Design and in vitro antibiofilm activity of propolis diffusion-controlled biopolymers.

In this study, a novel pH-sensitive hydrogel beads that is based on gelatin/sodium alginate/chitosan (GEL/SA/CS) loaded with propolis ethanolic extracts (PE) were synthesized. The swelling behavior of GEL/SA/CS hydrogel beads was studied in different pH solutions and compared with unloaded CS (GEL/SA) hydrogel beads. The in vitro release studies have been revealed using four different pH (1.3, 5.0, 6.0, and 6.8), a saliva environment (pH 6.8), a simulated gastric fluid (SGF) (pH 1.3), and a simulated intestinal fluid (SIF) (pH 6.8) to simulate the physiological conditions in gastrointestinal (GI) tract. Propolis-loaded hydrogel beads were found to be stable at pH 1.3, 5.0, 6.0, simulated saliva, SGF, and SIF mediums, whereas the beads lose their stability at pH 6.8 buffer solution. Tested microorganisms displayed greater sensitivity to PE-loaded hydrogel beads compared with pure propolis. Contrary to antimicrobial activity results, antibiofilm activity results of PE-loaded GEL/SA and GEL/SA/CS hydrogel beads were found at low levels. According to the obtained results, the propolis-loaded GEL/SA/CS hydrogel beads synthesized within this study can be used in the treatment of GI tract diseases such as oral mucositis, gastric ulcer, ulcerative colitis, and GI cancer, as controlled releasing carriers of propolis.

Phase I clinical trial of KML001 monotherapy in patients with advanced solid tumors.

BACKGROUND: We evaluated the tolerability, pharmacokinetics (PK) and preliminary efficacy of KML001, an oral trivalent arsenical, as a monotherapy in patients with advanced solid tumors. RESEARCH DESIGN AND METHODS: With a standard 3 + 3 design for dose-escalation stage, the planned dose levels of KML001 were 5, 7.5, 10, 12.5, and 15 mg/day for 28 days. Once the maximum tolerated dose was determined, 22 subjects were additionally enrolled for dose-expansion stage. PK analysis was performed in the 5, 10, and 15 mg/day cohort at the dose-escalation stage and also at the dose-expansion stage. Moreover, response was assessed using the standard RECIST 1.1. RESULTS: A total of 45 Korean subjects were enrolled. No DLT was reported at the dose-escalation stage. Three DLTs, two cases of prolonged QTc interval and one of neutropenia, were reported in the 12.5 mg/day cohort at the dose-expansion stage. Higher total daily doses up to 12.5 mg/day of KML001 resulted in higher trough plasma concentrations. Among the 18 subjects who completed 2 cycles of therapy, 15 had progressive disease and 3 had stable disease. CONCLUSIONS: Doses equal to or greater than 10 mg/day KML001 alone were tolerable and produced plasma concentrations higher than biologically relevant targets.

Metabolism and disposition of arsenic species from controlled dosing with sodium arsenite in adult and neonatal rhesus monkeys. VI. Toxicokinetic studies following oral administration.

Arsenic is a common toxic contaminant in food and drinking water. Metabolic activation of arsenic species produces reactive trivalent intermediates that can disrupt cellular regulatory systems by covalent binding to thiol groups. Arsenic exposures have been associated with human diseases including cancer, diabetes, lung and cardiovascular disorders and there is accumulating evidence that early life exposures are important in the etiology. Previous toxicokinetic studies of arsenite ingestion in neonatal CD-1 mice showed consistent evidence for metabolic and physiologic immaturity that led to elevated internal exposures to trivalent arsenic species in the youngest mice, relative to adults. The current study in rhesus monkeys showed that metabolism and binding of trivalent intermediates after arsenite ingestion were similar between adult monkeys and CD-1 mice. Unlike neonatal mice, monkeys from the age of 5-70 days showed similar metabolism and binding profiles, which were also similar to those in adults. The absence of evidence for metabolic immaturity in monkeys suggests that toxicological effects observed in mice from early postnatal exposures to arsenic could over-predict those possible in primates, based on significantly higher internal exposures.

Sodium arsenite exposure impairs B cell proliferation and enhances vascular inflammation in Plasmodium berghei mouse model.

Arsenic exposure has been linked to an impaired immune response and inflammation. Our study investigated the effects of sodium arsenite on host immune response and vascular inflammation during malarial infection. Mice were divided into three groups: control (C), Plasmodium berghei infection (I) and sodium arsenite exposure with Plasmodium berghei infection (As-I). The results showed that splenocyte proliferation stimulated by lipopolysaccharide (LPS) and pokeweed mitogen (PWM) was suppressed in the I group, and the suppression was more pronounced in the As-I group, suggesting that acquired immunity in infected mice was worsening following arsenic exposure. ICAM-1, an adhesion protein involved in parasite-infected red blood cell (iRBC) binding to endothelium, and HIF-1α, a hypoxia marker protein in the descending aorta, were increased in the As-I group compared to the I group. Collectively, our results suggest that arsenic may increase host susceptibility to malaria through suppression of B cell proliferation and enhancement of adhesion between iRBC and endothelium by increasing ICAM-1.

Metabolism and disposition of arsenic species from controlled dosing with sodium arsenite in adult female CD-1 mice. III. Toxicokinetic studies following oral and intravenous administration.

Arsenic is a ubiquitous contaminant, with typical dietary intake below 1 µg/kg bw/d and drinking water exposures up to 50 µg/kg bw/d. Arsenic exposures are associated with human diseases and doses of toxicological concern are similar to typical dietary intake. Metabolism of arsenite to dimethylarsinate (DMAV) by arsenite-3-methyltransferase (As3MT) promotes clearance, but also generates reactive trivalent intermediates that bind extensively to cellular thiols. This study measured pentavalent and trivalent arsenic species in blood and tissues after oral and intravenous administration of arsenite (50 µg/kg bw). After oral administration, the intestine and liver contained elevated levels of AsIII and MMAIII, relative to erythrocytes, lung, and kidney, suggesting incomplete conversion to DMA during first-pass metabolism. However, blood concentrations of the predominant species, DMA, were similar for oral and intravenous dosing. While all tissues examined contained DMAIII, muscle, brain, and plasma had undetectable levels of MMAIII. Tissue levels of arsenic species were similar following intravenous vs. oral administration, except lower in the intestine. The results confirm the role of metabolism in producing fluxes of putatively toxic trivalent arsenic intermediates. Tissue dosimetry suggests that the intestine, liver, lung, and kidney could be more susceptible to effects of bound arsenic, relative to muscle and brain.

Metabolism and disposition of arsenic species from controlled oral dosing with sodium arsenite in adult female CD-1 mice. I. Pilot study to determine dosing, analytical measurements, and sampling strategies.

Arsenic (As) is ubiquitous in the earth's crust, with typical dietary intake in developed countries <1 µg/kg bw/d, and atypical groundwater exposures in developing countries approaching 50 µg/kg bw/d. Arsenic exposures are linked with human diseases and doses of toxicological concern are similar to typical dietary intake estimates. The methylation of arsenite by arsenite-3-methyltransferase (As3MT) promotes the clearance of arsenic as pentavalent species, but also generates reactive trivalent intermediates. This study measured inorganic arsenic and its metabolites in pentavalent and trivalent states in blood, tissues, and excreta after oral administration of arsenite (50-200 µg/kg bw). While liver was a major site for clearance of arsenite and formation of methylated species, it also had extensive binding of trivalent intermediates; however, thiol exchange and oxidation reactions of trivalent arsenic were facile since dimethylarsinic acid (DMAV) was the predominant species in blood and urine. Consistent evidence was observed for a non-linear relationship between doses above 50 µg/kg bw and levels of bound trivalent As metabolites. The abundance of protein-bound trivalent arsenic within target tissues should correlate with disruption of critical cellular processes, which rely on defined interactions of thiol functional groups, and could provide dose-response relationships from animal models for human risk assessment.

α-Lipoic acid inhibits testicular and epididymal oxidative damage and improves fertility efficacy in arsenic-intoxicated rats.

The present study evaluates the protective effect of α-lipoic acid (LA) against arsenic-induced testicular and epididymal oxidative damage in rats. Arsenic caused significant reduction in the reproductive organ weights, serum testosterone levels, testicular daily sperm count, epididymal sperm count, sperm motility, sperm viability, and sperm membrane integrity. Significant reduction in the activity levels of superoxide dismutase, catalase, and glutathione levels with a concomitant increase in the lipid peroxidation and protein carbonyl content in the testis and the cauda epididymis of arsenic-exposed rats. Arsenic intoxication also enhanced the testicular caspase-3 mRNA levels, disorganization of testicular and cauda epididymal architecture as well as increased arsenic content in the testis and the cauda epididymis of rats. Arsenic exposure also deteriorated fertility ability in male rats over controls. Conversely, α-LA negated the testicular and cauda epididymal oxidative stress and restored the male reproductive health in arsenic-exposed rats.

Strain differences in arsenic-induced oxidative lesion via arsenic biomethylation between C57BL/6J and 129X1/SvJ mice.

Arsenic is a common environmental and occupational toxicant with dramatic species differences in its susceptibility and metabolism. Mouse strain variability may provide a better understanding of the arsenic pathological profile but is largely unknown. Here we investigated oxidative lesion induced by acute arsenic exposure in the two frequently used mouse strains C57BL/6J and 129X1/SvJ in classical gene targeting technique. A dose of 5 mg/kg body weight arsenic led to a significant alteration of blood glutathione towards oxidized redox potential and increased hepatic malondialdehyde content in C57BL/6J mice, but not in 129X1/SvJ mice. Hepatic antioxidant enzymes were induced by arsenic in transcription in both strains and many were higher in C57BL/6J than 129X1/SvJ mice. Arsenic profiles in the liver, blood and urine and transcription of genes encoding enzymes involved in arsenic biomethylation all indicate a higher arsenic methylation capacity, which contributes to a faster hepatic arsenic excretion, in 129X1/SvJ mice than C57BL/6J mice. Taken together, C57BL/6J mice are more susceptible to oxidative hepatic injury compared with 129X1/SvJ mice after acute arsenic exposure, which is closely associated with arsenic methylation pattern of the two strains.

Pharmacodynamics of S-dimethylarsino-glutathione, a putative metabolic intermediate of inorganic arsenic, in mice.

Inorganic arsenicals are well-known carcinogens, whereas arsenite (iAsIII) compounds are now recognized as potent therapeutic agents for several leukemias, and arsenic trioxide has been used for the treatment of recurrent acute promyelocytic leukemia (APL). However, recent clinical trials revealed that arsenite is not always effective for non-APL malignancies. Another arsenical, S-dimethylarsino-glutathione ([DMAIII(GS)]), which is a putative metabolic intermediate in the hepatic metabolism of iAsIII, shows promise for treating several types of lymphoma. However, the metabolism of [DMAIII(GS)] has not been well investigated, probably because [DMAIII(GS)] is not stable in biological fluids where the concentration of glutathione is low. In the present study, we injected [DMAIII(GS)] intravenously into mice and compared the tissue distribution and metabolic dynamics of [DMAIII(GS)] with those of sodium arsenite (NaAsO2). We found a unique organ preference for the distribution of [DMAIII(GS)] to the lung and brain in comparison to NaAsO2. Furthermore, [DMAIII(GS)] appeared to bind to serum albumin by exchanging its glutathione moiety quickly after administration, providing novel insights into the longer retention of [DMAIII(GS)] in plasma.

Bioavailability study of arsenic and mercury in traditional Chinese medicines (TCM) using an animal model after a single dose exposure.

Traditional Chinese medicines (TCM) are increasingly being used as alternative medicines in many countries, and this has caused concern because of adverse health effects from toxic metal bioavailability such as mercury (Hg) and arsenic (As). The aim of this study was to investigate the bioavailability of As and Hg from TCM after a single exposure dose using an animal model of female Sprague-Dawley rats. The rats were divided into 6 groups which included four groups treated with sodium arsenite (NaAsO2), arsenic sulfide (As2S3), mercuric chloride (HgCl2), mercuric sulfide (HgS), and two groups treated with TCM containing high Hg or As (Liu Shen Wan: As 7.7-9.1% and Hg 1.4-5.0%; Niuhang Jie du Pian: As 6.2-7.9% and Hg <0.001%). The samples of urine, faeces, kidney and liver were collected for analysis and histological assay. The results indicated that relatively low levels of As and Hg from these TCM were retained in liver and kidney tissues. The levels of As in these tissues after TCM treatment were consistent with the levels from the As sulphide treated group. With the exception of the mercuric chloride treated group, the levels of Hg in urine from other groups were very low, and high levels of As and Hg from TCM were excreted in faeces. The study showed poor bioavailability of As and Hg from TCM as indicated by low relative bioavailability of As (0.60-1.10%) and Hg (<0.001%). Histopathological examination of rat kidney and liver tissues did not show toxic effects from TCM.

Ameliorative effect of quercetin against arsenic-induced sperm DNA damage and daily sperm production in adult male rats.

In this study, the protective effect of quercetin was evaluated against arsenic induced reproductive ailments in male rats. For this purpose, male rats (n = 5/group) weighing 180-250 g were used. First group served as control, second group received arsenic (50 ppm) in drinking water. Third group was treated with quercetin (50 mg/kg) alone, while fourth group received arsenic + quercetin. All treatments were carried out for 49 days. After treatment, animals were killed by decapitation; testis and epididymis were dissected out. Right epididymis was minced immediately for comet assay, while left epididymis was processed for histology. Similarly, right testis was homogenized for estimation of daily sperm production (DSP) and detection of metal concentration. The results of our research revealed that arsenic treatment did not cause any significant change in body weight and testicular volume. Quercetin treatment significantly prevented tissue deposition of arsenic within the testis. Arsenic treatment caused a significant reduction in DSP, however, in the arsenic + quercetin-treated group and quercetin alone-treated group, DSP was significantly high as compared to the arsenic-treated group. Histological study of epididymis showed empty lumen in arsenic-treated group while in arsenic + quercetin-treated group and quercetin alone-treated group, lumen were filled with sperm and were comparable to control. Sperm DNA damage, induced by arsenic, was significantly reversed toward control levels by supplementation of quercetin. These results suggest that quercetin not only prevents deposition of arsenic in tissues, but can also protect the sperm DNA damage.

Arsenic-induced dyslipidemia in male albino rats: comparison between trivalent and pentavalent inorganic arsenic in drinking water.

BACKGROUND: Recent epidemiological evidences indicate close association between inorganic arsenic exposure via drinking water and cardiovascular diseases. However, the exact mechanism of this arsenic-mediated increase in cardiovascular risk factors remains enigmatic. METHODS: In order to investigate the effects of inorganic arsenic exposure on lipid metabolism, male albino rats were exposed to 50, 100 and 150 ppm arsenic as sodium arsenite and 100, 150 and 200 ppm arsenic as sodium arsenate respectively in their drinking water for 12 weeks. RESULTS: Dyslipidemia induced by the two arsenicals exhibited different patterns. Hypocholesterolemia characterised the effect of arsenite at all the doses, but arsenate induced hypercholesterolemia at the 150 ppm As dose. Hypertriglyceridemia was the hallmark of arsenate effect whereas plasma free fatty acids (FFAs) was increased by the two arsenicals. Reverse cholesterol transport was inhibited by the two arsenicals as evidenced by decreased HDL cholesterol concentrations whereas hepatic cholesterol was increased by arsenite (100 ppm As), but decreased by arsenite (150 ppm As) and arsenate (100 ppm As) respectively. Brain cholesterol and triglyceride were decreased by the two arsenicals; arsenate decreased the renal content of cholesterol, but increased renal content of triglyceride. Arsenite, on the other hand, increased the renal contents of the two lipids. The two arsenicals induced phospholipidosis in the spleen. Arsenite (150 ppm As) and arsenate (100 ppm As) inhibited hepatic HMG CoA reductase. At other doses of the two arsenicals, hepatic activity of the enzyme was up-regulated. The two arsenicals however up-regulated the activity of the brain enzyme. We observed positive associations between tissue arsenic levels and plasma FFA and negative associations between tissue arsenic levels and HDL cholesterol. CONCLUSION: Our findings indicate that even though sub-chronic exposure to arsenite and arsenate through drinking water produced different patterns of dyslipidemia, our study identified two common denominators of dyslipidemia namely: inhibition of reverse cholesterol transport and increase in plasma FFA. These two denominators (in addition to other individual perturbations of lipid metabolism induced by each arsenical), suggest that in contrast to strengthening a dose-dependent effect phenomenon, the two forms of inorganic arsenic induced lipotoxic and non-lipotoxic dyslipidemia at "low" or "medium" doses and these might be responsible for the cardiovascular and other disease endpoints of inorganic arsenic exposure through drinking water.

Pharmacokinetics of bromide in adult sheep following oral and intravenous administration.

OBJECTIVE: To determine the pharmacokinetics of bromide in sheep after single intravenous (IV) and oral (PO) doses. PROCEDURE: Sixteen Merino sheep were randomly assigned to two treatment groups and given 120 mg/kg bromide, as sodium bromide IV or potassium bromide PO. Serum bromide concentrations were determined by colorimetric spectrophotometry. RESULTS: After IV administration the maximum concentration (Cmax ) was 822.11 ± 93.61 mg/L, volume of distribution (Vd ) was 0.286 ± 0.031 L/kg and the clearance (Cl) was 0.836 ± 0.255 mL/h/kg. After PO administration the Cmax was 453.86 ± 43.37 mg/L and the time of maximum concentration (Tmax ) was 108 ± 125 h. The terminal half-life (t½ ) of bromide after IV and PO administration was 387.93 ± 115.35 h and 346.72 ± 94.05 h, respectively. The oral bioavailability (F) of bromide was 92%. No adverse reactions were noted in either treatment group during this study. The concentration versus time profiles exhibited secondary peaks, suggestive of gastrointestinal cyclic redistribution of the drug. CONCLUSIONS AND CLINICAL RELEVANCE: When administered PO, bromide in sheep has a long half-life (t½ ) of approximately 14 days, with good bioavailability. Potassium bromide is a readily available, affordable salt with a long history of medical use as an anxiolytic, sedative and antiseizure therapy in other species. There are a number of husbandry activities and flock level neurological conditions, including perennial ryegrass toxicosis, in which bromide may have therapeutic or prophylactic application.

High accumulation of arsenic in the esophagus of mice after exposure to arsenite.

Arsenic-induced toxicity appears to be dependent on the tissue- or cell-specific accumulation of this metalloid. An early study showed that arsenic was retained in the esophagus as well as the liver, kidney cortex and skin of marmosets after intraperitoneal administration of (74)As-arsenite. However, there is little available information regarding the distribution of arsenic in the esophagus. Here, we compared the retention of arsenic in the esophagus, liver, lung, kidney and heart in mice intraperitoneally administered 1 or 5 mg/kg sodium arsenite (As(III)) daily for 3 or 7 days. The results showed that the arsenic concentration was highest in the esophagus. We compared the mRNA levels of aquaglyceroporin (AQP) 3, AQP7 and AQP9, which are responsible for arsenic influx, and those of multidrug-resistance protein (MRP) 1 and MRP2, which are responsible for arsenic efflux. The levels of AQP3 mRNA in the esophagus were much higher than those in liver, lung and heart, while the mRNA levels of MRP2 were very low in the esophagus. In addition, we found extremely low expression of Nrf2 in the esophagus at the basal and under the activated conditions, which might have resulted in low levels of glutamyl-cysteine ligase catalytic and modulatory subunits, and subsequently in the low levels of glutathione. Thus, the highest retention of arsenic was detected in the esophagus after intraperitoneal administration of As(III) to mice, and this appeared to result from multiple factors, including high expression of AQP3, low expression of MRP2, low capacity of glutathione synthesis and low activation of Nrf2.

Hepatoprotective activity of Tephrosia purpurea against arsenic induced toxicity in rats.

AIM: The present study was conducted to evaluate the hepatoprotective activity of Tephrosia purpurea (TP) against sodium arsenite (NaAsO2) induced sub-acute toxicity in rats. MATERIALS AND METHODS: Twenty four wistar albino rats of either sex were randomly divided into three groups. Group II and III were orally administered with sodium arsenite (10 mg/kg) daily in drinking water for 28 days. Additionally Group III was orally treated with hydro-alcoholic extract of Tephrosia purpurea (TP) @ 500 mg/kg daily for the same time period, whereas only deionized water was given to Group I (control). Serum biomarker levels, oxidative stress parameters and arsenic concentration were assessed in liver. Histopathology was also conducted. RESULTS: It has been seen that TPE (500 mg/kg) significantly (P < 0.01) reduced serum ALT, AST, ALP activity and increased total protein and reduced necrosis and inflammation in liver of group III compared to group II. A significantly (P < 0.01) higher LPO and lower GSH levels without change in SOD activity in liver was also observed in group II compared to group III, though there was no significant difference in arsenic accumulation between them. The plant extract also protects the animals of group III from significant (P < 0.01) reduction in body weight. CONCLUSION: Our study shows that supplementation of Tephrosia purpurea extract (500 mg/kg) could ameliorate the hepatotoxic action of arsenic.

Alpha-lipoic acid protects oxidative stress, changes in cholinergic system and tissue histopathology during co-exposure to arsenic-dichlorvos in rats.

We investigated protective efficacy of α-lipoic acid (LA), an antioxidant against arsenic and DDVP co-exposed rats. Biochemical variables suggestive of oxidative stress, neurological dysfunction, and tissue histopathological alterations were determined. Male rats were exposed either to 50 ppm sodium arsenite in drinking water or in combination with DDVP (4 mg/kg, subcutaneously) for 10 weeks. α-Lipoic acid (50mg/kg, pos) was also co-administered in above groups. Arsenic exposure led to significant oxidative stress along, hepatotoxicity, hematotoxicity and altered brain biogenic amines levels accompanied by increased arsenic accumulation in blood and tissues. These altered biochemical variables were supported by histopathological examinations leading to oxidative stress and cell death. These biochemical alterations were significantly restored by co-administration of α-lipoic acid with arsenic and DDVP alone and concomitantly. The results indicate that arsenic and DDVP induced oxidative stress and cholinergic dysfunction can be significantly protected by the supplementation of α-lipoic acid.

Mouse assay for determination of arsenic bioavailability in contaminated soils.

A mouse assay for measuring the relative bioavailability (RBA) of arsenic (As) in soil was developed. In this study, results are presented of RBA assays of 16 soils, including multiple assays of the same soils, which provide a quantitative assessment of reproducibility of mouse assay results, as well as a comparison of results from the mouse assay with results from a swine and monkey assay applied to the same test soils. The mouse assay is highly reproducible; three repeated assays on the same soils yielded RBA estimates that ranged from 1 to 3% of the group mean. The mouse, monkey, and swine models yielded similar results for some, but not all, test materials. RBA estimates for identical soils (nine test soils and three standard reference materials [SRM]) assayed in mice and swine were significantly correlated (r = 0.70). Swine RBA estimates for 6 of the 12 test materials were higher than those from the mouse assay. RBA estimates for three standard reference materials (SRM) were not statistically different (mouse/swine ratio ranged from 0.86-1). When four test soils from the same orchard were assessed in the mouse, monkey, and swine assays, the mean soil As RBA were not statistically different. Mouse and swine models predicted similar steady state urinary excretion fractions (UEF) for As of 62 and 74%, respectively, during repeated ingestion doses of sodium arsenate, the water-soluble As form used as the reference in the calculation of RBA. In the mouse assay, the UEF for water soluble As(V) (sodium arsenate) and As(III) (sodium [meta] arsenite) were 62% and 66%, respectively, suggesting similar absolute bioavailabilities for the two As species. The mouse assay can serve as a highly cost-effective alternative or supplement to monkey and swine assays for improving As risk assessments by providing site-specific assessments of RBA of As in soils.

Proteomic analysis of arsenic-exposed zebrafish (Danio rerio) identifies altered expression in proteins involved in fibrosis and lipid uptake in a gender-specific manner.

The zebrafish (Danio rerio) was used to investigate protein expression in the liver following arsenic exposure. Several disorders have been linked to arsenic exposure, including cancer, diabetes, and cardiovascular disease. The mechanisms of arsenic toxicity are poorly understood. Prior studies have described altered gene expression, inflammation, and mitogenic signaling in acute or chronic exposure models. A proteomic approach was employed to investigate arsenic-induced alteration in the zebrafish liver proteome following a 7-day exposure to 50 ppb sodium arsenite. Over 740 unique proteins were identified, with fewer than 2% showing differential expression. Molecular pathway analysis software identified lipid metabolism and transport as potential molecular targets. Immunoblots were used to confirm protein expression changes, whereas qPCR was employed to investigate gene expression changes. Overall, 25 proteins were differentially expressed in a gender-specific manner, 11 in males and 14 in females. Of these 25, a single protein, hydroxysteroid dehydrogenase like 2, showed decreased expression in both males and females following arsenic exposure. These findings indicate that protein expression is altered following arsenic exposure. The changes presented here seem to be most prevalent in lipid transport and metabolic pathways, suggesting a potential increase in fibrosis in males and decreased lipid accumulation and uptake in females.

Effect of nicotine pretreatment on arsenic-induced oxidative stress in male Wistar rats.

Humans are commonly exposed to nicotine, one of the most important lifestyle chemicals. The occurrence of high levels of arsenic in the groundwater of the southeast region of Asia has received much attention in the past decade and has become a global health concern. Predominant occurrence of both these chemicals and ease of their human exposure led us to investigate the effect of nicotine, a major tobacco alkaloid, on arsenic toxicity. Adult male rats were pre-exposed to two different doses of nicotine (0.75 and 3 mg/kg, intraperitoneally) for 7 days followed by 30 days of arsenic exposure (50 ppm sodium arsenite in drinking water). Nicotine pre-exposure resulted in an increased brain arsenic accumulation and a decreased liver arsenic concentration. Arsenic also caused a significant oxidative stress in the blood, brain and liver of the exposed rats. Glutathione-S-transferase, a phase II enzyme, was inhibited by both arsenic and nicotine but no such inhibition was noted in arsenic-treated animals pre-exposed to nicotine. Upon nicotine pre-exposure, brain acetylcholinesterase increased, while monoamine oxidase (MAO) decreased. The toxic effects of MAO significantly attenuated with nicotine pre-exposure. The present study suggests that nicotine may not be the major contributing factor for the previously reported synergistic toxic interaction between tobacco and arsenic. Nicotine pre-exposure in arsenic-exposed animals revealed interesting toxicokinetics and oxidative stress modulating interactions in the brain and liver of rats, which requires further exploration.

Phase and size controllable synthesis of NaYbF4 nanocrystals in oleic acid/ionic liquid two-phase system for targeted fluorescent imaging of gastric cancer.

Upconversion nanocrystals with small size and strong fluorescent signals own great potential in applications such as biomolecule-labeling, in vivo tracking and molecular imaging. Herein we reported that NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals with small size and strong fluorescent signals were controllably synthesized by oleic acid (OA)/ ionic liquid (IL) two-phase system for targeted fluorescent imaging of gastric cancer in vivo. The optimal synthesis condition of NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals by OA/IL two-phase system was established, adding more metal ion such as Na(+) ion could facilitate the size control and crystal-phase transition, more importantly, markedly enhancing fluorescent intensity of beta-phase nanocrystals compared with traditional methods. Alpha-phase NaYbF4, 2%Tm upconversion nanocrystals with less than 10nm in diameter and beta-phase NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals with 30 nm or so in diameter and strong fluorescent signals were obtained, these synthesized nanocrystals exhibited very low cytotoxicity. Folic acid-conjugated silica-modified beta-phase NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals were prepared, could actively target gastric cancer tissues implanted into nude mice in vivo, and realized targeted fluorescent imaging. Folic acid-conjugated silica-modified NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals show great potential in applications such as targeted near infared radiation fluorescent imaging, magnetic resonance imaging and targeted therapy of gastric cancer in the near future.