Improved efficacy and reduced toxicity of doxorubicin encapsulated in sulfatide-containing nanoliposome in a glioma model

As a glycosphingolipid that can bind to several extracellular matrix proteins, sulfatide has the potential to become an effective targeting agent for tumors overexpressing tenasin-C in their microenvironment. To overcome the dose-limiting toxicity of doxorubicin (DOX), a sulfatide-containing nanoliposome (SCN) encapsulation approach was employed to improve treatment efficacy and reduce side effects of free DOX. This study analysed in vitro characteristics of sulfatidecontaining nanoliposomal DOX (SCN-DOX) and assessed its cytotoxicity in vitro, as well as biodistribution, therapeutic efficacy, and systemic toxicity in a human glioblastoma U-118MG xenograft model. SCN-DOX was shown to achieve highest drug to lipid ratio (0.5:1) and a remarkable in vitro stability. Moreover, DOX encapsulated in SCN was shown to be delivered into the nuclei and displayed prolonged retention over free DOX in U-118MG cells. This simple two-lipid SCN- DOX nanodrug has favourable pharmacokinetic attributes in terms of prolonged circulation time, reduced volume of distribution and enhanced bioavailability in healthy rats. As a result of the improved biodistribution, an enhanced treatment efficacy of SCNDOX was found in glioma-bearing mice compared to the free drug. Finally, a reduction in the accumulation of DOX in the drug’s principal toxicity organs achieved by SCN-DOX led to the diminished systemic toxicity as evident from the plasma biochemical analyses. Thus, SCN has the potential to be an effective and safer nano-carrier for targeted delivery of therapeutic agents to tumors with elevated expression of tenascin-C in their microenvironment.

Aquatic toxicity of manufactured nanomaterials: challenges and recommendations for future toxicity testing

 Aquatic nanotoxicologists and ecotoxicologists have begun to identify the unique properties of the nanomaterials (NMs) that potentially affect the health of wildlife. In this review the scientific aims are to discuss the main challenges nanotoxicologists currently face in aquatic toxicity testing, including the transformations of NMs in aquatic test media (dissolution, aggregation and small molecule interactions), and modes of NM interference (optical interference, adsorption to assay components and generation of reactive oxygen species) on common toxicity assays. Three of the major OECD (Organisation for Economic Co-operation and Development) priority materials, titanium dioxide (TiO2), zinc oxide (ZnO) and silver (Ag) NMs, studied recently by the Natural Sciences and Engineering Research Council of Canada (NSERC), National Research Council of Canada (NRC) and the Business Development Bank of Canada (BDC) Nanotechnology Initiative (NNBNI), a Canadian consortium, have been identified to cause both bulk effect, dissolution-based (i.e. free metal), or NM-specific toxicity in aquatic organisms. TiO2 NMs are most toxic to algae, with toxicity being NM size-dependent and principally associated with binding of the materials to the organism. Conversely, dissolution of Zn and Ag NMs and the subsequent release of their ionic metal counterparts appear to represent the primary mode of toxicity to aquatic organisms for these NMs. In recent years, our understanding of the toxicological properties of these specific OECD relevant materials has increased significantly. Specifically, researchers have begun to alter their experimental design to identify the different behaviour of these materials as colloids and, by introducing appropriate controls and NM characterisation, aquatic nanotoxicologists are now beginning to possess a clearer understanding of the chemical and physical properties of these materials in solution, and how these materials may interact with organisms. Arming nanotoxicologists with this understanding, combined with knowledge of the physics, chemistry and biology of these materials is essential for maintaining the accuracy of all future toxicological assessments.

Glutaredoxin1 protects neuronal cells from copper-induced toxicity

Glutaredoxin1 (GRX1) is a glutathione (GSH)-dependent thiol oxidoreductase. The GRX1/GSH system is important for the protection of proteins from oxidative damage and in the regulation of protein function. Previously we demonstrated that GRX1/GSH regulates the activity of the essential copper-transporting P1B-Type ATPases (ATP7A, ATP7B) in a copper-responsive manner. It has also been established that GRX1 binds copper with high affinity and regulates the redox chemistry of the metallochaperone ATOX1, which delivers copper to the copper-ATPases. In this study, to further define the role of GRX1 in copper homeostasis, we examined the effects of manipulating GRX1 expression on copper homeostasis and cell survival in mouse embryonic fibroblasts and in human neuroblastoma cells (SH-SY5Y). GRX1 knockout led to cellular copper retention (especially when cultured with elevated copper) and reduced copper tolerance, while in GRX1-overexpressing cells challenged with elevated copper, there was a reduction in both intracellular copper levels and copper-induced reactive oxygen species, coupled with enhanced cell proliferation. These effects are consistent with a role for GRX1 in regulating ATP7A-mediated copper export, and further support a new function for GRX1 in neuronal copper homeostasis and in protection from copper-mediated oxidative injury.

Toxicity and dose intensity of FOLFOX in patients with increased body mass index

This study was conducted at St James‘s Hospital, Dublin, Ireland, in 2010. It evaluated the dose intensity and toxicities experienced by patients of normal and increased body mass index treated with FOLFOX chemotherapy, and demonstrated that overweight patients may tolerate doses based on actual body weight.

Fructose-1, 6-diphosphate (FDP) as a novel antidote for yellow oleander-induced cardiac toxicity: a randomized controlled double blind study

BACKGROUND: Cardiac toxicity due to ingestion of oleander plant seeds in Sri Lanka and some other South Asian countries is very common. At present symptomatic oleander seed poisoning carries a mortality of 10% in Sri Lanka and treatment of yellow oleander poisoning is limited to gastric decontamination and atropine administration. The only proven effective antidote is digoxin antibodies but these are not available for routine use because of the high cost. The main objective of this study is to investigate the effectiveness of a new and inexpensive antidote for patients with life threatening arrhythmias due oleander poisoning. METHOD/DESIGN: We set up a randomised double blind clinical trial to assess the effectiveness of Fructose 1, 6 diphosphate (FDP) in acute yellow oleander poisoning patients admitted to the adult medical wards of a tertiary hospital in Sri Lanka. Patients will be initially resuscitated following the national guidelines and eligible patients will be randomised to receive either FDP or an equal amount of normal saline. The primary outcome measure for this study is the sustained reversion to sinus rhythm with a heart rate greater than 50/min within 2 hours of completion of FDP/placebo bolus. Secondary outcomes include death, reversal of hyperkalaemia on the 6, 12, 18 and 24 hour samples and maintenance of sinus rhythm on the holter monitor. Analysis will be on intention-to-treat. DISCUSSION: This trial will provide information on the effectiveness of FDP in yellow oleander poisoning. If FDP is effective in cardiac glycoside toxicity, it would provide substantial benefit to the patients in rural Asia. The drug is inexpensive and thus could be made available at primary care hospitals if proven to be effective. TRIAL REGISTRATION: Current Controlled trial ISRCTN71018309.

Acute human lethal toxicity of agricultural pesticides: a prospective cohort study

BACKGROUND: agricultural pesticide poisoning is a major public health problem in the developing world, killing at least 250,000-370,000 people each year. Targeted pesticide restrictions in Sri Lanka over the last 20 years have reduced pesticide deaths by 50% without decreasing agricultural output. However, regulatory decisions have thus far not been based on the human toxicity of formulated agricultural pesticides but on the surrogate of rat toxicity using pure unformulated pesticides. We aimed to determine the relative human toxicity of formulated agricultural pesticides to improve the effectiveness of regulatory policy. METHODS AND FINDINGS: we examined the case fatality of different agricultural pesticides in a prospective cohort of patients presenting with pesticide self-poisoning to two clinical trial centers from April 2002 to November 2008. Identification of the pesticide ingested was based on history or positive identification of the container. A single pesticide was ingested by 9,302 patients. A specific pesticide was identified in 7,461 patients; 1,841 ingested an unknown pesticide. In a subset of 808 patients, the history of ingestion was confirmed by laboratory analysis in 95% of patients. There was a large variation in case fatality between pesticides-from 0% to 42%. This marked variation in lethality was observed for compounds within the same chemical and/or WHO toxicity classification of pesticides and for those used for similar agricultural indications. CONCLUSION: the human data provided toxicity rankings for some pesticides that contrasted strongly with the WHO toxicity classification based on rat toxicity. Basing regulation on human toxicity will make pesticide poisoning less hazardous, preventing hundreds of thousands of deaths globally without compromising agricultural needs. Ongoing monitoring of patterns of use and clinical toxicity for new pesticides is needed to identify highly toxic pesticides in a timely manner.

NDRG2 promotes myoblast proliferation and caspase 3/7 activities during differentiation, and attenuates hydrogen peroxide - but not palmitate-induced toxicity

The function of the stress-responsive N-myc downstream-regulated gene 2 (NDRG2) in the control of myoblast growth, and the amino acids contributing to its function, are not well characterized. Here, we investigated the effect of increased NDRG2 levels on the proliferation, differentiation and apoptosis in skeletal muscle cells under basal and stress conditions. NDRG2 overexpression increased C2C12 myoblast proliferation and the expression of positive cell cycle regulators, cdk2, cyclin B and cyclin D, and phosphorylation of Rb, while the serine/threonine-deficient NDRG2, 3A-NDRG2, had less effect. The onset of differentiation was enhanced by NDRG2 as determined through the myogenic regulatory factor expression profiles and myocyte fusion index. However, the overall level of differentiation in myotubes was not different. While NDRG2 up-regulated caspase 3/7 activities during differentiation, no increase in apoptosis was measured by TUNEL assay or through cleavage of caspase 3 and PARP proteins. During H2O2 treatment to induce oxidative stress, NDRG2 helped protect against the loss of proliferation and ER stress as measured by GRP78 expression with 3A-NDRG2 displaying less protection. NDRG2 also attenuated apoptosis by reducing cleavage of PARP and caspase 3 and expression of pro-apoptotic Bax while enhancing the pro-survival Bcl-2 and Bcl-xL levels. In contrast, Mcl-1 was not altered, and NDRG2 did not protect against palmitate-induced lipotoxicity. Our findings show that NDRG2 overexpression increases myoblast proliferation and caspase 3/7 activities without increasing overall differentiation. Furthermore, NDRG2 attenuates H2O2-induced oxidative stress and specific serine and threonine amino acid residues appear to contribute to its function in muscle cells.

Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) have increasingly replaced tricyclic antidepressants (TCAs) in the treatment of depression. They appear to be safer in overdose, but there is little information on their spectrum of toxicity in overdose, or relative toxicity of each agent. OBJECTIVE: To determine the effect of SSRIs in overdose, as a group, and the relative toxicity of five different SSRIs. METHODS: A review of consecutive SSRI poisoning admissions to a single toxicology unit. Outcomes examined were length of stay [LOS], intensive care [ICU] admission rate, coma, seizures, electrocardiographic [ECG] abnormalities, and presence of serotonin syndrome [SS]. Logistic regression was used to model the outcome QTc >440 msec. RESULTS: There were 469 SSRI poisoning admissions analyzed after exclusions. The median LOS for all SSRI overdose admissions was 15.3 h (IQR: 10.5-21.3) and 30 of 469 (6.4%; 95% CI 4.3-9.0%) cases were admitted to ICU. The incidence of seizures was 1.9% and coma was 2.4%. Serotonin syndrome occurred in 14% of overdoses. Comparison of median QTc intervals of the five SSRIs was significantly different (p=0.0002); citalopram (450 IQR: 436-484) was individually different to fluoxetine (p=0.045), fluvoxamine (p=0.022), paroxetine (p=0.0002), and sertraline (p=0.001). The proportion of citalopram overdoses with a QTc >440 msec was 68%, differing significantly from sertraline (adjusted OR: 5.11 95% CI 2.32-11.27). Comparison of median QT intervals of the five SSRIs was statistically different (p=0.026); citalopram (400 IQR: 380-440) was individually different from sertraline (p=0.023). CONCLUSIONS: This study shows SSRIs are relatively safe in overdose despite serotonin syndrome being common. The exception was citalopram, which was significantly associated with QTc prolongation. We believe that cardiac monitoring should be considered in citalopram overdose, particularly with large ingestions and patients with associated cardiac disease.

Toxicity prediction in cancer using multiple instance learning in a multi-task framework

Treatments of cancer cause severe side effects called toxicities. Reduction of such effects is crucial in cancer care. To impact care, we need to predict toxicities at fortnightly intervals. This toxicity data differs from traditional time series data as toxicities can be caused by one treatment on a given day alone, and thus it is necessary to consider the effect of the singular data vector causing toxicity. We model the data before prediction points using the multiple instance learning, where each bag is composed of multiple instances associated with daily treatments and patient-specific attributes, such as chemotherapy, radiotherapy, age and cancer types. We then formulate a Bayesian multi-task framework to enhance toxicity prediction at each prediction point. The use of the prior allows factors to be shared across task predictors. Our proposed method simultaneously captures the heterogeneity of daily treatments and performs toxicity prediction at different prediction points. Our method was evaluated on a real-word dataset of more than 2000 cancer patients and had achieved a better prediction accuracy in terms of AUC than the state-of-art baselines.

Low toxicity ionic liquid surface coating for biodegradable Mg-based stents

 Biodegradable Mg stents are a new treatment means for the human coronary artery disease. This study works on investigating a low toxic and corrosion protective surface coating material- phosphate based ionic liquid to control the degradation rate of Mg alloys in the body.

Lipids in Amyloid-β processing, aggregation, and toxicity

Aggregation of amyloid-beta (Aβ) peptide is the major event underlying neuronal damage in Alzheimer's disease (AD). Specific lipids and their homeostasis play important roles in this and other neurodegenerative disorders. The complex interplay between the lipids and the generation, clearance or deposition of Aβ has been intensively investigated and is reviewed in this chapter. Membrane lipids can have an important influence on the biogenesis of Aβ from its precursor protein. In particular, increased cholesterol in the plasma membrane augments Aβ generation and shows a strong positive correlation with AD progression. Furthermore, apolipoprotein E, which transports cholesterol in the cerebrospinal fluid and is known to interact with Aβ or compete with it for the lipoprotein receptor binding, significantly influences Aβ clearance in an isoform-specific manner and is the major genetic risk factor for AD. Aβ is an amphiphilic peptide that interacts with various lipids, proteins and their assemblies, which can lead to variation in Aβ aggregation in vitro and in vivo. Upon interaction with the lipid raft components, such as cholesterol, gangliosides and phospholipids, Aβ can aggregate on the cell membrane and thereby disrupt it, perhaps by forming channel-like pores. This leads to perturbed cellular calcium homeostasis, suggesting that Aβ-lipid interactions at the cell membrane probably trigger the neurotoxic cascade in AD. Here, we overview the roles of specific lipids, lipid assemblies and apolipoprotein E in Aβ processing, clearance and aggregation, and discuss the contribution of these factors to the neurotoxicity in AD.

Seawater temperature effect on metal accumulation and toxicity in the subantarctic Macquarie Island isopod, Exosphaeroma gigas

Very little is currently known of subantarctic nearshore invertebrates' sensitivity to environmental metals and the role of temperature in this relationship. This study investigated Cu and Zn toxicity in the common subantarctic intertidal isopod, Exosphaeroma gigas, and the influence of temperature on Cu toxicity and bioaccumulation kinetics. Adult E. gigas are insensitive to Cu and Zn at concentrations of 3200 and 7400μg/L respectively in non-renewal tests at 5.5°C (ambient subtidal temperature) over 14days. Under renewed exposures over the same temperature and time period the LC50 for copper was 2204μg/L. A 10-fold increase in Cu body burden occurred relative to zinc, indicating E. gigas has different strategies for regulating the two metals. Copper toxicity and time to mortality both increased with elevated temperature. However, temperature did not significantly affect Cu uptake rate and efflux rate constants derived from biodynamic modelling at lower Cu concentrations. These results may be attributable to E. gigas being an intertidal species with physiological mechanisms adapted to fluctuating environmental conditions. Cu concentrations required to elicit a toxicity response indicates that E. gigas would not be directly threatened by current levels of Cu or Zn present in Macquarie Island intertidal habitats, with the associated elevated temperature fluctuations. This study provides evidence that the sensitivity of this subantarctic intertidal species to metal contaminants is not as high as expected, and which has significance for the derivation of relevant guidelines specific to this distinct subpolar region of the world.

Genotoxicity evaluation of chlorpyrifos: a gender related approach in regular toxicity testing

The oral intubation of chlorpyrifos, an extensively used organophosphate insecticide, was tested for its capability to induce in vivo genotoxic upshot in blood lymphocytes of 24 male and female Wistar rats using biomarker of genotoxicity. Rats were orally administered with daily doses 3 and 12 mg/kg body weight (BW) of chlorpyrifos (CPF). The blood lymphocytes were harvested after 7 and 14 days of treatment and subjected to bi-nucleus (BN), multi-nucleus (MN) and single cell gel electrophoresis (comet assay) to evaluate the extent of DNA damage. Other than BN and MN assay, damage to DNA was assessed through comet length, height, area, head diameter, head DNA percentage and tail DNA percentage along with tail movement. A significant boost was noticed in the frequency of BN cells formation after 12 mg/kg BW CPF treatment. However, the propensity to produce MN cells was significantly more (P ≤ 0.05) in males than that of females. Likewise, the frequency of comet formation, mean comet length, height and area were more (P ≤ 0.05) in males than females even with 12 mg/kgBW. Comet head DNA % and tail length remained non-significant. Olive movement also revealed a significant increase (P ≤ 0.05) in males than females. The study inferred that the CPF can induce DNA damage in both male and female subjects but more pronounced in the male individuals.