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At least 883 records · Page 49

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DOE OSTI2015

Fatty acid transport protein-2 inhibitor Grassofermata/CB5 protects cells against lipid accumulation and toxicity

The inhibition of the fatty acid uptake into non-adipose tissues provides an attractive target for prevention of lipotoxicity leading to obesity-associated non-alcoholic fatty liver disease and type 2 diabetes. Fatty acid transport proteins (FATPs) are bifunctional proteins involved in the uptake and activation of fatty acids by esterification with coenzyme A. Here we characterize Grassofermata/CB5, previously identified as a fatty acid uptake inhibitor directed against HsFATP2. The compound was effective in inhibiting the uptake of fatty acids in the low micro-molar range (IC{sub 50} 8–11 μM) and prevented palmitate-mediated lipid accumulation and cell death in cell lines that are models for intestines, liver, muscle and pancreas. In adipocytes, uptake inhibition was less effective (IC{sub 50} 58 μM). Inhibition was specific for long chain fatty acids and was ineffective toward medium chain fatty acids, which are transported by diffusion. Kinetic analysis of Grassofermata-dependent FA transport inhibition verified a non-competitive mechanism. By comparison with Grassofermata, several atypical antipsychotic drugs previously implicated as inhibitors of FA uptake were ineffectual. In mice Grassofermata decreased absorption of {sup 13}C-oleate demonstrating its potential as a therapeutic agent. - Highlights: • Grassofermata is a small compound inhibitor of FATP2. • Uptake inhibition is specific for long chain fatty acids. • Uptake kinetics shows low specificity for adipocytes compared to other cell types. • Inhibition is by a non-competitive mechanism. • Atypical antipsychotics do not inhibit FA uptake by comparison with Grassofermata.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

Low toxic and high soluble camptothecin derivative 2–47 effectively induces apoptosis of tumor cells in vitro

The cytotoxic activity of camptothecin derivatives is so high that these compounds need to be further modified before their successful application as anti-cancer agents clinically. In this study, we reported the synthesis and biological evaluation of a novel camptothecin derivative called compound 2–47. The changes in structure did not reduce its activity to inhibit DNA topoisomerase I. Compound 2–47 induced apoptosis of many tumor cells including leukemia cells K562, Jurkat, HL-60, breast cancer cell BT-549, colon cancer cell HT-29 and liver cancer cell HepG2 with a half maximal inhibitory concentration (IC{sub 50}) of 2- to 3-fold lower than HCPT as a control. In particular, 2–47 inhibited the proliferation of Jurkat cells with an IC{sub 50} of as low as 40 nM. By making use of Jurkat cell as a model, following treatment of Jurkat cells, compound 2–47 activated caspase-3 and PARP, resulting in a decreased Bcl-2/Bax ratio. These data showed that compound 2–47 induces Jurkat cell death through the mitochondrial apoptotic pathway. In addition, compound 2–47 showed a decreased cytotoxic activity against normal cells and an improved solubility in low-polar solvent. For example, compound 2–47 solutes in CHCl{sub 3} 130-fold higher than HCPT. Taken together, our data demonstrated that camptothecin derivative 2–47 notably inhibits the tumor cell proliferation through mitochondrial-mediated apoptosis in vitro. - Highlights: • Compound 2–47 showed a wide inhibitory effect on the tested tumor cell lines with an IC{sub 50} of 3 times lower than that of HCPT in general. • Compound 2–47 inhibited the proliferation of the human leukemia cell Jurkat at an IC{sub 50} of as low as 40 nM. • As compared to HCPT, compound 2–47 showed much reduced cytotoxicity on normal human cells. • As compared to others, compound 2–47 showed a hundreds-fold higher solubility in non-polar organic solution.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

Novel glyceryl glucoside is a low toxic alternative for cryopreservation agent

Glyceryl glucoside (GG, α-D-glucosyglycerol) is a natural glycerol derivative found in alcoholic drinks. Recently GG has been used as an alternative for glycerol in cosmetic products. However, the safety of using GG is still unclear. Currently, dimethyl sulfoxide (DMSO) and glycerol are wildly used in cryopreservation. Despite GG being a derivative of glycerol, the ability of GG in cryopreservation is still unknown. By using a system of Chinese Hamster Ovary cells (CHO), A549 cells and AG1522 cells, the study examined the cryoprotective effects of DMSO, glycerol and GG. Cytotoxic and genotoxic responses induced by the three chemicals were also investigated with CHO to determine the safety of GG for cosmetic products. Our data suggests that GG has great cryopresearvation ability in the concentration of 30%–40% (v/v). For cytotoxic studies, DMSO showed the highest cytotoxicity above 3% (v/v) in cell doubling time delay among three chemicals. For the acute cytotoxicity with trypan blue dye exclusion assay, GG showed stronger cell killing effect within 24 h above 4% (v/v). For the continuous cytotoxicity with colony formation assay for 7 days, DMSO showed significantly reduced clonogenic ability above 2%. In genotoxicity studies, CHO treated with glycerol at 2% concentration induced three times higher frequencies of sister chromatid exchange (SCE) than background levels. GG did not induce significant amounts of SCE compared to background. Micronuclei formation was equally observed in the 2% and above concentrations of glycerol and GG. Our data showed that GG has significant effects on cryopreservation compared to DMSO. Glycerol and GG have similar cytotoxicity effects to CHO, but glycerol induced genotoxic responses in the same concentration. Therefore, we conclude that GG may be a safer alternative compound to glycerol in cosmetic products and safer alternative to DMSO in cryopreservation. -- Highlights: •Glyceryl Glucoside is low cytotoxicity and genotoxicity. •Glyceryl Glucoside is better cyroprotective agent than glycerol. •Glycerol has higher genotoxicity than Glyceryl Glucoside. •DMSO has higher cytotoxicity than Glyceryl Glucoside.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Low dose administration of Bisphenol A induces liver toxicity in adult rats

Highlights: • Bisphenol A is one of the most widely used synthetic biphenoil xenoestrogens. • BPA administration increased nucleus aggregation, infiltration of inflammatory cells and cell necrosis in liver tissues. • Bisphenol A significant decrease in ALP and AST serum levels. • Bisphenol A can increased Gama protein and decreased Beta-2 protein serum levels. Bisphenol A (BPA) is one of the most widely used chemicals, often used in epoxy resins, health products and colors. This study aims to investigate the effect of various doses of BPA on hepatotoxicity in rats.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Toxic elements and speciation in seafood samples from different contaminated sites in Europe

The presence of cadmium (Cd), lead (Pb), mercury (THg), methylmercury (MeHg), arsenic (TAs), inorganic arsenic (iAs), cobalt (Co), copper (Cu), zinc (Zn), nickel (Ni), chromium (Cr) and iron (Fe) was investigated in seafood collected from European marine ecosystems subjected to strong anthropogenic pressure, i.e. hotspot areas. Different species (Mytilus galloprovincialis, n=50; Chamelea gallina, n=50; Liza aurata, n=25; Platichthys flesus, n=25; Laminaria digitata, n=15; and Saccharina latissima, n=15) sampled in Tagus estuary, Po delta, Ebro delta, western Scheldt, and in the vicinities of a fish farm area (Solund, Norway), between September and December 2013, were selected to assess metal contamination and potential risks to seafood consumers, as well as to determine the suitability of ecologically distinct organisms as bioindicators in environmental monitoring studies. Species exhibited different elemental profiles, likely as a result of their ecological strategies, metabolism and levels in the environment (i.e. seawater and sediments). Higher levels of Cd (0.15–0.94 mg kg{sup −1}), Pb (0.37−0.89 mg kg{sup −1}), Co (0.48–1.1 mg kg{sup −1}), Cu (4.8–8.4 mg kg{sup −1}), Zn (75–153 mg kg{sup −1}), Cr (1.0–4.5 mg kg{sup −1}) and Fe (283–930 mg kg{sup −1}) were detected in bivalve species, particularly in M. galloprovincialis from Ebro and Po deltas, whereas the highest content of Hg was found in P. flesus (0.86 mg kg{sup −1}). In fish species, most Hg was organic (MeHg; from 69 to 79%), whereas lower proportions of MeHg were encountered in bivalve species (between 20 and 43%). The highest levels of As were found in macroalgae species L. digitata and S. latissima (41 mg kg{sup −1} and 43 mg kg{sup −1}, respectively), with iAs accounting almost 50% of the total As content in L. digitata but not with S. latissima nor in the remaining seafood samples. This work highlights that the selection of the most appropriate bioindicator species is a fundamental step in environmental monitoring of each contaminant, especially in coastal areas. Furthermore, data clearly shows that the current risk assessment and legislation solely based on total As or Hg data is limiting, as elemental speciation greatly varies according to seafood species, thus playing a key role in human exposure assessment via food.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2018

Combined effects of microplastics and chemical contaminants on the organ toxicity of zebrafish (Danio rerio)

Highlights: • Microplastics did not produce effects on gene expression in zebrafish after 3 weeks. • Microplastics and sorbed chemicals had a greater effect than chemicals alone. • Effects were detected mainly in the liver. • Perfluorinated compounds were detected mainly in the liver. • Adverse effect of microplastics and sorbed chemicals should be considered in risk assessment. Microplastics contamination of the aquatic environment is considered a growing problem. The ingestion of microplastics has been documented for a variety of aquatic animals. Studies have shown the potential of microplastics to affect the bioavailability and uptake route of sorbed co-contaminants of different nature in living organisms. Persistent organic pollutants and metals have been the co-contaminants majorly investigated in this field. The combined effect of microplastics and sorbed co-contaminants in aquatic organisms still needs to be properly understood. To address this, we have subjected zebrafish to four different feeds: A) untreated feed; B) feed supplemented with microplastics (LD-PE 125–250 µm of diameter); C) feed supplemented with 2% microplastics to which a mixture of PCBs, BFRs, PFCs and methylmercury were sorbed; and D) feed supplemented with the mixture of contaminants only. After 3 weeks of exposure fish were dissected and liver, intestine, muscular tissue and brain were extracted. After visual observation, evaluation of differential gene expression of some selected biomarker genes in liver, intestine and brain were carried out. Additionally, quantification of perfluorinated compounds in liver, brain, muscular tissue and intestine of some selected samples were performed. The feed supplemented with microplastics with sorbed contaminants produced the most evident effects especially on the liver. The results indicate that microplastics alone does not produce relevant effects on zebrafish in the experimental conditions tested; on the contrary, the combined effect of microplastics and sorbed contaminants altered significantly their organs homeostasis in a greater manner than the contaminants alone.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2011

Localized Orbital Mucosa-Associated Lymphoma Tissue Lymphoma Managed With Primary Radiation Therapy: Efficacy and Toxicity

Purpose: To evaluate the clinical outcomes and late effects of radiation therapy (RT) in localized primary orbital mucosa-associated lymphoma tissue (MALT) lymphoma (POML). Methods and Materials: From 1989 to 2007, 89 patients with Stage IE POML received RT. The median age was 56 years old. Sites involved conjunctiva (59 patients [66%]), lacrimal gland (20 patients [23%]), and soft tissue (10 patients [11%]). Megavoltage beam(s) was used in 91%, electrons in 7%, and orthovoltage in 2% of cases. The dose given was 25 Gy in 97% and 30 Gy in 3% of patients. Lens shielding was possible in 57% of patients. Results: The median follow-up was 5.9 years. Complete response or unconfirmed complete response was seen in 88 patients (99%). Relapse occurred in 22 patients (25%). First relapse sites were local (2 patients [9%]), in the contralateral orbit (5 patients [23%]), and distant (15 patients [68%]). The 7-year overall survival (OS), cause-specific survival (CSS), relapse-free survival (RFS), and local control (LC) rates were 91%, 96%, 64%, and 97%, respectively. Radiation-related late sequelae were documented in 40 patients (45%). Cataracts were observed in 22 patients (Grade 1 in 2 patients; Grade 3 in 20 patients). The incidence of Grade 3 cataract at 7 years was 25%. Other late sequelae (n = 28) were dry eye(s) (22 patients [Grade 1 in 14 patients; Grade 2 in 2 patients; Grade 3 in 2 patients; n/s in 4 patients), keratitis (3 patients), macular degeneration/cystoid edema (2 patients), and vitreous detachment (1 patient). Five patients developed Grade 3 noncataract late effects. Lens shielding reduced the incidence of Grade 3 cataract and all Grade {>=}2 late sequelae. Seventeen patients (16 with cataracts) underwent surgery; 23 patients were treated conservatively. The outcome for managing late effects was generally successful, with 30 patients completely improved, and 9 patients with persisting late sequelae (10%). Conclusions: POML responds favorably to moderate doses of RT but results in significant late morbidity. The majority of late effects were successfully managed. Lens shielding reduced the risk of cataracts and other late sequelae.