Exhibiting the diagnostic face of selenium nanoparticles as a radio-platform for tumor imaging.

Selenium nanoparticles (SeNPs) have become one of the most prospective and promising tools in the course of cancer diagnosis and therapy. Here we describe the synthesis of a novel radioactive platform for tumor imaging using selenium nanoparticles. SeNPs were synthetized using dithionite and glutathione as reducing and capping agent respectively with 5 mmol/L sodium selenite as a precursor and then SeNPs radiolabeled with technetium-99 m, the most common and famous radioactive isotope used for imaging purposes. A characteristic profile for the synthesized SeNPs was performed including size analysis, zeta potential, antioxidant activity, radiochemical yield and in-vivo biodistribution in normal and solid tumor bearing mice. Size analysis showed amorphous SeNP cores of a mean diameter of 21 ± 5 nm with a hydrodynamic size of 43 ± 8 nm and -28 mV zeta potential. The particles also showed a superior antioxidant activity of radical scavenging activity 55.6% according to DPPH assay, in addition, satisfying radiochemical yield up to 97 ± 1.5 was achieved. In vivo studies were applied on male Swiss albino mice that demonstrated a good biodistribution pattern in normal mice with a moderate accumulation in liver at 30 min post injection. Excellent T/NT ratios were obtained in solid tumor bearing mice throughout the experimental time points. The as-synthetized selenium nanoparticles demonstrated surprising and satisfying features which make them promising enough for tumor theranosis.

The clinical effect of glutathione on skin color and other related skin conditions: A systematic review.

BACKGROUND: Glutathione is one of agents which is commonly used to lighten skin color in Asia as a dietary supplement. Previous studies suggest its potential effect of glutathione on skin color. However, the clinical efficacy of glutathione in oral form is still questionable due to its limited absorption and bioavailability. AIM: To determine the clinical effects of glutathione on skin color and related skin conditions. PATIENTS/METHODS: A systematic review was conducted using PubMed, CINAHL, Scopus, EMBASE and Cochrane library were searched from inceptions to October 2017. All clinical studies evaluating the effect of glutathione on any skin effects in healthy volunteer were included. RESULTS: A total of four studies were included. Three studies were RCTs with placebo control, while one was a single-arm trial. One study used topical form, while others used oral form of glutathione with 250 to 500 mg/day. We found that both oral glutathione with the dosage of 500 mg/day and topical 2.0% oxidized glutathione could brighten skin color in sun-exposed area measured by skin melanin index. No significant differences in the reduction in skin melanin index were observed in sun-protected area for any products. In addition, glutathione also has a trend to improve skin wrinkle, skin elasticity, and UV spots. Some adverse events but nonserious were reported. CONCLUSIONS: Current evidence of the skin whitening effect of glutathione is still inconclusive due to the quality of included studies and inconsistent findings. However, there is a trend that glutathione might brighten skin color at skin-exposed area.

The acute effect of high-dose intravenous vitamin C and other nutrients on blood pressure: a cohort study.

BACKGROUND: Regular intake of vitamin C/ascorbate reduces blood pressure (BP) in hypertensives. High-dose intravenous vitamin C (IVC) achieves higher plasma levels; however, there is a paucity of research on acute BP effects. Our study is the first to investigate the effect of high-dose IVC, with or without concomitant i.v. nutrients, on BP during i.v. METHODS: A cohort of adult patients scheduled to receive IVC treatment for infection, cancer or fatigue, as prescribed by their treating doctor, participated at a Melbourne clinic, Australia. Ambulatory BP was assessed every 10 min over 90 min during i.v. TREATMENT: Patients received 15-100 g of IVC alone or in addition to i.v. vitamin B, glutathione, magnesium or zinc. BP change over time adjusted for baseline BP, IVC dosage, i.v. treatment and BMI was analysed. RESULTS: A total of 77 mostly normotensive patients participated, with a third receiving IVC alone (42±20 g), and two-thirds also received other i.v. nutrients. IVC alone (>30 g) reduced the mean BP up to 8-9 mmHg in prehypertensive patients. In contrast, concomitant intravenous vitamin B12 (IVB12) significantly increased the mean BP by 11-13 mmHg. Comparison of BP change during IVC versus IVC+IVB12 indicated a highly significant difference [systolic blood pressure: mean difference (SD)=16.6 (17.8) mmHg, P<0.001; diastolic blood pressure: mean difference (SD)=12.5 (16.7) mmHg, P=0.003]. CONCLUSION: Our study suggests an acute BP-reducing effect of high-dose IVC, particularly with dosages above 30 g, and in patients with prehypertension and normal BMI. Furthermore, our study indicated a marked and clinically relevant hypertensive effect of IVB12, suggesting routine BP monitoring during i.v. therapy in clinical practice.

Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study.

Glutathione (GSH) is critical to fight against oxidative stress. Its very low bioavailability limits the interest of a supplementation. The purpose of this study was to compare the bioavailability, the effect on oxidative stress markers and the safety of a new sublingual form of GSH with two commonly used dietary supplements, N-acetylcysteine (NAC) and oral GSH. The study was a three-week randomized crossover trial. 20 Volunteers with metabolic syndrome were enrolled. GSH levels and several oxidative stress markers were determined at different times during each 21-days period. Compared to oral GSH group, an increase of total and reduced GSH levels in plasma and a higher GSH/GSSG ratio (p=0.003) was observed in sublingual GSH group. After 3 weeks of administration, there was a significant increase of vitamin E level in plasma only in sublingual GSH group (0.83 µmol/g; p=0.04). Our results demonstrate the superiority of a new sublingual form of GSH over the oral GSH form and NAC in terms of GSH supplementation.

[The study of hypotensive action of dinitrosyl-iron complex with glutathione containing drug oxacom in healthy volunteers].

On the basis of earlier executed studies of hypotensive effect of dinitrosyl iron complexes (DNIC) with glutathione, the drug has been created in industrial conditions named oxacom. Preliminary pharmacological studies of oxacom have not revealed negative qualities. The drug has been now tested in 14 healthy men in whom at single intravenous introduction it caused typical response - a decrease of diastolic as well as systolic arterial pressure on 24-27 mmHg through 3-4 min with subsequent very slow restoration in 8-10 hours. The heart rate after initial rise was quickly normalized. Echocardiography revealed unaltered cardiac output in spite of reduced cardiac filling by 28%. The multilateral analysis of clinical and biochemical data has revealed an absence of essential alterations which could lead to pathological consequences. The drug is recommended for carrying out of the second phase of clinical trial. The comparative study of the efficiency of hypotensive action of oxacom, S-nitrosoglutathione (GS-NO) and sodium nitrite (NO2) in rats has shown that the duration of effect was the greatest at oxacom action.

Selenium-dependent and -independent transport of arsenic by the human multidrug resistance protein 2 (MRP2/ABCC2): implications for the mutual detoxification of arsenic and selenium.

Simultaneous exposure of lab animals to toxic doses of the human carcinogen arsenic (As) and the essential trace element selenium (Se) results in a remarkable mutual detoxification. A likely basis for this is the in vivo formation and biliary excretion of seleno-bis(S-glutathionyl) arsinium ion [(GS)(2)AsSe](-); however, the transport protein responsible for the biliary efflux of [(GS)(2)AsSe](-) has not been identified. The multidrug resistance protein 2 (MRP2/ABCC2) is an adenosine triphosphate (ATP)-binding cassette transporter expressed at the canalicular membrane of hepatocytes. Rat Mrp2 is known to excrete the As glutathione (GSH/GS-) conjugates arsenic triglutathione [As(GS)(3)] and monomethyl arsenic diglutathione [CH(3)As(GS)(2)] into bile, and in vitro studies have established As(GS)(3) as a substrate for human MRP2. In the present study, membrane vesicles prepared from human embryonic kidney (HEK293T) cells transfected with human MRP2 were used to demonstrate that MRP2 transports [(GS)(2)AsSe](-). In addition, the characteristics of MRP2 transport of As(GS)(3) and [(GS)(2)AsSe](-) were investigated. As(GS)(3) and [(GS)(2)AsSe](-) are chemically labile and have the potential to dissociate. However, arsenite (As(III)) +/- selenite (Se(IV)) transport was not detected in the absence of GSH or in the presence of the non-reducing GSH analog, ophthalmic acid, suggesting that the conjugates are the transported forms. The apparent K(m) values for [(GS)(2)AsSe](-) and As(GS)(3) were 1.7 and 4.2 microM, respectively, signifying high relative affinities. Membrane vesicles prepared from human erythrocytes, which express the MRP2-related MRP1/ABCC1, MRP4/ABCC4 and MRP5/ABCC5, transported As(GS)(3) in an MRP1- and ATP-dependent manner but did not transport [(GS)(2)AsSe](-). These results have important implications for the Se-dependent and -independent disposition of As.

Darinaparsin: a novel organic arsenical with promising anticancer activity.

Darinaparsin is an organic arsenical composed of dimethylated arsenic linked to glutathione, and is being investigated for antitumor properties in vitro and in vivo. While other arsenicals, including arsenic trioxide, have been used clinically, none have shown significant activity in malignancies outside of acute promyelocytic leukemia. Darinaparsin has significant activity in a broad spectrum of hematologic and solid tumors in preclinical models. Here, we review the literature describing the signaling pathways and mechanisms of action of darinaparsin and compare them to mechanisms of cell death induced by arsenic trioxide. Darinaparsin has overlapping, but distinct, signaling mechanisms. We also review the current results of clinical trials with darinaparsin (both intravenous and oral formulations) that demonstrate significant antitumor activity.

In utero ethanol exposure impairs defenses against experimental group B streptococcus in the term Guinea pig lung.

BACKGROUND: The effects of fetal alcohol exposure on the risks of neonatal lung injury and infection remain under investigation. The resident alveolar macrophage (AM) is the first line of immune defense against pulmonary infections. In utero ethanol (ETOH) exposure deranges the function of both premature and term guinea pig AM. We hypothesized that fetal ETOH exposure would increase the risk of pulmonary infection in vivo. METHODS: We developed a novel in vivo model of group B Streptococcus (GBS) pneumonia using our established guinea pig model of fetal ETOH exposure. Timed-pregnant guinea pigs were pair fed +/-ETOH and some were supplemented with the glutathione (GSH) precursor S-adenosyl-methionine (SAM-e). Term pups were given GBS intratracheally while some were pretreated with inhaled GSH prior to the experimental GBS. Neonatal lung and whole blood were evaluated for GBS while isolated AM were evaluated using fluorescent microscopy for GBS phagocytosis. RESULTS: Ethanol-exposed pups demonstrated increased lung infection and sepsis while AM phagocytosis of GBS was deficient compared with control. When SAM-e was added to the maternal diet containing ETOH, neonatal lung and systemic infection from GBS was attenuated and AM phagocytosis was improved. Inhaled GSH therapy prior to GBS similarly protected the ETOH-exposed pup from lung and systemic infection. CONCLUSIONS: In utero ETOH exposure impaired the neonatal lung's defense against experimental GBS, while maintaining GSH availability protected the ETOH-exposed lung. This study suggested that fetal alcohol exposure deranges the neonatal lung's defense against bacterial infection, and support further investigations into the potential therapeutic role for exogenous GSH to augment neonatal AM function.

Efectos de la suplementación con glutamina sobre el sistema antioxidante y la peroxidación lipídica en pacientes críticos con nutrición parenteral / Effects of supply with glutamine on antioxidant system and lipid peroxidation in patients with parenteral nutrition

Introducción: En el paciente crítico hay una continua producción de especies reactivas de oxígeno (ERO) que necesitan se neutralizadas para evitar el estrés oxidativo (EO). Entre las defensas antioxidantes endógenas, el sistema glutatión (GSH) es cuantitativamente el más importante, pero en situaciones de estrés severo se encuentra disminuido. Para incrementarlo, la suplementación con glutamina ha demostrado ser efectiva, ejerciendo protección contra el daño oxidativo y reduciendo la morbi-mortalidad. Objetivo: Valorar el efecto de la adición de un dipéptidoal anyl-glutamina a la NP sobre la peroxidación lipídica y el metabolismo del glutatión y su relación con la morbilidad de los pacientes críticos. Métodos: Determinación, mediante técnicas espectrofo-tométricas, de glutatión peroxidasa, glutatión reductasa, glutatión total y malonil aldehído al ingreso y tras siete días de estancia en la Unidad de Cuidados Intensivos (UCI) de 20 pacientes mayores de 18 años con tratamiento nutricional parenteral. Resultados: El grupo de pacientes que recibió nutrición parenteral con adición de glutamina experimentó aumentos significativos a la semana de tratamiento nutricional en la concentración del glutatión total (42,35 ± 13 vs 55,29 ± 12 μmol/l; p < 0,05), junto a un incremento de la actividad de la enzima glutatión peroxidasa (470 ± 195 vs 705 ± 214 μmol/l; p < 0,05). En cambio, el grupo con nutrición parenteral convencional no presentó modificaciones significativas en ninguno de los parámetros estudiados (p > 0,05). Sin embargo, tanto la mortalidad como la estancia en UCI no fue diferente para los grupos estudiados, mientras que si se observó una menor gravedad, valorada por e SOFA score, en el grupo de pacientes que recibieron glutamina (SOFA 5 ± 2 vs 8 ± 1,8; p < 0,05).Conclusiones: El aporte de glutamina en pacientes críticos mejora las defensas antioxidantes, lo que repercute en una menor peroxidación lipídica y menor morbilidad durante la estancia en UCI

Introduction: In the critically ill patient, there is a continuous production of reactive oxygen species (ROS) that need to be neutralized to prevent oxidative stress (OS). Quantitatively speaking, the glutathionesystem (GSH) is the most important anti-oxidant endogenous defense. To increase it, glutamine supplementation has been shown to be effective by protecting against the oxidative damage and reducing the morbimortality. Objective: To assess the effect of adding an alanylglutamine dipeptide to PN on lipid peroxidation lipidica and glutathione metabolism, as well as its relationship with morbidity in critically ill patients. Methods: Determination through spectrophotometry techniques of glutathione peroxidase, glutathione reductase, total glutathione, and maloniladdehyde at admission and after seven days of hospitalization at the Intensive Care Unit (ICU) in 20 patients older than 18 years on parenteral nutrition therapy. Results: The group of patients receiving parenteral nutrition with glutamine supplementation had significant increases in total glutathione (42.35 ± 13 vs 55.29 ±12 μmol/l; p < 0.05) and the enzymatic activity of glutathione peroxidasa (470 ± 195 vs 705 ± 214 μmol/l; p < 0.05) within one week of nutritional therapy, where as the group on conventional parenteral nutrition did not show significant changes of any of the parameters studied(p > 0.05). However, both mortality and ICU stay were not different between the study group, whereas the severity (assessed by the SOFA score) was lower in the group of patients receiving glutamine (SOFA 5 ± 2 vs 8 ±1.8; p < 0.05).Conclusions: Glutamine intake in critically ill patients improves the antioxidant defenses, which leads to lower lipid peroxidation and lower morbidity during admission at the ICU

Long-term combined administration of quercetin and daidzein inhibits quercetin-induced suppression of glutathione antioxidant defenses.

In this study, we investigated the effects of long-term administration of quercetin with or without daidzein on glutathione and the enzymes involved in its metabolism in rat liver in vivo. Male Sprague-Dawley rats were divided randomly into four groups and given oral quercetin (20 mg/day) and daidzein (20 mg/day) alone or in combination, or vehicle alone for six weeks. The serum and liver alpha-tocopherol concentrations were significantly increased following administration of quercetin and daidzein alone or in combination. Glutathione concentration and glutathione reductase activity was significantly (p < 0.05) decreased with quercetin treatment, while no such effect was observed with daidzein treatment. Interestingly, decrease in glutathione concentration and glutathione reductase activity by quercetin treatment was inhibited by combined administration of daidzein and quercetin. The malondialdehyde concentration was significantly decreased following administration of quercetin and daidzein alone or in combination. These results suggest that quercetin, but not daidzein, acts as a pro-oxidant agent by decreasing glutathione concentration and glutathione reductase activity. Interestingly, this pro-oxidant effect of quercetin was inhibited by the combined administration of quercetin and daidzein.

Impact of oral L-glutamine on glutathione, glutamine, and glutamate blood levels in volunteers.

OBJECTIVE: We investigated the effect of glutamine supplementation on plasma glutamine (Gln), glutamate (Glu), and whole-blood glutathione (GSH) concentrations in human volunteers. METHODS: Subjects first adapted to a standard diet with known intakes of protein, total GSH, cysteine, methionine, and total Glu (Glu values include Glu and Gln) for 3 d. Plasma Gln, Glu, and whole-blood GSH levels were then measured at 4-h intervals over 24 h. Supplemental oral Gln (0.3 g x kg(-1) x d(-1)) was ingested for 10 d and then 24-h plasma levels of Gln, Glu, and whole-blood GSH were measured. RESULTS: The plasma concentrations of Glu (116%; P = 0.006) and Gln (20%; P = 0.046) were significantly higher, whereas concentrations of GSH were significantly lower (37%; P = 0.00091) after oral Gln supplementation. CONCLUSION: Oral Gln increases Glu and Gln levels in plasma of healthy subjects but does not increase GSH red cell (whole-blood) levels. Thus, GSH biosynthesis and preservation of GHS stores in red blood cells may involve rate-limiting substrates other than Gln.

The systemic availability of oral glutathione.

When the plasma glutathione concentration is low, such as in patients with HIV infection, alcoholics, and patients with cirrhosis, increasing the availability of circulating glutathione by oral administration might be of therapeutic benefit. To assess the feasibility of supplementing oral glutathione we have determined the systemic availability of glutathione in 7 healthy volunteers. The basal concentrations of glutathione, cysteine, and glutamate in plasma were 6.2, 8.3, and 54 mumol.l-1 respectively. During the 270 min after the administration of glutathione in a dose of 0.15 mmol.kg-1 the concentrations of glutathione, cysteine, and glutamate in plasma did not increase significantly, suggesting that the systemic availability of glutathione is negligible in man. Because of hydrolysis of glutathione by intestinal and hepatic gamma-glutamyltransferase, dietary glutathione is not a major determinant of circulating glutathione, and it is not possible to increase circulating glutathione to a clinically beneficial extent by the oral administration of a single dose of 3 g of glutathione.

Glutathione levels and related enzyme activities in vitamin B-6-deficient rats fed a high methionine and low cystine diet.

We examined the change in glutathione metabolism in vitamin B-6-deficient rats. Vitamin B-6-deficient rats were fed a vitamin B-6-deficient diet containing 0.56% methionine and 0.075% cystine for 8 wk. Controls were fed an identical diet supplemented with 10 mg pyridoxine hydrochloride/kg diet. Glutathione concentrations in each organ examined were similar in control and vitamin B-6-deficient rats, and the values were comparably lower after intraperitoneal injection of diethylmaleate. However, buthionine sulfoximine caused a significantly greater decrease in glutathione levels in the liver and lungs of vitamin B-6-deficient rats relative to controls. Glutathione peroxidase activity in the liver of vitamin B-6-deficient rats was higher than in control animals; however, glutathione transferase activity in tissues other than liver of vitamin B-6-deficient rats was higher than in the controls. The activities of gamma-glutamyl-transferase in the liver and spleen of vitamin B-6-deficient rats were significantly lower than control values. The holoenzyme activities of cystathionine beta-synthase and cystathionine gamma-lyase in the liver of vitamin B-6-deficient rats were markedly reduced. These findings indicate that although the activities of enzymes that synthesize cysteine from methionine were decreased by vitamin B-6 deficiency, the level of synthesis and supply of cysteine in vitamin B-6-deficient rats were sufficient to maintain the same glutathione level as in controls, and that glutathione utilization in the liver was accelerated by vitamin B-6 deficiency.

High-dose intravenous glutathione in man. Pharmacokinetics and effects on cyst(e)ine in plasma and urine.

Parenteral glutathione has therapeutic potential for targeted delivery of cysteine equivalents. Thus, high doses of reduced glutathione (GSH) protect from the nephrotoxic and urotoxic effects of cisplatinum and oxazaphosphorines. In order to elucidate the underlying mechanisms the kinetics and the effect of glutathione on plasma and urine sulphydryls were studied in 10 healthy volunteers. Following the intravenous infusion of 2 g m-2 of glutathione the concentration of total glutathione in plasma increased from 17.5 +/- 13.4 mumol l-1 (mean +/- SD) to 823 +/- 326 mumol l-1. The volume of distribution of exogenous glutathione was 176 +/- 107 ml kg-1 and the elimination rate constant was 0.063 +/- 0.027 min-1 corresponding to a half-life of 14.1 +/- 9.2 min. Cysteine in plasma increased from 8.9 +/- 3.5 mumol l-1 to 114 +/- 45 mumol l-1 after the infusion. In spite of the increase in cysteine, the plasma concentration of total cyst(e)ine (i.e. cysteine, cystine, and mixed disulphides) decreased, suggesting an increased uptake of cysteine from plasma into cells. Urinary excretion of glutathione and of cyst(e)ine was increased 300-fold and 10-fold, respectively, in the 90 min following the infusion. The present data suggest that the concentration of sulphydryls in the urinary tract and, more importantly, the intracellular availability of cysteine increase markedly following parenteral glutathione. The high intracellular concentration of cysteine may protect against cisplatinum and oxazaphosphorine toxicity either directly or indirectly by supporting the synthesis of glutathione.