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Concept: Nephrotoxicity

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Three-dimensional models of kidney tissue that recapitulate human responses are needed for drug screening, disease modeling, and, ultimately, kidney organ engineering. Here, we report a bioprinting method for creating 3D human renal proximal tubules in vitro that are fully embedded within an extracellular matrix and housed in perfusable tissue chips, allowing them to be maintained for greater than two months. Their convoluted tubular architecture is circumscribed by proximal tubule epithelial cells and actively perfused through the open lumen. These engineered 3D proximal tubules on chip exhibit significantly enhanced epithelial morphology and functional properties relative to the same cells grown on 2D controls with or without perfusion. Upon introducing the nephrotoxin, Cyclosporine A, the epithelial barrier is disrupted in a dose-dependent manner. Our bioprinting method provides a new route for programmably fabricating advanced human kidney tissue models on demand.

Concepts: Kidney, Extracellular matrix, Nephron, Basement membrane, Organ, Skin, Renal pelvis, Nephrotoxicity

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Background  Although long-term cyclosporine administration may induce toxic effects, it may be the only option for the treatment of severe psoriasis. The objective of the present study was to retrospectively evaluate efficacy and safety of long-term cyclosporine treatment in a cohort of patients affected with moderate to severe psoriasis, recalcitrant or unresponsive to other treatments. Possible risk factors predicting an intolerance to cyclosporine were also investigated. Materials and methods  Data were collected on psoriatic patients treated with cyclosporine for at least six months at our Psoriasis Outpatient Unit between January 2005 and September 2010. The primary measure for clinical efficacy was the PASI 75 response. Cyclosporine safety was assessed through the review of both laboratory tests and the adverse events registered during the treatment. Results  Twenty patients affected with plaque or erythrodermic psoriasis were evaluated. At Week 16, the PASI 75 response was achieved by 85% of patients. Adverse events occurred in eight patients (40%): four experienced an increase in serum creatinine levels to more than 30% of their pre-treatment values and four developed hypertension. Among these patients, five discontinued cyclosporine. Side effects resolved after stopping treatment. Conclusions  Our findings suggest that long-term cyclosporine regimen can be justified in severe psoriasis not responsive to other treatments. When cyclosporine administration is required, obesity, pre-treatment controlled hypertension, increased age (>70 years), and metabolic syndrome should be taken into consideration, as a significant correlation with occurrence of cyclosporine-induced side effects has been found.

Concepts: Clinical trial, Hypertension, Obesity, Creatinine, Metabolic syndrome, Psoriasis, Nephrotoxicity, Psoriatic erythroderma

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The current medications used to treat leishmaniasis have many side effects for patients; in addition, some cases of the disease are refractory to treatment. Therefore, the search for new leishmanicidal compounds is indispensable. Recently, it was demonstrated that oleanolic- and ursolic-containing fraction from Baccharis uncinella leaves eliminated the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis and L. (Viannia) braziliensis without causing toxic effects for J774 macrophages. Thus, the aim of the present work was to characterize the therapeutic effect of the triterpenic fraction in L. (L.) amazonensis-infected BALB/c mice. Oleanolic- and ursolic acid-containing fraction was extracted from B. uncinella leaves using organic solvents and chromatographic procedures. L. (L.) amazonensis-infected BALB/c mice were treated intraperitoneally with triterpenic fraction during five consecutive days with 1.0 and 5.0 mg/kg of triterpenic fraction, or with 10.0 mg/kg of amphotericin B drug. Groups of mice treated with the triterpenic fraction, presented with decreased lesion size and low parasitism of the skin-both of which were associated with high amounts of interleukin-12 and interferon gamma. The curative effect of this fraction was similar to amphotericin B-treated mice; however, the final dose, required to eliminate amastigotes, was lesser than amphotericin B. Moreover, triterpenic fraction did not cause microscopic alterations in liver, spleen, heart, lung, and kidney of experimental groups. This work suggests that this fraction possesses compounds that are characterized by leishmanicidal and immunomodulatory activities. From this perspective, the triterpenic fraction can be explored as a new therapeutic agent for use against American Tegumentar Leishmaniasis.

Concepts: Immune system, Therapeutic effect, Pharmacology, Macrophage, Interferon, Visceral leishmaniasis, Leishmania, Nephrotoxicity

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Abstract Objective: The conventional liposomal amphotericin B causes many unwanted side effects like blood disorder, nephrotoxicity, dose-dependent side effects, highly variable oral absorption and formulation-related instability. The objective of the present investigation was to develop cost-effective nanoemulsion as nanocarreir for enhanced and sustained delivery of amphotericin B into the skin. Methods and characterizations: Different oil-in-water nanoemulsions were developed by varying the composition of hydrophilic (Tween® 80) surfactants and co-surfactant by the spontaneous titration method. The developed formulation were characterized, optimized, evaluated and compared for the skin permeation with commercial formulation (fungisome 0.01% w/w). Optimized formulations loaded with amphotericin B were screened using varied concentrations of surfactants and co-surfactants as decided by the ternary phase diagram. Results and discussion: The maximum % transmittance obtained were 96.9 ± 1.0%, 95.9 ± 3.0% and 93.7 ± 1.2% for the optimized formulations F-I, F-III and F-VI, respectively. These optimized nanoemulsions were subjected to thermodynamic stability study to get the most stable nanoemulsions (F-I). The results of the particle size and zeta potential value were found to be 67.32 ± 0.8 nm and -3.7 ± 1.2 mV for the final optimized nanoemulsion F-I supporting transparency and stable nanoemulsion for better skin permeation. The steady state transdermal flux for the formulations was observed between 5.89 ± 2.06 and 18.02 ± 4.3 µg/cm(2)/h whereas the maximum enhancement ratio were found 1.85- and 3.0-fold higher than fungisome and drug solution, respectively, for F-I. The results of the skin deposition study suggests that 231.37 ± 3.6 µg/cm(2) drug deposited from optimized nanoemulsion F-I and 2.11-fold higher enhancement ratio as compared to fungisome. Optimized surfactants and co-surfactant combination-mediated transport of the drug through the skin was also tried and the results were shown to have facilitated drug permeation and skin perturbation (SEM). Conclusion: The combined results suggested that amphotericin B nanoemulsion could be a better option for localized topical drug delivery and have greater potential as an effective, efficient and safe approach.

Concepts: Thermodynamics, Topical, Amphotericin B, Gilead Sciences, Antifungals, Flucytosine, Ergosterol, Nephrotoxicity

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Environmental contamination has exposed humans to various metal agents, including mercury. It has been determined that mercury is not only harmful to the health of vulnerable populations such as pregnant women and children, but is also toxic to ordinary adults in various ways. For many years, mercury was used in a wide variety of human activities. Nowadays, the exposure to this metal from both natural and artificial sources is significantly increasing. Recent studies suggest that chronic exposure, even to low concentration levels of mercury, can cause cardiovascular, reproductive, and developmental toxicity, neurotoxicity, nephrotoxicity, immunotoxicity, and carcinogenicity. Possible biological effects of mercury, including the relationship between mercury toxicity and diseases of the cardiovascular system, such as hypertension, coronary heart disease, and myocardial infarction, are being studied. As heart rhythm and function are under autonomic nervous system control, it has been hypothesized that the neurotoxic effects of mercury might also impact cardiac autonomic function. Mercury exposure could have a long-lasting effect on cardiac parasympathetic activity and some evidence has shown that mercury exposure might affect heart rate variability, particularly early exposures in children. The mechanism by which mercury produces toxic effects on the cardiovascular system is not fully elucidated, but this mechanism is believed to involve an increase in oxidative stress. The exposure to mercury increases the production of free radicals, potentially because of the role of mercury in the Fenton reaction and a reduction in the activity of antioxidant enzymes, such as glutathione peroxidase. In this review we report an overview on the toxicity of mercury and focus our attention on the toxic effects on the cardiovascular system.

Concepts: Antioxidant, Heart, Heart disease, Toxicology, Autonomic nervous system, Toxicity, Parasympathetic nervous system, Nephrotoxicity

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Firemaster 550 (FM 550) is a flame retardant (FR) mixture that has become one of the most commonly used FRs in foam-based furniture and baby products. Human exposure to this commercial mixture, comprised of brominated and organophosphate components, is widespread. We have repeatedly shown that developmental exposure can lead to sex-specific behavioral effects in rats. Accruing evidence of endocrine disruption and potential neurotoxicity have raised concerns regarding the neurodevelopmental effects of FM 550 exposure, but the specific mechanisms of action remains unclear. Additionally, we observed significant, and in some cases sex-specific, accumulation of FM 550 in placental tissue following gestational exposure. Because the placenta is an important source of hormones and neurotransmitters for the developing brain, it may be a critical target of toxicity to consider in the context of developmental neurotoxicity. Using a mixture of targeted and exploratory approaches, the goal of the present study was to identify possible mechanisms of action in the developing forebrain and placenta. Wistar rat dams were orally exposed to FM 550 (0, 300, or 1,000 µg/day;) for 10 days during gestation and placenta and fetal forebrain tissue collected for analysis. In placenta, evidence of endocrine, inflammatory, and neurotransmitter signaling pathway disruption was identified. Notably, 5-HT turnover was reduced in placental tissue and fetal forebrains indicating that 5-HT signaling between the placenta and the embryonic brain may be disrupted. These findings demonstrate that environmental contaminants, like FM 550, have the potential to impact the developing brain by disrupting normal placental functions.

Concepts: Nervous system, Embryo, Fetus, Developmental biology, Placenta, Toxicity, Tyrosine, Nephrotoxicity

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Nano-zerovalent iron (nZVI) is widely used for its ability to remove or degrade environmental contaminants. However, the effect of nZVI-pollutant complexes on organisms has not been tested. We demonstrate the ability of a sulfidized derivative of nZVI (FeSSi) to sorb cadmium (Cd) from aqueous media and alleviate Cd toxicity to a freshwater alga for 32 days. FeSSi particles removed over 80% of the aqueous Cd in the first hour and nearly the same concentration of free Cd remained unbound at the end of the experiment. We found that FeSSi particles with Cd sorbed onto them are an order of magnitude more toxic than FeSSi alone. Further, algal-produced organic material facilitates safer remediation of Cd by FeSSi by decreasing the toxicity of FeSSi itself. We developed a dynamic model to predict the maximum Cd concentration FeSSi can remediate without replacing Cd toxicity with its own. FeSSi can remediate four times as much Cd to phytoplankton populations when organic material is present compared to the absence of organic material. We demonstrate the effectiveness of FeSSi as an environmental remediator and the strength of our quantitative model of the mitigation of nanoparticle toxicity by algal-produced organic material.

Concepts: Chemistry, Toxicology, Cadmium, Toxicity, Phytoplankton, Nephrotoxicity, Organic matter, Nickel-cadmium battery

3

The involvement of Amyloid-β (Aβ) in the pathogenesis of Alzheimer’s disease (AD) is well established. However, it is becoming clear that the amyloid load in AD brains consists of a heterogeneous mixture of Aβ peptides, implying that a thorough understanding of their respective role and toxicity is crucial for the development of efficient treatments. Besides the well-studied Aβ40 and Aβ42 species, recent data have raised the possibility that Aβ43 peptides might be instrumental in AD pathogenesis, because they are frequently observed in both dense and diffuse amyloid plaques from human AD brains and are highly amyloidogenic in vitro. However, whether Aβ43 is toxic in vivo is currently unclear. Using Drosophila transgenic models of amyloid pathology, we show that Aβ43 peptides are mainly insoluble and highly toxic in vivo, leading to the progressive loss of photoreceptor neurons, altered locomotion and decreased lifespan when expressed in the adult fly nervous system. In addition, we demonstrate that Aβ43 species are able to trigger the aggregation of the typically soluble and non-toxic Aβ40, leading to synergistic toxic effects on fly lifespan and climbing ability, further suggesting that Aβ43 peptides could act as a nucleating factor in AD brains. Altogether, our study demonstrates high pathogenicity of Aβ43 species in vivo and supports the idea that Aβ43 contributes to the pathological events leading to neurodegeneration in AD.

Concepts: Alzheimer's disease, Neuron, Amyloid, Toxicology, Toxicity, Beta amyloid, Neurotoxicity, Nephrotoxicity

3

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity and anaemia. Protocols to minimise toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardised protocol of pre-emptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolytes, and creatinine over 14 days were analysed in relation to AmBd dose, treatment duration (short course, 5-7 days or standard, 14 days), addition of flucytosine, and outcome. In the 368 patients studied, haemoglobin dropped by a mean(95% CI) of 1.5(1.0-1.9) g/dL following 7 days of AmBd, and 2.3(1.1-3.6) g/dL after 14 days. Serum creatinine increased by 37(30-45) μmol/L by day 7 and 49(35-64) μmol/L by day 14 of AmBd. Overall 33% of patients developed grade III/IV anaemia, 5.6% developed grade III hypokalaemia, in 9.5% creatinine exceeded 220μmol and 6% discontinued AmBd prematurely. Addition of 5FC was associated with a slight increase in anaemia but not neutropenia. Laboratory abnormalities stabilised or reversed during the second week in patients on short course induction. Grade III/IV anaemia(aOR 2.2, 95% CI 1.1-4.3, p= 0.028); and nephrotoxicity(aOR 4.5, 95% CI 1.8-11, p=0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and pre-emptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimised incidence of hypokalaemia and nephrotoxicity. Anaemia remained a concerning adverse effect. Addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.

Concepts: Chemotherapy, Intracranial pressure, Electrolyte, Toxicity, Amphotericin B, Flucytosine, Nephrotoxicity, Hypokalemia

3

Aquatic communities are often subject to complex contaminant mixtures, usually at sublethal concentrations, that can cause long-term detrimental effects. Chemicals within mixtures can effectively interact, resulting in synergism, antagonism or additivity. We investigated the tertiary mixture effects of two pyrethroids, lambda-cyhalothrin and permethrin, and the organophosphate chlorpyrifos, evaluating sublethal endpoints; immobility and growth, on Chironomus dilutus in 10-day exposures. We utilized a toxic units (TU) approach, based on median lethal concentrations (LC50) for each compound. The concepts of independent action and concentration addition were used to compare predicted mixture toxicity to observed mixture toxicity. Increased immobility resulted from mixture concentrations ≥1 TU (7.45 ng/L lambda-cyhalothrin × 24.90 ng/L permethrin × 129.70 ng/L chlorpyrifos), and single pesticides concentrations ≥0.25 TU (5.50 ng/L lambda-cyhalothrin, 24.23 ng/L permethrin, 90.92 ng/L chlorpyrifos, respectively). Growth was inhibited by pesticide mixtures ≥0.125 TU (1.04 ng/L lambda-cyhalothrin × 3.15 ng/L permethrin × 15.47 ng/L chlorpyrifos), and singly by lambda-cyhalothrin ≥0.25 TU (5.50 ng/L), and permethrin ≥0.167 TU (18.21 ng/L). The no observed effect concentrations (NOEC) for immobility and growth, for both mixture and single-pyrethroid exposure, were up to 8.0 and 12.0 times respectively lower than the corresponding NOEC for survival. The median effective concentrations (EC50) for growth (mixture and single-pyrethroid exposure) were up to 7.0 times lower than the respective LC50. This study reinforces that the integration of sublethal endpoints in monitoring efforts is powerful in discerning toxic effects that would otherwise be missed by solely utilizing traditional toxicity assessments.

Concepts: Chemical substance, Toxicology, Chemical compound, Toxicity, Poison, Insecticide, Neurotoxicity, Nephrotoxicity