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At least 1,081 records · Page 60
All sourcesNASA NTRSDOE OSTI
DOE OSTI2013

Increased bile acids in enterohepatic circulation by short-term calorie restriction in male mice

Previous studies showed glucose and insulin signaling can regulate bile acid (BA) metabolism during fasting or feeding. However, limited knowledge is available on the effect of calorie restriction (CR), a well-known anti-aging intervention, on BA homeostasis. To address this, the present study utilized a “dose–response” model of CR, where male C57BL/6 mice were fed 0, 15, 30, or 40% CR diets for one month, followed by BA profiling in various compartments of the enterohepatic circulation by UPLC-MS/MS technique. This study showed that 40% CR increased the BA pool size (162%) as well as total BAs in serum, gallbladder, and small intestinal contents. In addition, CR “dose-dependently” increased the concentrations of tauro-cholic acid (TCA) and many secondary BAs (produced by intestinal bacteria) in serum, such as tauro-deoxycholic acid (TDCA), DCA, lithocholic acid, ω-muricholic acid (ωMCA), and hyodeoxycholic acid. Notably, 40% CR increased TDCA by over 1000% (serum, liver, and gallbladder). Interestingly, 40% CR increased the proportion of 12α-hydroxylated BAs (CA and DCA), which correlated with improved glucose tolerance and lipid parameters. The CR-induced increase in BAs correlated with increased expression of BA-synthetic (Cyp7a1) and conjugating enzymes (BAL), and the ileal BA-binding protein (Ibabp). These results suggest that CR increases BAs in male mice possibly through orchestrated increases in BA synthesis and conjugation in liver as well as intracellular transport in ileum. - Highlights: • Dose response effects of short-term CR on BA homeostasis in male mice. • CR increased the BA pool size and many individual BAs. • CR altered BA composition (increased proportion of 12α-hydroxylated BAs). • Increased mRNAs of BA enzymes in liver (Cyp7a1 and BAL) and ileal BA binding protein.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Effect of various antibiotics on modulation of intestinal microbiota and bile acid profile in mice

Antibiotic treatments have been used to modulate intestinal bacteria and investigate the role of intestinal bacteria on bile acid (BA) homeostasis. However, knowledge on which intestinal bacteria and bile acids are modified by antibiotics is limited. In the present study, mice were administered various antibiotics, 47 of the most abundant bacterial species in intestine, as well as individual BAs in plasma, liver, and intestine were quantified. Compared to the two antibiotic combinations (vancomycin + imipenem and cephalothin + neomycin), the three single antibiotics (metronidazole, ciprofloxacin and aztreonam) have less effect on intestinal bacterial profiles, and thus on host BA profiles and mRNA expression of genes that are important for BA homeostasis. The two antibiotic combinations decreased the ratio of Firmicutes to Bacteroidetes in intestine, as well as most secondary BAs in serum, liver and intestine. Additionally, the two antibiotic combinations significantly increased mRNA of the hepatic BA uptake transporters (Ntcp and Oatp1b2) and canalicular BA efflux transporters (Bsep and Mrp2), but decreased mRNA of the hepatic BA synthetic enzyme Cyp8b1, suggesting an elevated enterohepatic circulation of BAs. Interestingly, the two antibiotic combinations tended to have opposite effect on the mRNAs of most intestinal genes, which tended to be inhibited by vancomycin + imipenem but stimulated by cephalothin + neomycin. To conclude, the present study clearly shows that various antibiotics have distinct effects on modulating intestinal bacteria and host BA metabolism. - Highlights: • Various antibiotics have different effects on intestinal bacteria. • Antibiotics alter bile acid composition in mouse liver and intestine. • Antibiotics influence genes involved in bile acid homeostasis. • Clostridia appear to be important for secondary bile acid formation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

DNA damage in internal organs after cutaneous exposure to sulphur mustard

Sulphur mustard (SM) is a chemical warfare agent that attacks mainly skin, eye and lungs. Due to its lipophilic properties, SM is also able to diffuse through the skin and reach internal organs. DNA represents one of the most critical molecular targets of this powerful alkylating agent which modifies DNA structure by forming monoadducts and biadducts. These DNA lesions are involved in the acute toxicity of SM as well as its long-term carcinogenicity. In the present work we studied the formation and persistence of guanine and adenine monoadducts and guanine biadducts in the DNA of brain, lungs, kidneys, spleen, and liver of SKH-1 mice cutaneously exposed to 2, 6 and 60 mg/kg of SM. SM-DNA adducts were detected in all studied organs, except in liver at the two lowest doses. Brain and lungs were the organs with the highest level of SM-DNA adducts, followed by kidney, spleen and liver. Monitoring the level of adducts for three weeks after cutaneous exposure showed that the lifetime of adducts were not the same in all organs, lungs being the organ with the longest persistence. Diffusion from skin to internal organs was much more efficient at the highest compared to the lowest dose investigated as the result of the loss of the skin barrier function. These data provide novel information on the distribution of SM in tissues following cutaneous exposures and indicate that brain is an important target. - Highlights: • Sulphur mustard reaches internal organs after skin exposure • Adducts are detected in the DNA of internal organs • Brain is the organ with the highest level of DNA damage • The barrier function of skin is lost at high dose of sulphur mustard • DNA adducts persist in organs for 2 or 3 weeks.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Sulforaphane, a cancer chemopreventive agent, induces pathways associated with membrane biosynthesis in response to tissue damage by aflatoxin B{sub 1}

Aflatoxin B{sub 1} (AFB{sub 1}) is one of the major risk factors for liver cancer globally. A recent study showed that sulforaphane (SF), a potent inducer of phase II enzymes that occurs naturally in widely consumed vegetables, effectively induces hepatic glutathione S-transferases (GSTs) and reduces levels of hepatic AFB{sub 1}-DNA adducts in AFB{sub 1}-exposed Sprague Dawley rats. The present study characterized the effects of SF pre-treatment on global gene expression in the livers of similarly treated male rats. Combined treatment with AFB{sub 1} and SF caused reprogramming of a network of genes involved in signal transduction and transcription. Changes in gene regulation were observable 4 h after AFB{sub 1} administration in SF-pretreated animals and may reflect regeneration of cells in the wake of AFB{sub 1}-induced hepatotoxicity. At 24 h after AFB{sub 1} administration, significant induction of genes that play roles in cellular lipid metabolism and acetyl-CoA biosynthesis was detected in SF-pretreated AFB{sub 1}-dosed rats. Induction of this group of genes may indicate a metabolic shift toward glycolysis and fatty acid synthesis to generate and maintain pools of intermediate molecules required for tissue repair, cell growth and compensatory hepatic cell proliferation. Collectively, gene expression data from this study provide insights into molecular mechanisms underlying the protective effects of SF against AFB{sub 1} hepatotoxicity and hepatocarcinogenicity, in addition to the chemopreventive activity of this compound as a GST inducer. - Highlights: • This study revealed sulforaphane (SF)-deregulated gene sets in aflatoxin B{sub 1} (AFB{sub 1})-treated rat livers. • SF redirects biochemical networks toward lipid biosynthesis in AFB{sub 1}-dosed rats. • SF enhanced gene sets that would be expected to favor cell repair and regeneration.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Diethylene glycol-induced toxicities show marked threshold dose response in rats

Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments. - Highlights: • DEG produces a steep threshold dose response for kidney injury in rats. • Wistar and F-344 rats do not differ in response to DEG-induced renal injury. • The dose response for renal injury closely mirrors that for renal DGA accumulation. • Results demonstrate the importance of DGA accumulation in producing kidney injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Potential of extracellular microRNAs as biomarkers of acetaminophen toxicity in children

Developing biomarkers for detecting acetaminophen (APAP) toxicity has been widely investigated. Recent studies of adults with APAP-induced liver injury have reported human serum microRNA-122 (miR-122) as a novel biomarker of APAP-induced liver injury. The goal of this study was to examine extracellular microRNAs (miRNAs) as potential biomarkers for APAP liver injury in children. Global levels of serum and urine miRNAs were examined in three pediatric subgroups: 1) healthy children (n = 10), 2) hospitalized children receiving therapeutic doses of APAP (n = 10) and 3) children hospitalized for APAP overdose (n = 8). Out of 147 miRNAs detected in the APAP overdose group, eight showed significantly increased median levels in serum (miR-122, -375, -423-5p, -30d-5p, -125b-5p, -4732-5p, -204-5p, and -574-3p), compared to the other groups. Analysis of urine samples from the same patients had significantly increased median levels of four miRNAs (miR-375, -940, -9-3p and -302a) compared to the other groups. Importantly, correlation of peak serum APAP protein adduct levels (an indicator of the oxidation of APAP to the reactive metabolite N-acetyl-para-quinone imine) with peak miRNA levels showed that the highest correlation was observed for serum miR-122 (R = 0.94; p < 0.01) followed by miR-375 (R = 0.70; p = 0.05). Conclusion: Our findings demonstrate that miRNAs are increased in children with APAP toxicity and correlate with APAP protein adducts, suggesting a potential role as biomarkers of APAP toxicity. - Highlights: • Serum miR-122 and miR-375 levels were increased in children with APAP overdose. • Urine levels of miR-375 and miR-940 were increased in the APAP overdose group. • Peak serum miR-122 levels were correlated with peak serum APAP protein adducts.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Metabolic activation of hepatotoxic drug (benzbromarone) induced mitochondrial membrane permeability transition

The risk of drug-induced liver injury (DILI) is of great concern to the pharmaceutical industry. It is well-known that metabolic activation of drugs to form toxic metabolites (TMs) is strongly associated with DILI onset. Drug-induced mitochondrial dysfunction is also strongly associated with increased risk of DILI. However, it is difficult to determine the target of TMs associated with exacerbation of DILI because of difficulties in identifying and purifying TMs. In this study, we propose a sequential in vitro assay system to assess TM formation and their ability to induce mitochondrial permeability transition (MPT) in a one-pot process. In this assay system, freshly-isolated rat liver mitochondria were incubated with reaction solutions of 44 test drugs preincubated with liver microsomes in the presence or absence of NADPH; then, NADPH-dependent MPT pore opening was assessed as mitochondrial swelling. In this assay system, several hepatotoxic drugs, including benzbromarone (BBR), significantly induced MPT in a NADPH-dependent manner. We investigated the rationality of using BBR as a model drug, since it showed the most prominent MPT in our assay system. Both the production of a candidate toxic metabolite of BBR (1′,6-(OH){sub 2} BBR) and NADPH-dependent MPT were inhibited by several cytochrome P450 (CYP) inhibitors (clotrimazole and SKF-525A, 100 μM). In summary, this assay system can be used to evaluate comprehensive metabolite-dependent MPT without identification or purification of metabolites. - Highlights: • We constructed a sequential assay system for toxic metabolite induced MPT in one pot. • 14 drugs (e.g. benzbromarone (BBR)) induced toxic metabolite dependent MPT. • Both the production of toxic metabolite and MPT could be inhibited by CYP inhibitors. • This system could evaluate the comprehensive MPT without purification of metabolites.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Taurine zinc solid dispersions attenuate doxorubicin-induced hepatotoxicity and cardiotoxicity in rats

The clinical efficacy of anthracycline anti-neoplastic agents is limited by cardiac and hepatic toxicities. The aim of this study was to assess the hepatoprotective and cardioprotective effects of taurine zinc solid dispersions, which is a newly-synthesized taurine zinc compound, against doxorubicin-induced toxicity in Sprague–Dawley rats intraperitoneally injected with doxorubicin hydrochloride (3 mg/kg) three times a week (seven injections) over 28 days. Hemodynamic parameters, levels of liver toxicity markers and oxidative stress were assessed. Taurine zinc significantly attenuated the reductions in blood pressure, left ventricular pressure and ± dp/dtmax, increases in serum alanine aminotransferase and aspartate aminotransferase activities, and reductions in serum Zn{sup 2+} and albumin levels (P < 0.05 or 0.01) induced by doxorubicin. In rats treated with doxorubicin, taurine zinc dose-dependently increased liver superoxide dismutase activity and glutathione concentration, and decreased malondialdehyde level (P < 0.01). qBase{sup +} was used to evaluate the stability of eight candidate reference genes for real-time quantitative reverse-transcription PCR. Taurine zinc dose-dependently increased liver heme oxygenase-1 and UDP-glucuronyl transferase mRNA and protein expression (P < 0.01). Western blotting demonstrated that taurine zinc inhibited c-Jun N-terminal kinase phosphorylation by upregulating dual-specificity phosphoprotein phosphatase-1. Additionally, taurine zinc inhibited cardiomyocyte apoptosis as there was decreased TUNEL/DAPI positivity and protein expression of caspase-3. These results indicate that taurine zinc solid dispersions prevent the side-effects of anthracycline-based anticancer therapy. The mechanisms might be associated with the enhancement of antioxidant defense system partly through activating transcription to synthesize endogenous phase II medicine enzymes and anti-apoptosis through inhibiting JNK phosphorylation. - Highlights: • Dissolution of taurine zinc complex can be increased by solid dispersions (SDs). • Taurine zinc SDs blocked doxorubicin-induced hepatotoxicity and cardiotoxicity. • Taurine zinc SDs can alleviate oxidative stress and dampen JNK phosphorylation. • Taurine zinc SDs increased the expression of UGT, HO-1 at mRNA and protein level. • Taurine zinc SDs revealed greater hepatoprotective effects than silymarin.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Calcium channel blockers ameliorate iron overload-associated hepatic fibrosis by altering iron transport and stellate cell apoptosis

Liver fibrosis is the principal cause of morbidity and mortality in patients with iron overload. Calcium channel blockers (CCBs) can antagonize divalent cation entry into renal and myocardial cells and inhibit fibrogenic gene expression. We investigated the potential of CCBs to resolve iron overload-associated hepatic fibrosis. Kunming mice were assigned to nine groups (n = 8 per group): control, iron overload, deferoxamine, high and low dose verapamil, high and low dose nimodipine, and high and low dose diltiazem. Iron deposition and hepatic fibrosis were measured in mouse livers. Expression levels of molecules associated with transmembrane iron transport were determined by molecular biology approaches. In vitro HSC-T6 cells were randomized into nine groups (the same groups as the mice). Changes in proliferation, apoptosis, and metalloproteinase expression in cells were detected to assess the anti-fibrotic effects of CCBs during iron overload conditions. We found that CCBs reduced hepatic iron content, intracellular iron deposition, the number of hepatic fibrotic areas, collagen expression levels, and hydroxyproline content. CCBs rescued abnormal expression of α1C protein in L-type voltage-dependent calcium channel (LVDCC) and down-regulated divalent metal transporter-1 (DMT-1) expression in mouse livers. In iron-overloaded HSC-T6 cells, CCBs reduced iron deposition, inhibited proliferation, induced apoptosis, and elevated expression of matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP-1). CCBs are potential therapeutic agents that can be used to address hepatic fibrosis during iron overload. They resolve hepatic fibrosis probably correlated with regulating transmembrane iron transport and inhibiting HSC growth. - Highlights: • Calcium channel blockers (CCBs) reduced hepatic iron content. • CCBs decreased hepatic fibrotic areas and collagen expression levels. • CCBs resolve fibrosis by regulating iron transport and inhibiting HSC growth.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Effects and mechanisms of cavidine protecting mice against LPS-induced endotoxic shock

LPS sensitized mice are usually considered as an experimental model of endotoxin shock. The present study aims to evaluate effects of cavidine on LPS-induced endotoxin shock. Mice were intraperitoneally administrated with cavidine (1, 3 and 10 mg/kg) or DEX (5 mg/kg) at 1 and 12 h before injecting LPS (30 mg/kg) intraperitoneally. Blood samples, liver, lung and kidney tissues were harvested after LPS injection. The study demonstrated that pretreatment with cavidine reduced the mortality of mice during 72 h after endotoxin injection. In addition, cavidine administration significantly attenuated histological pathophysiology features of LPS-induced injury in lung, liver and kidney. Furthermore, cavidine administration inhibited endotoxin-induced production of pro-inflammatory cytokines including TNF-α, IL-6 and HMGB1. Moreover, cavidine pretreatment attenuated the phosphorylation of mitogen-activated protein kinase primed by LPS. In summary, cavidine protects mice against LPS-induced endotoxic shock via inhibiting early pro-inflammatory cytokine TNF-α, IL-6 and late-phase cytokine HMGB1, and the modulation of HMGB1 may be related with MAPK signal pathway. - Highlights: • Cavidine significantly reduced mortality in mice during 72 h after LPS injection. • Cavidine attenuated histopathological changes in lung, liver and kidney. • Cavidine decreased the level of early inflammatory cytokine TNF-α, IL-6 in LPS- stimulated mice. • Cavidine inhibited late inflammatory cytokine HMGB1 through MAPK pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Characterization of heme oxygenase and biliverdin reductase gene expression in zebrafish (Danio rerio): Basal expression and response to pro-oxidant exposures

While heme is an important cofactor for numerous proteins, it is highly toxic in its unbound form and can perpetuate the formation of reactive oxygen species. Heme oxygenase enzymes (HMOX1 and HMOX2) degrade heme into biliverdin and carbon monoxide, with biliverdin subsequently being converted to bilirubin by biliverdin reductase (BVRa or BVRb). As a result of the teleost-specific genome duplication event, zebrafish have paralogs of hmox1 (hmox1a and hmox1b) and hmox2 (hmox2a and hmox2b). Expression of all four hmox paralogs and two bvr isoforms were measured in adult tissues (gill, brain and liver) and sexually dimorphic differences were observed, most notably in the basal expression of hmox1a, hmox2a, hmox2b and bvrb in liver samples. hmox1a, hmox2a and hmox2b were significantly induced in male liver tissues in response to 96 h cadmium exposure (20 μM). hmox2a and hmox2b were significantly induced in male brain samples, but only hmox2a was significantly reduced in male gill samples in response to the 96 h cadmium exposure. hmox paralogs displayed significantly different levels of basal expression in most adult tissues, as well as during zebrafish development (24 to 120 hpf). Furthermore, hmox1a, hmox1b and bvrb were significantly induced in zebrafish eleutheroembryos in response to multiple pro-oxidants (cadmium, hemin and tert-butylhydroquinone). Knockdown of Nrf2a, a transcriptional regulator of hmox1a, was demonstrated to inhibit the Cd-mediated induction of hmox1b and bvrb. These results demonstrate distinct mechanisms of hmox and bvr transcriptional regulation in zebrafish, providing initial evidence of the partitioning of function of the hmox paralogs. - Highlights: • hmox1a, hmox2a, hmox2b and bvrb are sexually dimorphic in expression. • hmox paralogs were induced in adult tissues by cadmium exposure. • hmox1a, hmox1b and bvrb were induced by multiple pro-oxidants zebrafish embryos. • Differential expression of zebrafish hmox paralogs suggest partitioning of function. • Nrf2a mediates the induction of hmox1b and bvrb by cadmium in zebrafish embryos.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2017

High-fat diet aggravates 2,2′,4,4′-tetrabromodiphenyl ether-inhibited testosterone production via DAX-1 in Leydig cells in rats

Growing evidence has revealed that a high-fat diet (HFD) could lead to disorders of glycolipid metabolism and insulin-resistant states, and HFDs have been associated with the inhibition of testicular steroidogenesis. Our previous study demonstrated that 2,2′,4,4′-tetrabromodiphenyl ether (BDE47) could increase the risk of diabetes in humans and reduce testosterone production in rats. However, whether the HFD affects BDE47-inhibited testosterone production by elevating insulin levels and inducing related pathways remains unknown. In male rats treated with BDE47 by gavage for 12 weeks, the HFD significantly increased the BDE47 content of the liver and testis and increased the weight of the adipose tissue; increased macrovesicular steatosis in the liver and the levels of triglycerides, fasting glucose and insulin; further aggravated the disruption of the seminiferous epithelium; and lowered the level of testosterone, resulting in fewer sperm in the epididymis. Of note, the HFD enhanced BDE47-induced DAX-1 expression and decreased the expression levels of StAR and 3β-HSD in the testicular interstitial compartments in rats. In isolated primary Leydig cells from rats, BDE47 or insulin increased DAX-1 expression, decreased the expression of StAR and 3β-HSD, and reduced testosterone production, which was nearly reversed by knocking down DAX-1. These results indicated that the HFD aggravates BDE47-inhibited testosterone production through hyperinsulinemia, and the accumulation of testicular BDE47 that induces the up-regulation of DAX-1 and the subsequent down-regulation of steroidogenic proteins, i.e., StAR and 3β-HSD, in Leydig cells. - Highlights: • High-fat diet (HFD) aggravates the accumulation of BDE47 in liver and testis in rats. • HFD aggravates BDE47-inhibited testosterone production via DAX-1 in Leydig cells. • HFD enhances BDE47-induced the disorder of glycolipid metabolism and hyperinsulinemia. • Both hyperinsulinemia and accumulation of BDE47 inhibited testosterone via DAX-1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Zuotai and HgS differ from HgCl{sub 2} and methyl mercury in Hg accumulation and toxicity in weanling and aged rats

Mercury sulfides are used in Ayurvedic medicines, Tibetan medicines, and Chinese medicines for thousands of years and are still used today. Cinnabar (α-HgS) and metacinnabar (β-HgS) are different from mercury chloride (HgCl{sub 2}) and methylmercury (MeHg) in their disposition and toxicity. Whether such scenario applies to weanling and aged animals is not known. To address this question, weanling (21 d) and aged (450 d) rats were orally given Zuotai (54% β-HgS, 30 mg/kg), HgS (α-HgS, 30 mg/kg), HgCl{sub 2} (34.6 mg/kg), or MeHg (MeHgCl, 3.2 mg/kg) for 7 days. Accumulation of Hg in kidney and liver, and the toxicity-sensitive gene expressions were examined. Animal body weight gain was decreased by HgCl{sub 2} and to a lesser extent by MeHg, but unaltered after Zuotai and HgS. HgCl{sub 2} and MeHg produced dramatic tissue Hg accumulation, increased kidney (kim-1 and Ngal) and liver (Ho-1) injury-sensitive gene expressions, but such changes are absent or mild after Zuotai and HgS. Aged rats were more susceptible than weanling rats to Hg toxicity. To examine roles of transporters in Hg accumulation, transporter gene expressions were examined. The expression of renal uptake transporters Oat1, Oct2, and Oatp4c1 and hepatic Oatp2 was decreased, while the expression of renal efflux transporter Mrp2, Mrp4 and Mdr1b was increased following HgCl{sub 2} and MeHg, but unaffected by Zuotai and HgS. Thus, Zuotai and HgS differ from HgCl{sub 2} and MeHg in producing tissue Hg accumulation and toxicity, and aged rats are more susceptible than weanling rats. Transporter expression could be adaptive means to reduce tissue Hg burden. - Highlights: • Aged rats are more susceptible to HgCl{sub 2} and MeHg toxicity than weanling rats. • Zuotai and HgS differ from HgCl{sub 2} and MeHg in producing toxicity. • Zuotai and HgS differ from HgCl{sub 2} and MeHg in much less tissue Hg accumulation. • Renal transporters are altered by HgCl{sub 2} and MeHg, but unaffected by Zuotai and HgS • Liver transporters are less affected than kidney transporters by HgCl{sub 2} and MeHg.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Morin impedes Yap nuclear translocation and fosters apoptosis through suppression of Wnt/β-catenin and NF-κB signaling in Mst1 overexpressed HepG2 cells

Recent clinical and experimental evidences strongly acclaim Yes-associated protein (Yap), a key oncogenic driver in liver carcinogenesis, as a therapeutic target. Of the known multiple schemes to inhibit Yap activity, activation of Mammalian Sterile 20-like Kinase 1 (Mst1), an upstream regulator of Yap, appears to be a promising one. In this study, we hypothesize that morin, a bioflavonoid, mediates its anti-cancer effect through the activation of Mst1/hippo signaling in liver cancer cells. To test this hypothesis, both full length Mst1 (F-Mst1) and kinase active N-terminal Mst1 (N-Mst1)-overexpressed HepG2 cells were used. Exposure of F-Mst1 overexpressed HepG2 cells to morin activated Mst1 by caspase-3 cleavage and thereby inhibited Yap nuclear translocation and fostered apoptosis. Morin suppressed NF-κB p65 and Wnt/β-catenin signaling through Mst1 activation via cleavage and phosphorylation, leading to cell death. Annexin-V/PI staining further confirmed the induction of apoptosis in morin treated F-Mst1 overexpressed cells. The present study shows that morin targets cell survival molecules such as NF-κB p65 and β-catenin through activation of hippo signaling. Therefore, morin could be considered as a potential anti-cancer agent against liver cancer. - Highlights: • Morin induced cytotoxicity in cultured HepG2 cells. • Morin activated hippo pathway via Mst1 activation in transfected HepG2 cells. • Morin suppressed Wnt/β-catenin signaling and induced G0/G1 cell cycle arrest. • Morin inhibited NF-κB signaling through Mst1 activation in transfected HepG2 cells. • Morin potentiates apoptosis through Mst1-JNK-caspase mediated mechanism in HepG2 cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Maternal undernutrition modulates hepatic MicroRNAs expression in the early life of offspring

Emerging studies revealed that a poor intrauterine environment elicited by maternal nutrient restriction (MNR) is associated with an increased risk of metabolic diseases in adulthood. Previous research has shown that microRNAs (miRNAs) exert pivotal roles in modulating molecular pathways involved in disease pathogenesis and progression. In this respect, we herein examined miRNA profiles in samples of liver from offspring whose mothers were fed either with a 50% food-restricted diet or standard laboratory chow during pregnancy. Our findings enumerated that miR-181a, involved in lipid metabolism, was found to be downregulated in the liver of MNR offspring at 1 day of age when compared to that of control offspring. We also noted that overexpression of miR-181a reduced the lipid droplets after treatment with oleic acid for 48 h, which suppressed the expressions levels of SIRT1, FOXO1, KLF6 and PPARγ in BRL-3A cells, while the opposite results were observed with decreased expression of miR-181a. Furthermore, the luciferase reporter assay confirmed the direct interactions between miR-181a with KLF6 and SIRT1. In adults, the MNR offspring elucidated increased TG content, decreased expression of miR-181a, and increased expressions levels of SIRT1, FOXO1, KLF6, and PPARγ in liver tissues. Collectively, these findings provided novel evidence that MNR could regulate miRNAs expression, which might be related to lipid metabolism in MNR offspring.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

The study of equivalent dose of uranium in long bean (V. U. Sesquipedalis) and the effect on human

In the case of accidental release of Uranium-238 ({sup 238}U) radionuclides in a nuclear facility or in the environment, internal contamination by either acute or chronic exposure has the potential to induce both radiological and chemical toxic effects. A study was conducted to estimate the {sup 238}U radionuclide concentration in the long beans using Induced Coupled Mass Plasma-Spectrometry (ICP-MS). {sup 238}U radionuclide is a naturally occurring radioactive material that can be found in soil and can be transferred to the long bean (Vigna unguiculata subsp. Sesquapedalis) directly or indirectly via water or air. Kidney and liver are the major sites of deposition of {sup 238}U radionuclide. The obtained dose exposed in the liver and kidney is used to assess the safety level for public intake of {sup 238}U radionuclide from the consumption of long beans. The concentration of {sup 238}U radionuclide measured in long bean samples was 0.0226 ± 0.0009 mg/kg. Total activity of {sup 238}U radionuclide was 0.0044 ± 0.0002 Bq/day with the daily intake of 0.3545 ± 0.0143 µg/day and the annual committed effective dose due to ingestion of {sup 238}U radionuclide in long beans was 0.2230 ± 0.0087 µSv/year. The committed equivalent dose of {sup 238}U radionuclide from the assessment in the liver and kidney are 0.4198 ± 0.0165 nSv and 10.9335 ± 0.4288 nSv. The risk of cancer of {sup 238}U radionuclide was determined to be (86.0466 ± 3.3748) × 10-9. Thus, the results concluded that {sup 238}U radionuclide in local long beans was in the permitted level and safe to consume without posing any significant radiological threat to population.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2012

Biological-based optimization and volumetric modulated arc therapy delivery for stereotactic body radiation therapy

Purpose: To describe biological-based optimization and Monte Carlo (MC) dose calculation-based treatment planning for volumetric modulated arc therapy (VMAT) delivery of stereotactic body radiation therapy (SBRT) in lung, liver, and prostate patients. Methods: Optimization strategies and VMAT planning parameters using a biological-based optimization MC planning system were analyzed for 24 SBRT patients. Patients received a median dose of 45 Gy [range, 34-54 Gy] for lung tumors in 1-5 fxs and a median dose of 52 Gy [range, 48-60 Gy] for liver tumors in 3-6 fxs. Prostate patients received a fractional dose of 10 Gy in 5 fxs. Biological-cost functions were used for plan optimization, and its dosimetric quality was evaluated using the conformity index (CI), the conformation number (CN), the ratio of the volume receiving 50% of the prescription dose over the planning target volume (Rx/PTV50). The quality and efficiency of the delivery were assessed according to measured quality assurance (QA) passing rates and delivery times. For each disease site, one patient was replanned using physical cost function and compared to the corresponding biological plan. Results: Median CI, CN, and Rx/PTV50 for all 24 patients were 1.13 (1.02-1.28), 0.79 (0.70-0.88), and 5.3 (3.1-10.8), respectively. The median delivery rate for all patients was 410 MU/min with a maximum possible rate of 480 MU/min (85%). Median QA passing rate was 96.7%, and it did not significantly vary with the tumor site. Conclusions: VMAT delivery of SBRT plans optimized using biological-motivated cost-functions result in highly conformal dose distributions. Plans offer shorter treatment-time benefits and provide efficient dose delivery without compromising the plan conformity for tumors in the prostate, lung, and liver, thereby improving patient comfort and clinical throughput. The short delivery times minimize the risk of patient setup and intrafraction motion errors often associated with long SBRT treatment delivery times.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Magnitude of speed of sound aberration corrections for ultrasound image guided radiotherapy for prostate and other anatomical sites

Purpose: The purpose of this work is to assess the magnitude of speed of sound (SOS) aberrations in three-dimensional ultrasound (US) imaging systems in image guided radiotherapy. The discrepancy between the fixed SOS value of 1540 m/s assumed by US systems in human soft tissues and its actual nonhomogeneous distribution in patients produces small but systematic errors of up to a few millimeters in the positions of scanned structures. Methods: A correction, provided by a previously published density-based algorithm, was applied to a set of five prostate, five liver, and five breast cancer patients. The shifts of the centroids of target structures and the change in shape were evaluated. Results: After the correction the prostate cases showed shifts up to 3.6 mm toward the US probe, which may explain largely the reported positioning discrepancies in the literature on US systems versus other imaging modalities. Liver cases showed the largest changes in volume of the organ, up to almost 9%, and shifts of the centroids up to more than 6 mm either away or toward the US probe. Breast images showed systematic small shifts of the centroids toward the US probe with a maximum magnitude of 1.3 mm. Conclusions: The applied correction in prostate and liver cancer patients shows positioning errors of several mm due to SOS aberration; the errors are smaller in breast cancer cases, but possibly becoming more important when breast tissue thickness increases.

60 APPLIED LIFE SCIENCES↗