a natural flavanone glycoside that has pharmacological and therapeutic activities, such as anti-inflammation, anti-apoptotic, and antioxidant properties. Therefore, the present study was undertaken to evaluate the protective effect of NG against CP-induced hepatotoxicity and nephrotoxicity in rats. Rats were pre-treated with NG (50 and 100 mg/kg b.w.) for 7 days before administering a single dose of CP (200 mg/kg b.w.) on the seventh day. CP-induced hepatotoxicity and nephrotoxicity were associated with an increase in serum toxicity markers and a decrease in antioxidant enzyme activities. CP also induced inflammatory responses by increasing the levels of tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), and interleukin-1β (IL-1β), and activities of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, it activated the apoptotic and autophagic pathway by increasing cysteine aspartate-specific protease-3 (caspase-3) expression and light chain 3B (LC3B) level and also increased the expression of 8-hydroxy-2′-deoxyguanosine (8-OHdG), which is the marker of oxidative DNA damage. Pre-treatment with NG (50 and 100 mg/kg), however, significantly decreased serum toxicity markers, increased antioxidant enzyme activities, and regulated inflammation, apoptosis, autophagy, and oxidative DNA damage in hepatic and renal tissues. These results indicated that NG was an effective protectant against CP-induced hepatotoxicity and nephrotoxicity.

Sex and interleukin-6 are prognostic factors for autoimmune toxicity following treatment with anti-CTLA4 blockade.

Abstract: Ipilimumab is a licensed immunotherapy for metastatic melanoma patients and, in the US, as adjuvant treatment for high risk melanoma radically resected. The use of ipilimumab is associated with a typical but unpredictable pattern of side effects. The purpose of this study was to identify clinical features and blood biomarkers capable of predicting ipilimumab related toxicity. We performed a prospective study aimed at analyzing potential clinical and biological markers associated with immune-related toxicity in patients treated with ipilimumab (3 mg/kg, q3w). We enrolled 140 consecutive melanoma patients treated with ipilimumab for metastatic disease. The following prospectively collected data were utilized: patient characteristics, previous therapies, level of circulating biomarkers associated with tumour burden or immune-inflammation status (lactic dehydrogenase, C-reactive protein, β2-microglobulin, vascular endothelial growth factor, interleukin-2, interleukin-6, S-100, alkaline phosphatase, transaminases) and blood cells subsets (leukocyte and lymphocyte subpopulations). Logistic regression was used for multivariate analysis of data. Out of 140 patients, 36 (26%) experienced a severe adverse event, 33 (24%) discontinued treatment for severe toxicity. Among the immune-profile biomarkers analyzed, only interleukin-6 was associated with the risk of toxicity. Female patients had a further increase of immune-related adverse events. Low baseline interleukin-6 serum levels (OR = 2.84, 95% CI 1.34–6.03, P = 0.007) and sex female (OR = 1.5, 95% CI 1.06–2.16 P = 0.022) and were significant and independent risk factors for immune related adverse events. Baseline IL6 serum levels and female sex were significantly and independently associated with higher risk of severe toxicity and could be exploited in clinical practice to personalize toxicity surveillance in patients treated with ipilimumab.

Prediction of liver toxicity and mode of action using metabolomics in vitro in HepG2 cells

Abstract: Liver toxicity is a leading systemic toxicity of drugs and chemicals demanding more human-relevant, high throughput, cost effective in vitro solutions. In addition to contributing to animal welfare, in vitro techniques facilitate exploring and understanding the molecular mechanisms underlying toxicity. New 'omics technologies can provide comprehensive information on the toxicological mode of action of compounds, as well as quantitative information about the multi-parametric metabolic response of cellular systems in normal and patho-physiological conditions. Here, we combined mass-spectroscopy metabolomics with an in vitro liver toxicity model. Metabolite profiles of HepG2 cells treated with 35 test substances resulted in 1114 cell supernatants and 3556 intracellular samples analyzed by metabolomics. Control samples showed relative standard deviations of about 10-15%, while the technical replicates were at 5-10%. Importantly, this procedure revealed concentration-response effects and patterns of metabolome changes that are consistent for different liver toxicity mechanisms (liver enzyme induction/inhibition, liver toxicity and peroxisome proliferation). Our findings provide evidence that identifying organ toxicity can be achieved in a robust, reliable, human-relevant system, representing a non-animal alternative for systemic toxicology.

Improving the Reliability and Utility of Streptozotocin-Induced Rat Diabetic Model.

Abstract: The Streptozotocin- (STZ-) induced diabetic model is widely used; however, unexplained acute toxicity has given the model an unreliable reputation To improve the reliability and utility of this model, we characterize the age dependence of STZ toxicity and introduce novel endpoints to assess diabetic complications and reveal possible mechanisms for diabetic development Diabetes was induced by STZ injection into male, 6 to 23 weeks old, Sprague-Dawley rats Their metabolic (glucose, lipids, and hormones), inflammatory (cytokines), histologic and behavioral endpoints were observed for 12 years Analgesic compounds were assessed for efficacy treating neuropathy Acute mortality, within a week of STZ injection (50–65 mg/kg iv), was inversely correlated to animal age Only 3% of rats, age 6–11 weeks, died in the week following STZ injection, whereas 83% of rats 12 to 17 weeks old and 91% of rats 18 weeks or older died in the same week Partial model recovery (normalized insulin, glucose and food/water intake) was observed starting at week 36; however, pain scores, kidney enlargement, and cataract formation continued to show progression consistent with the diabetic state Unique noninvasive observational measurements, such as haircoat quality and diarrhea scores, served as useful endpoints for this model The increased plasma cytokines (such as TNF-α, IL-4, and IL-6) and inflammatory cell infiltration into the pancreatic islets are strong evidence of inflammation in the STZ-induced diabetic model Pancreatic tissue staining revealed total islet area reduction and confirmed STZ-specific pancreatic toxicity; however, the β-cell density per area in pancreatic islets and insulin levels statistically increased over time in the diabetic rats, suggesting a mechanism for partial recovery of diabetic symptoms Voltage-gated sodium channel (NaV17 specific, peripherally restricted) blocker, CC4148, inhibited neuropathy without side effects as compared to a nonspecific sodium channel inhibitor, Mexiletine, or GABA analog, Pregabalin, which inhibited neuropathy with side effects

Histopathological lesions and toxicity in common carp (Cyprinus carpio L. 1758) induced by copper nanoparticles.

Abstract: Different types of metal oxide nanoparticles (NPs) have been suggested for various applications such as water treatment and construction of agricultural pesticides; however, there are concerns about the potential toxicity of these compounds for the nontarget organism especially aquatic organisms. The aims of this study were assessing toxicity and histopathological effects of copper oxide NPs (NPs-CuO) on common carp (Cyprinus carpio) as a model organism. For this purpose 150 common carp with an average weight 7 ± 1 g were exposed to 0, 10, 20, 30, 40, 60, 80, 100, 150, and 200 mg/l of CuO-NPs (10 treatment with three replicates) for 96 hrs. After 24, 48, 72, and 96 hrs exposures, mortality rates recorded and gill samples were collected. Statistical analysis showed significant differences in carp survival between control and treatment groups (p < 0.05); regression between fish mortality rate and NPs-CuO concentration was also revealed (p < 0.01). The LC50 96h of NPs-CuO for common carp was estimated as 124.9 mg/l in this study. Various tissue damages were observed in gill of treatments; such as, hypertrophy, hyperplasia, lamellar fusions, erythrocyte infiltration, epithelial lifting; also, there was significant correlation between intensity of tissue lesions and concentration of NPs-CuO (p < 0.01). The findings of the present study demonstrate that sublethal concentration of NPs-CuO can lead to serious tissue lesions. Whats more, concentrations above 30 ml/l of NPs-CuO can lead to some clinical signs; such as skin darkening and death with open mouth as well as definite fish death.

Lipid Emulsion for Treating Local Anesthetic Systemic Toxicity.

Abstract: Lipid emulsion has been shown to be an effective treatment for systemic toxicity induced by local anesthetics, which is reflected in case reports. A systemic review and meta-analysis confirm the efficacy of this treatment. Investigators have suggested mechanisms associated with the lipid emulsion-mediated recovery of cardiovascular collapse caused by local anesthetic systemic toxicity; these mechanisms include lipid sink, a widely accepted theory in which highly soluble local anesthetics (particularly bupivacaine) are absorbed into the lipid phase of plasma from tissues (e.g., the heart) affected by local-anesthetic-induced toxicity; enhanced redistribution (lipid shuttle); fatty acid supply; reversal of mitochondrial dysfunction; inotropic effects; glycogen synthase kinase-3β phosphorylation associated with inhibition of the mitochondrial permeability transition pore opening; inhibition of nitric oxide release; and reversal of cardiac sodium channel blockade. The current review includes the following: 1) an introduction, 2) a list of the proposed mechanisms, 3) a discussion of the best lipid emulsion treatment for reversal of local anesthetic toxicity, 4) a description of the effect of epinephrine on lipid emulsion-mediated resuscitation, 5) a description of the recommended lipid emulsion treatment, and 6) a conclusion.

The Role of miRNAs in the Pathophysiology of Liver Diseases and Toxicity

Abstract: Both acute and chronic liver toxicity represents a major global health burden and an important cause of morbidity and lethality worldwide Despite epochal progress in the treatment of hepatitis C virus infections, pharmacological treatment strategies for most liver diseases are still limited and new targets for prevention or treatment of liver disease are urgently needed MicroRNAs (miRNAs) represent a new class of highly conserved small non-coding RNAs that are involved in the regulation of gene expression by targeting whole networks of so called “targets” Previous studies have shown that the expression of miRNAs is specifically altered in almost all acute and chronic liver diseases In this context, it was shown that miRNA can exert causal roles, being pro- or anti-inflammatory, as well as pro- or antifibrotic mediators or being oncogenes as well as tumor suppressor genes Recent data suggested a potential therapeutic use of miRNAs by targeting different steps in the hepatic pathophysiology Here, we review the function of miRNAs in the context of acute and chronic liver diseases Furthermore, we highlight the potential role of circulating microRNAs in diagnosis of liver diseases and discuss the major challenges and drawbacks that currently prevent the use of miRNAs in clinical routine

Comparative study of selenium and selenium nanoparticles with reference to acute toxicity, biochemical attributes, and histopathological response in fish

Abstract: Recent studies have demonstrated that selenium (Se) and selenium nanoparticles (Se-NPs) exhibited toxicity at a higher concentration. The lethal concentration of Se and Se-NPs was estimated as 5.29 and 3.97 mg/L at 96 h in Pangasius hypophthalmus. However, the effect of different definite concentration of Se (4.5, 5.0, 5.5, and 6.0 mg/L) and Se-NPs (2.5, 3.0, 3.5, and 4.0 mg/L) was decided for acute experiment. Selenium and Se-NPs alter the biochemical attributes such as anti-oxidative status [catalase (CAT), superoxide dismutase (SOD), and glutathione-S-transferase (GST) activities], neurotransmitter enzyme, cellular metabolic enzymes, stress marker, and histopathology of P. hypophthalmus in a dose- and time-dependent manner. CAT, SOD, and GST were significantly elevated (p < 0.01) when exposed to Se and Se-NPs, and similarly, a neurotransmitter enzyme (acetylcholine esterase (AChE)) was significantly inhibited in a time- and dose-dependent manner. Further, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and malate hydrogenase were noticeably (p < 0.01) affected by Se and Se-NPs from higher concentration to lower concentration. Stress markers such as cortisol and HSP 70 were drastically enhanced by exposure to Se and Se-NPs. All the cellular metabolic and stress marker parameters were elevated which might be due to hyperaccumulation of Se and Se-NPs in the vital organ and target tissues. The histopathology of liver and gill was also altered such as large vacuole, cloudy swelling, focal necrosis, interstitial edema, necrosis in liver, and thickening of primary lamellae epithelium and curling of secondary lamellae due to Se and Se-NP exposure. The study suggested that essential trace element in both forms (inorganic and nano) at higher concentration in acute exposure of Se and Se-NPs led to pronounced deleterious alteration on histopathology and cellular and metabolic activities of P. hypophthalmus.

Halobenzoquinone-Induced Developmental Toxicity, Oxidative Stress, and Apoptosis in Zebrafish Embryos.

Abstract: The developmental toxicity of water disinfection byproducts remains unclear. Here we report the study of halobenzoquinone (HBQ)-induced in vivo developmental toxicity and oxidative stress using zebrafish embryos as a model. Embryos were exposed to 0.5–10 μM of individual HBQs and 0.5–5 mM haloacetic acids for up to 120 h postfertilization (hpf). LC50 values of the HBQs at 24 hpf were 4.6–9.8 μM, while those of three haloacetic acids were up to 200 times higher at 1900–2600 μM. HBQ exposure resulted in significant developmental malformations in larvae, including failed inflation of the gas bladder, heart malformations, and curved spines. An increase in reactive oxygen species was observed, together with a decrease in superoxide dismutase activity and glutathione content. Additionally, the antioxidant N-acetyl-l-cysteine significantly mitigated all HBQ-induced effects, supporting that oxidative stress contributes to HBQ toxicity. Further experiments examined HBQ-induced effects on DNA and genes. HBQ exposur...

The Toxic Effects of Aflatoxin B1 and Aflatoxin M1 on Kidney through Regulating L-Proline and Downstream Apoptosis.

Abstract: The toxic effects and potential mechanisms of aflatoxin B1 (AFB1), aflatoxin M1 (AFM1), and AFB1+AFM1 in the kidney were studied and compared in HEK 293 cells model and CD-1 mice model. The 35-day subacute toxicity mice model was constructed, biochemical indicators and kidney pathological staining were detected, kidney metabonomics detection was performed, and the metabolites were analyzed, and then the related toxicity mechanism was validated. Results showed that AFB1 (0.5 mg/kg), AFM1 (3.5 mg/kg), and AFB1 (0.5 mg/kg)+AFM1 (3.5 mg/kg) activated oxidative stress and caused renal damage. The relative concentration of the metabolite L-proline was found to be lower in aflatoxins treatment groups when compared with the control ( ). Moreover, with the treatment of aflatoxins, proline dehydrogenase (PRODH) and proapoptotic factors (Bax, Caspase-3) were upregulated, while the inhibitor of apoptosis Bcl-2 was downregulated, at both the mRNA and the protein levels, comparing with the control ( ). In addition, the combined effect of AFB1 and AFM1 was validated, for the toxicity of the combination was stronger than the other two groups. In conclusion, AFB1 and AFM1 caused kidney toxicity by activating oxidative stress through altering expression of PRODH and L-proline levels, which then induced downstream apoptosis.

Oxidative Stress in Methylmercury-Induced Cell Toxicity

Abstract: Methylmercury (MeHg) is a hazardous environmental pollutant, which elicits significant toxicity in humans. The accumulation of MeHg through the daily consumption of large predatory fish poses potential health risks, and the central nervous system (CNS) is the primary target of toxicity. Despite well-described neurobehavioral effects (i.e., motor impairment), the mechanisms of MeHg-induced toxicity are not completely understood. However, several lines of evidence point out the oxidative stress as an important molecular mechanism in MeHg-induced intoxication. Indeed, MeHg is a soft electrophile that preferentially interacts with nucleophilic groups (mainly thiols and selenols) from proteins and low-molecular-weight molecules. Such interaction contributes to the occurrence of oxidative stress, which can produce damage by several interacting mechanisms, impairing the function of various molecules (i.e., proteins, lipids, and nucleic acids), potentially resulting in modulation of different cellular signal transduction pathways. This review summarizes the general aspects regarding the interaction between MeHg with regulators of the antioxidant response system that are rich in thiol and selenol groups such as glutathione (GSH), and the selenoenzymes thioredoxin reductase (TrxR) and glutathione peroxidase (Gpx). A particular attention is directed towards the role of the PI3K/Akt signaling pathway and the nuclear transcription factor NF-E2-related factor 2 (Nrf2) in MeHg-induced redox imbalance.

Environmental Toxin Screening Using Human-Derived 3D Bioengineered Liver and Cardiac Organoids.

Abstract: Introduction: Environmental toxins, such as lead and other heavy metals, pesticides, and other compounds, represent a significant health concern within the USA and around the world. Even in the 21st century, a plethora of cities and towns in the U.S. have suffered from exposures to lead in drinking water or other heavy metals in food or the earth, while there is a high possibility of further places to suffer such exposures in the near future. Methods: We employed bioengineered 3D human liver and cardiac organoids to screen a panel of environmental toxins (lead, mercury, thallium, and glyphosate), and charted the response of the organoids to these compounds. Liver and cardiac organoids were exposed to lead (10 μM - 10 mM), mercury (200 nM - 200 μM), thallium (10 nM - 10 μM), or glyphosate (25 μM - 25 mM) for a duration of 48 hours. The impacts of toxin exposure were then assessed by LIVE/DEAD viability and cytotoxicity staining, measuring ATP activity and determining IC50 values, and determining changes in cardiac organoid beating activity. Results: As expected, all of the toxins induced toxicity in the organoids. Both ATP and LIVE/DEAD assays showed toxicity in both liver and cardiac organoids. In particular, thallium was the most toxic, with IC50 values of 13.5 μM and 1.35 μM in liver and cardiac organoids, respectively. Conversely, glyphosate was the least toxic of the four compounds, with IC50 values of 10.53 mM and 10.85 mM in liver and cardiac organoids, respectively. Additionally, toxins had a negative influence on cardiac organoid beating activity as well. Thallium resulting in the most significant decreases in beating rate, followed by mercury, then glyphosate, and finally, lead. These results suggest that the 3D organoids have significant utility to be deployed in additional toxicity screening applications, and future development of treatments to mitigate exposures. Conclusion: 3D organoids have significant utility to be deployed in additional toxicity screening applications, such as future development of treatments to mitigate exposures, drug screening, and environmental toxin detection.