PPARα agonist fenofibrate attenuates iron-induced liver injury in mice by modulating the Sirt3 and ß-catenin signaling.

Iron accumulation is frequently associated with chronic liver diseases. However, our knowledge on how iron contributes to the liver injury is limited. Aberrant Wnt/ß-catenin signaling is a hallmark of several hepatic pathologies. We recently reported that peroxisome proliferator-activated receptor α (PPARα) agonist, fenofibrate, prevents iron-induced oxidative stress and ß-catenin signaling by chelating the iron. Sirtuin3 (Sirt3), a type of NAD+-dependent deacetylase, that plays a critical role in metabolic regulation was found to prevent ischemia reperfusion injury (IRI) by normalizing the Wnt/ß-catenin pathway. In the present study, we explored if fenofibrate prevents iron-induced liver injury by regulating the Sirt3 and ß-catenin signaling. In vitro and in vivo iron treatment resulted in the downregulation of PPARα, Sirt3, active ß-catenin, and its downstream target gene c-Myc in the mouse liver. Pharmacological activation of Sirt3, both in vitro and in vivo, by Honokiol (HK), a known activator of Sirt3, abrogated the inhibitory effect of iron overload on active ß-catenin expression and prevented the iron-induced upregulation of α smooth muscle actin (αSMA) and TGFß expression. Intrinsically, PPARα knockout mice showed significant downregulation of hepatic Sirt3 levels. In addition, treatment of iron overload mice with PPARα agonist fenofibrate reduced hepatic iron accumulation and prevented iron-induced downregulation of liver Sirt3 and active ß-catenin, mitigating the progression of fibrosis. Thus, our results establish a novel link between hepatic iron and PPARα, Sirt3, and ß-catenin signaling. Further exploration on the mechanisms by which fenofibrate ameliorates iron-induced liver injury likely has significant therapeutic impact on iron-associated chronic liver diseases.NEW & NOTEWORTHY Hepatic intracellular iron accumulation has been implicated in the pathophysiology of chronic liver diseases. In this study, we identified a novel mechanism involved in the progression of fibrosis. Excess iron accumulation in liver caused downregulation of PPARα-Sirt3-Wnt signaling leading to fibrosis. This work has significant translational potential as PPARα agonist fenofibrate could be an attractive therapeutic drug for the treatment of liver disorders associated with iron overload.

A Hypoxia-Targeted Boron Neutron Capture Therapy Agent for the Treatment of Glioma.

PURPOSE: Boron neutron capture therapy (BNCT) has the potential to become a viable cancer treatment modality, but its clinical translation has been limited by the poor tumor selectivity of agents. To address this unmet need, a boronated 2-nitroimidazole derivative (B-381) was synthesized and evaluated for its capability of targeting hypoxic glioma cells. METHODS: B-381 has been synthesized from a 1-step reaction. Using D54 and U87 glioma cell lines, the in vitro cytotoxicity and cellular accumulation of B-381 has been evaluated under normoxic and hypoxic conditions compared to L-boronophenylalanine (BPA). Furthermore, tumor retention of B-381 was evaluated in vivo. RESULTS: B-381 had low cytotoxicity in normal and cancer cells. Unlike BPA, B-381 illustrated preferential retention in hypoxic glioma cells compared to normoxic glioma cells and normal tissues in vitro. In vivo, B-381 illustrated significantly higher long-term tumor retention compared to BPA, with 9.5-fold and 6.5-fold higher boron levels at 24 and 48 h, respectively. CONCLUSIONS: B-381 represents a new class of BNCT agents in which their selectivity to tumors is based on hypoxic tumor metabolism. Further studies are warranted to evaluate B-381 and similar compounds as preclinical candidates for future BNCT clinical trials for the treatment of glioma.

Fenofibrate prevents iron induced activation of canonical Wnt/ß-catenin and oxidative stress signaling in the retina.

Accumulating evidence strongly implicates iron in the pathogenesis of aging and disease. Iron levels have been found to increase with age in both the human and mouse retinas. We and others have shown that retinal diseases such as age-related macular degeneration and diabetic retinopathy are associated with disrupted iron homeostasis, resulting in retinal iron accumulation. In addition, hereditary disorders due to mutation in one of the iron regulatory genes lead to age dependent retinal iron overload and degeneration. However, our knowledge on whether iron toxicity contributes to the retinopathy is limited. Recently, we reported that iron accumulation is associated with the upregulation of retinal and renal renin-angiotensin system (RAS). Evidences indicate that multiple genes/components of the RAS are targets of Wnt/ß-catenin signaling. Interestingly, aberrant activation of Wnt/ß-catenin signaling is observed in several degenerative diseases. In the present study, we explored whether iron accumulation regulates canonical Wnt signaling in the retina. We found that in vitro and in vivo iron treatment resulted in the upregulation of Wnt/ß-catenin signaling and its downstream target genes including renin-angiotensin system in the retina. We confirmed further that iron activates canonical Wnt signaling in the retina using TOPFlash T-cell factor/lymphoid enhancer factor promoter assay and Axin2-LacZ reporter mouse. The presence of an iron chelator or an antioxidant reversed the iron-mediated upregulation of Wnt/ß-catenin signaling in retinal pigment epithelial (RPE) cells. In addition, treatment of RPE cells with peroxisome proliferator-activated receptor (PPAR) α-agonist fenofibrate prevented iron-induced activation of oxidative stress and Wnt/ß-catenin signaling by chelating the iron. The role of fenofibrate, an FDA-approved drug for hyperlipidemia, as an iron chelator has potentially significant therapeutic impact on iron associated degenerative diseases.

Real-time measurement of size-resolved elemental composition ratio for flame synthesized composite nanoparticle aggregates using a tandem SMPS-ICP-OES.

Composite nanoparticles find application in catalysis, drug delivery, and energy storage and require increasingly fine control of their physical properties and composition. While composite nanoparticles have been widely synthesized and characterized, little work has systematically correlated the initial concentration of precursors and the final composition of flame synthesized composite nanoparticles. This relationship is explored in a diffusion flame aerosol reactor by coupling a scanning mobility particle sizer (SMPS) with an inductively coupled plasma optical emission spectrometer (ICP-OES). A framework for studying the relationship between the initial precursor concentrations of different elements and the final nanoparticle composition is explored. The size-resolved elemental composition was measured by directly injecting size-selected fractions of aggregated magnetite and silicon dioxide composite nanoparticles into the ICP-OES plasma. This work showed a correlation between precursor molar ratio and the measured elemental ratio in the mobility size range of 50 to 140 nm. Building on previous work studying size resolved elemental composition of engineered nanoparticles, the analysis is extended to flame synthesized composite nanoparticle aggregates in this work.

Quantitative Understanding of Nanoparticle Uptake in Watermelon Plants.

The use of agrochemical-nutrient fertilizers has come under scrutiny in recent years due to concerns that they damage the ecosystem and endanger public health. Nanotechnology offers many possible interventions to mitigate these risks by use of nanofertilizers, nanopesticides, and nanosensors; and concurrently increases profitability, yields, and sustainability within the agricultural industry. Aerosol based foliar delivery of nanoparticles may help to enhance nanoparticle uptake and reduce environmental impacts of chemical fertilizers conventionally applied through a soil route. The purpose of this work was to study uptake, translocation, and accumulation of various gold nanostructures, 30-80 nm, delivered by aerosol application to a watermelon plant. Cellular uptake and accumulation of gold nanoparticles were quantified by Inductively Coupled Plasma-Mass Spectroscopy (ICP-MS). Observations suggested that nanoparticles could be taken up by the plant through direct penetration and transport through the stomatal opening. Observed translocation of nanoparticles from leaf to root shows evidence that nanoparticles travel by the phloem transport mechanism. Accumulation and transport of nanoparticles depend on nanoparticle shape, application method, and nature of plant tissues.

Biocompatibility of gold nanoparticles in retinal pigment epithelial cell line.

Gold nanoparticles (Au NPs) have been tested as targeted delivery agents because of their high chemical stability and surface plasmon properties. Here, we investigated the biocompatibility of Au spheres (5-, 10-, 20-, 30-, 50-. and 100-nm), cubes (50-nm), and rods (10×90nm) on a retinal pigment epithelial (ARPE-19) cell line. The lethal dose for killing 50% of the cells (LD50) was evaluated using an MTT (3-[4, 5 dimethyl-thiazoly-2-yl] 2-5 diphenyl tetrazolium bromide) assay. At and above LD50, based on mass concentrations, the confluent cell layer began to detach, as shown by real-time measurements of electric impedance. We found that the biocompatibility of spheres improved with increasing nanoparticle size. The Au rods were less biocompatible than 10-nm spheres. Confocal microscopy showed that cubic (50-nm) and spherical NPs (50- and 100-nm) neither had cytotoxic effects nor entered cells. Lethal doses for internalized spherical NPs, which were toxic, were recalculated based on surface area (LD50,A) concentrations. Indeed, when biocompatibility was expressed as the surface area concentration of NPs, the curve was independent of size. The LD50,A of Au nanospheres was 23cm2/ml. Our findings demonstrate that the sole modulation of the surface area would make it possible to use Au NPs for therapeutic purposes.

Mechanistic evaluation of translocation and physiological impact of titanium dioxide and zinc oxide nanoparticles on the tomato (Solanum lycopersicum L.) plant.

Sustainable use of nanotechnology for agricultural practice requires an understanding of the plant's life cycle and potential toxicological impacts of nanomaterials. The main objective of this study was to compare the impact of TiO2 and ZnO nanoparticles of similar size (25 ± 3.5 nm) over a range of concentrations (0 to 1000 mg kg(-1)) on translocation and accumulation of nanoparticles in different plant sections; as well as to establish physiological impact on tomato plants. The results indicated that there is a critical concentration of TiO2 and ZnO nanoparticles upto which the plant's growth and development are promoted; with no improvement beyond that. Aerosol mediated application was found to be more effective than the soil mediated application on the uptake of the nanoparticles was in plants. A mechanistic description of nanoparticle uptake, translocation and resultant plant response is unraveled. The present investigation demonstrates the concept of nanoparticle farming by understanding plant - nanoparticle interaction and biodistribution.