Seleno-organic Compound Research Articles

Treating atopic-dermatitis-like skin lesions in mice with gelatin-alginate films containing 1,4-anhydro-4-seleno-d-talitol (SeTal)

New compounds and pharmacological strategies offer alternatives for treating chronic skin diseases, such as atopic dermatitis (AD). Here, we investigated the incorporation of 1,4-anhydro-4-seleno-d-talitol (SeTal), a bioactive seleno-organic compound, in gelatin and alginate (Gel-Alg) polymeric films as a strategy for improving the treatment and attenuation of AD-like symptoms in a mice model. Hydrocortisone (HC) or vitamin C (VitC) were incorporated with SeTal in the Gel-Alg films, and their synergy was investigated. All the prepared film samples were able to retain and release SeTal in a controlled manner. In addition, appreciable film handling facilitates SeTal administration. A series of in-vivo/ex-vivo experiments were performed using mice sensitized with dinitrochlorobenzene (DNCB), which induces AD-like symptoms. Long-term topical application of the loaded Gel-Alg films attenuated disease symptoms and pruritus, with suppression of the levels of inflammatory markers, oxidative damage, and the skin lesions associated with AD. Moreover, the loaded films showed superior efficiency in attenuating the analyzed symptoms when compared to hydrocortisone (HC) cream, a traditional AD-treatment, and decreased the inherent drawbacks of this compound. In short, incorporating SeTal (by itself or with HC or VitC) in biopolymeric films provides a promising alternative for the long-term treatment of AD-type skin diseases.

Ebselen suitably interacts with the potential SARS-CoV-2 targets: an in-silico approach

Ebselen (SPI-1005) is an active selenoorganic compound that can be found potential inhibitory activity against different types of viral infections such as zika virus, influenza A virus, HCV, and HIV-1; and also be found to exhibit promising antiviral activity against SARS-CoV-2 in cell-based assays but its particular target action against specific non-structural and structural proteins of SARS-CoV-2 is unclear to date. The purpose of this study is to evaluate the anti-SARS-CoV-2 efficacy of Ebselen along with the determination of the specific target among the 12 most common target proteins of SARS-CoV-2. AutoDock Vina in PyRx platform was used for docking analysis against the 12 selected SARS-CoV-2 encoded drug targets. ADME profiling was examined by using SwissADME online server. The stability of binding mode in the target active sites was evaluated using molecular dynamics (MD) simulation studies through NAMD and Desmond package software application. In this docking study, we recognized that Ebselen possesses the highest affinity to N protein (C domain) (PDB ID: 6YUN) and PLpro (PDB ID: 6WUU) among the selected SARS-CoV-2 targets showing −7.4 kcal/mol binding energy. The stability of Ebselen-6YUN and Ebselen-6WUU was determined by a 100 ns trajectory of all-atom molecular dynamics simulation. Structural conformation of these two complexes displayed stable root mean square deviation (RMSD), while root mean square fluctuations (RMSF) were also found to be consistent. This molecular docking study may propose the efficiency of Ebselen against SARS-CoV-2 to a significant extent which makes it a candidature of COVID-19 treatment.

A New Tellurium- and Selenoorganic Compound as an Inhibitor of Acetylcholinesterase in Brain.

We studied the effect of a new cyanine dye containing selenium and tellurium on acetylcholinesterase activity in synaptic membrane in rat brain. The cyanine dye dose-dependently inhibits activity of this enzyme, and the concentration of half-maximal inhibition of acetylcholinesterase activity was 20.46 μM. The cyanine dye instantly inhibits the enzyme; the degree of inhibition depends on acetylthiocholine concentration: the lower is acetylthiocholine concentration, the higher is the degree of inhibition. On the Lineweaver-Burk plot, the concentration dependence curves of acetylcholinesterase with and without cyanine dye intersect in one point on the abscissa axis. In this case, the cyanine dye reduces the maximum inhibition rate (Vmax) and does not affect Michaelis constant (Km). The calculated inhibition constant Ki for the cyanine dye is 7.74 μM. Thus, the cyanine dye is a non-competitive inhibitor of acetylcholinesterase.

Repeated administration of a selenium-containing indolyl compound attenuates behavioural alterations by streptozotocin through modulation of oxidative stress in mice

Although the pathophysiology of major depression disorder (MDD) is still poorly understood, mounting evidence suggests that the brains of depressed patients are under oxidative stress, leading to depressive symptoms that may include anxiety and cognitive impairment. This study aimed to investigate if the seleno-organic compound 1-methyl-3-(phenylselanyl)-1H-indole (MFSeI) reverses the depression- and anxiogenic-like behaviour, cognitive impairment and oxidative stress induced by the intra-cerebroventricular injection of streptozotocin (STZ; 0.2 mg/4 μl/per mouse) in Swiss male mice. Twenty-four hours after the STZ injection, mice were treated with MFSeI (10 mg/kg, intra-gastrically), or vehicle solution, once daily for seven days. The behavioural tests were performed 30 min after the final MFSeI administration, followed by euthanasia and collection of the cerebral cortex and hippocampus. Administration of MFSeI reversed the depression- and anxiogenic-like behaviour and cognitive impairment induced by STZ, in mice. Neurochemical analyses demonstrated that MFSeI reversed the STZ-increased levels of reactive species, nitrite, lipid peroxidation and acetylcholinesterase activity in the cerebral cortex and hippocampus of mice. Moreover, a single administration of MFSeI (300 mg/kg, intra-gastrically) did not cause acute toxicity in Swiss male mice. Altogether, our data suggest that MFSeI exhibits antidepressant- and anxiolytic-like effects and improves the cognition of STZ-treated mice, without any toxicity.

Depression- and anxiogenic-like behaviors induced by lipopolysaccharide in mice are reversed by a selenium-containing indolyl compound: Behavioral, neurochemical and computational insights involving the serotonergic system

Major depression and anxiety are highly incapacitating psychiatric disorders often present simultaneously, and the causal relationship between these disorders and inflammation are under extensive investigation. The treatment for this comorbidity still relies on drugs acting on the serotonergic neurotransmission, but the modulation of immune-inflammatory pathways has attained an increasing interest in the drug discovery. We have previously demonstrated that the selenoorganic compound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) possess antioxidant, anti-inflammatory, antinociceptive and antidepressant-like effect in mice. Considering these pharmacological properties and the structural similarities between tryptophan, serotonin and CMI, the aim of the present study was to investigate whether CMI ameliorates depression- and anxiogenic-like behavior induced by lipopolysaccharide (LPS) in Swiss male mice by modulating the serotonergic system and reducing neuroinflammation. The administration of CMI (1 mg/kg, i.g) reversed the behavioral deficits induced by LPS (0.83 mg/kg, i.p) in the tail suspension test, splash test and elevated plus maze. The pre-treatment of mice with WAY100635 (5-HT1A receptor antagonist), ketanserin (5-HT2A/2C receptor antagonist) and ondansetron (5-HT3 receptor antagonist) prevented the antidepressant- and anxiolytic-like effect elicited by CMI treatment after the LPS challenge. The administration of CMI also counteracted the increased expression of pro-inflammatory cytokines and indoleamine 2,3-dioxygenase (IDO) in the prefrontal cortex and hippocampus of mice challenged with LPS. Additionally, a molecular docking analysis showed that CMI binds to the active site of the serotonin transporter and IDO. These findings suggest that CMI reversed behavioral and biochemical alterations in the depression-anxiety comorbidity induced by LPS, possibly by modulation of neuroinflammatory mediators and the serotonergic system.

A multifunctional compound ebselen reverses memory impairment, apoptosis and oxidative stress in a mouse model of sporadic Alzheimer's disease

Alzheimer 's disease (AD) is characterized by progressive cognitive decline including memory impairment, cortical dysfunction, and neuropsychiatric disturbances. The drug discovery to treat AD consists to develop compounds able to act in multiple molecular targets involved in the pathogenesis of the disease and the repositioning of old drugs for new application. This way, the intracerebroventricular (icv) injection of streptozotocin (STZ) has been used as a metabolic model of sporadic AD. The aim of the present study was to investigate whether ebselen (1–10 mg/kg), a multifunctional selenoorganic compound, ameliorates memory impairment, hippocampal oxidative stress, apoptosis and cell proliferation in a mouse model of sporadic AD induced by icv STZ (3 mg/kg, 1 μl/min). The administration of ebselen (10 mg/kg, i.p.) reversed memory impairment and hippocampal oxidative stress, by increasing the activities of antioxidant enzymes and the level of a non-enzymatic antioxidant defense, in Swiss mice administered with icv STZ. The anti-apoptotic property of ebselen was demonstrated by its effectiveness against the increase in the ratios of Bax/Bcl-2, cleaved PARP/PARP and the cleaved caspase-3 levels in the hippocampus of icv STZ mice. Although ebselen reversed memory impairment, it was ineffective against the reduction in the number of BrdU positive cells induced by icv STZ. In conclusion, the multifunctional selenoorganic compound ebselen was effective to reverse memory impairment, hippocampal oxidative stress and apoptosis in a mouse model of sporadic AD induced by icv STZ.

Can ebselen prevent cisplatin-induced ovarian damage?

The occurrence of ovarian damage is a major shortcoming in treating tumors with cisplatin (CP). The present study investigates the beneficial effects of ebselen-a seleno-organic compound with antioxidant and antiinflammatory properties-vis-à-vis CP-induced ovarian damage. Twenty-eight adult female rats were divided into four study groups. Group 1 received no treatment. The rats in Groups 2, 3, and 4 were intraperitoneally administered CP (2mg/kg/day) twice per week, for 5weeks. Those in Group 2 received 0.3ml saline (0.9% NaCl) intraperitoneally 60min before each CP treatment, while those in Group 3 received 0.2ml dimethyl sulfoxide (DMSO) and 0.3ml saline intraperitoneally 60min before each CP treatment. The rats in Group 4 were pretreated with an intraperitoneal injection of 15mg/kg/day ebselen 60min before each CP treatment. Ovarian tissue malondialdehyde (MDA), total nitric oxide (NOx), glutathione (GSH), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), and catalase levels, as well as histopathological damage scores (HDSs) and serum antimullerian hormone (AMH) levels, were assessed. Cu/Zn-SOD and GSH levels were significantly higher, and MDA and NOx levels significantly lower, in Group 4 than in Groups 2 and 3. Pretreatment with ebselen significantly improved serum AMH levels, relative to Groups 2 and 3. Additionally, HDS values were significantly lower in Group 4 than in Groups 2 and 3. Our results from using an experimental rat model of CP chemotherapy suggest that ebselen use may ameliorate ovarian damage by preventing oxidative injury.

Ebselen suppresses inflammation induced by Helicobacterpylori lipopolysaccharide via the p38 mitogen-activated protein kinase signaling pathway.

Ebselen is a seleno-organic compound that has been demonstrated to have antioxidant and anti-inflammatory properties. A previous study determined that ebselen inhibits airway inflammation induced by inhalational lipopolysaccharide (LPS), however, the underlying molecular mechanism remains to be elucidated. The present study investigated the effect of ebselen on the glutathione peroxidase (GPX)‑reactive oxygen species (ROS) pathway and interleukin‑8 (IL‑8) expression induced by Helicobacterpylori LPS in gastric cancer (GC) cells. Cells were treated with 200ng/ml H. pylori‑LPS in the presence or absence of ebselen for various durations and concentrations (µmol/l). The expression of toll‑like receptor 4 (TLR4), GPX2, GPX4, p38 mitogen‑activated protein kinase (p38 MAPK), phosphorylated‑p38 MAPK, ROS production and IL‑8 expression were detected with western blotting or ELISA. The present study revealed that TLR4 expression was upregulated; however, GPX2 and GPX4 expression was reduced following treatment with H. pylori LPS, which led to increased ROS production, subsequently altering the IL‑8 expression level in GC cells. Additionally, it was determined that ebselen prevented the reduction in GPX2/4 levels induced by H. pylori LPS, however, TLR4 expression was not affected. Ebselen may also block the expression of IL‑8 by inhibiting phosphorylation of p38 MAPK. These data suggest ebselen may inhibit ROS production triggered by H. pylori LPS treatment via GPX2/4 instead of TLR4 signaling and reduce phosphorylation of p38 MAPK, resulting in altered production of IL‑8. Ebselen may, therefore, be a potential therapeutic agent to mediate H. pylori LPS-induced cell damage.

No-carrier-added labeling of the neuroprotective Ebselen with selenium-73 and selenium-75.

Selenium-73 is a positron emitting non-standard radionuclide, which is suitable for positron emission tomography. A copper-catalyzed reaction allowed no-carrier-added labeling of the anti-inflammatory seleno-organic compound Ebselen with (73) Se and (75) Se under addition of sulfur carrier in a one-step reaction. The new authentically labeled radioselenium molecule is thus available for preclinical evaluation and positron emission tomography studies.

Redox pioneer: professor Helmut Sies.

Dr. Helmut Sies (MD, 1967) is recognized as a Redox Pioneer, because he authored five articles on oxidative stress, lycopene, and glutathione, each of which has been cited more than 1000 times, and coauthored an article on hydroperoxide metabolism in mammalian systems cited more than 5000 times (Google Scholar). He obtained preclinical education at the University of Tübingen and the University of Munich, clinical training at Munich (MD, 1967) and Paris, and completed Habilitation at Munich (Physiological Chemistry and Physical Biochemistry, 1972). In early research, he first identified hydrogen peroxide (H2O2) as a normal aerobic metabolite and devised a method to quantify H2O2 concentration and turnover in cells. He quantified central redox systems for energy metabolism (NAD, NADP systems) and antioxidant GSH in subcellular compartments. He first described ebselen, a selenoorganic compound, as a glutathione peroxidase mimic. He contributed a fundamental discovery to the physiology of GSH, selenium nutrition, singlet oxygen biochemistry, and health benefits of dietary lycopene and cocoa flavonoids. He has published more than 600 articles, 134 of which are cited at least 100 times, and edited 28 books. His h-index is 115. During the last quarter of the 20th century and well into the 21st, he has served as a scout, trailblazer, and pioneer in redox biology. His formulation of the concept of oxidative stress stimulated and guided research in oxidants and antioxidants; his pioneering research on carotenoids and flavonoids informed nutritional strategies against cancer, cardiovascular disease, and aging; and his quantitative approach to redox biochemistry provides a foundation for modern redox systems biology. Helmut Sies is a true Redox Pioneer.

The seleno-organic compound ebselen impairs mitochondrial physiology and induces cell death in AR42J cells

Ebselen is a seleno-organic compound that causes cell death in several cancer cell types. The mechanisms underlying its deleterious effects have not been fully elucidated. In this study, the effects of ebselen (1μM–40μM) on AR42J tumor cells have been examined. Cell viability was studied using AlamarBlue® test. Cell cycle phase determination was carried out by flow cytometry. Changes in intracellular free Ca2+ concentration were followed by fluorimetry analysis of fura-2-loaded cells. Distribution of mitochondria, mitochondrial Ca2+ concentration and mitochondrial membrane potential were monitored by confocal microscopy of cells loaded with Mitotracker Green™ FM, rhod-2 or TMRM respectively. Caspase-3 activity was calculated following the luorogenic substrate ACDEVD-AMC signal with a spectrofluorimeter. Results show that cell viability decreased in the presence of ebselen. An increase in the number of cells in the S-phase of the cell cycle was observed. Ebselen induced a concentration-dependent mobilization of Ca2+ from agonist- and thapsigargin-sensitive Ca2+ pools. Ebselen induced also a transient increase in mitochondrial Ca2+ concentration, a progressive decrease of the mitochondrial membrane potential and a disruption of the mitochondrial network. Finally, a concentration-dependent increase in caspase-3 activity was detected. We conclude that ebselen exerts deleterious actions on the cells that involve the impairment of mitochondrial physiology and the activation of caspase-3-mediated apoptotic pathway.

Ebselen induces reactive oxygen species (ROS)-mediated cytotoxicity in Saccharomyces cerevisiae with inhibition of glutamate dehydrogenase being a target

Ebselen is a synthetic, lipid-soluble seleno-organic compound. The high electrophilicity of ebselen enables it to react with multiple cysteine residues of various proteins. Despite extensive research on ebselen, its target molecules and mechanism of action remains less understood. We performed biochemical as well as in vivo experiments employing budding yeast as a model organism to understand the mode of action of ebselen. The growth curve analysis and FACS (florescence activated cell sorting) assays revealed that ebselen exerts growth inhibitory effects on yeast cells by causing a delay in cell cycle progression. We observed that ebselen exposure causes an increase in intracellular ROS levels and mitochondrial membrane potential, and that these effects were reversed by addition of antioxidants such as reduced glutathione (GSH) or N-acetyl-l-cysteine (NAC). Interestingly, a significant increase in ROS levels was noticed in gdh3-deleted cells compared to wild-type cells. Furthermore, we showed that ebselen inhibits GDH function by interacting with its cysteine residues, leading to the formation of inactive hexameric GDH. Two-dimensional gel electrophoresis revealed protein targets of ebselen including CPR1, the yeast homolog of Cyclophilin A. Additionally, ebselen treatment leads to the inhibition of yeast sporulation. These results indicate a novel direct connection between ebselen and redox homeostasis.

Induction of Apoptosis in Human Multiple Myeloma Cell Lines by Ebselen via Enhancing the Endogenous Reactive Oxygen Species Production

Ebselen a selenoorganic compound showing glutathione peroxidase like activity is an anti-inflammatory and antioxidative agent. Its cytoprotective activity has been investigated in recent years. However, experimental evidence also shows that ebselen causes cell death in several cancer cell types whose mechanism has not yet been elucidated. In this study, we examined the effect of ebselen on multiple myeloma (MM) cell lines in vitro. The results showed that ebselen significantly enhanced the production of reactive oxygen species (ROS) accompanied by cell viability decrease and apoptosis rate increase. Further studies revealed that ebselen can induce Bax redistribution from the cytosol to mitochondria leading to mitochondrial membrane potential ΔΨm changes and cytochrome C release from the mitochondria to cytosol. Furtherly, we found that exogenous addition of N-acetyl cysteine (NAC) completely diminished the cell damage induced by ebselen. This result suggests that relatively high concentration of ebselen can induce MM cells apoptosis in culture by enhancing the production of endogenous ROS and triggering mitochondria mediated apoptotic pathway.

GW24-e3722 Ebselen protected myocardium from overtraining-induced oxidative damage in rats

ObjectivesGeneration of large amount of ROS is considered to be a causative factor of structure damage or apoptotic in the myocardium and to be involved in the progress of exercise...

Oxidant balance in brain of rats receiving different compounds of selenium

The influence of two organic selenocompounds and sodium selenite on oxidant processes in rat brain tissue was investigated. The study was performed on male Wistar rats. The animals were divided into four groups: I—control; II—administered with sodium selenite; III—provided with selenoorganic compound A of chain structure 4-(o-tolyl-)-selenosemicarbazide of 2-chlorobenzoic acid and IV—provided with selenoorganic compound B of ring structure 3-(2-chlorobenzoylamino-)-2-(o-tolylimino-)-4-methyl-4-selenazoline. Rats were treated by stomach tube at a dose of 5 × 10−4 mg of selenium/g of b.w. once a day for a period of 10 days. In brain homogenates total antioxidant status (TAS), activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx), concentrations of ascorbic acid (AA) and reduced glutathione (GSH) as well as concentration of malonyl dialdehyde (MDA) were determined. TAS was insignificantly diminished in all selenium-supplemented groups versus control. SOD was not significantly influenced by administration of selenium. GPx was markedly decreased in group III versus control, whereas increased in group IV versus control and group III. Selenosemicarbazide depleted AA in well-marked way versus group II. GSH was significantly depressed in group III versus both control and group II and diminished in group IV versus group II. MDA was significantly decreased in group III versus both control and group II, whereas in group IV increased versus group III. As selenazoline A did not decrease elements of antioxidant barrier and increased GPx activity, it seems to be a promising agent for future studies concerning its possible application as a selenium supplement.

Ebselen Alters Mitochondrial Physiology and Reduces Viability of Rat Hippocampal Astrocytes

The seleno-organic compound and radical scavenger ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) have been extensively employed as an anti-inflammatory and neuroprotective compound. However, its glutathione peroxidase activity at the expense of cellular thiols groups could underlie certain deleterious actions of the compound on cell physiology. In this study, we have analyzed the effect of ebselen on rat hippocampal astrocytes in culture. Cellular viability, the intracellular free-Ca(2+) concentration ([Ca(2+)]c), the mitochondrial free-Ca(2+) concentration ([Ca(2+)]m), and mitochondrial membrane potential (ψm) were analyzed. The caspase-3 activity was also assayed. Our results show that cell viability was reduced by treatment of cells with ebselen, depending on the concentration employed. In the presence of ebselen, we observed an initial transient increase in [Ca(2+)]c that was then followed by a progressive increase to an elevated plateau. We also observed a transient increase in [Ca(2+)]m in the presence of ebselen that returned toward a value over the prestimulation level. The compound induced depolarization of ψm and altered the permeability of the mitochondrial membrane. Additionally, a disruption of the mitochondrial network was observed. Finally, we did not detect changes in caspase-3 activation in response to ebselen treatment. Collectively, these data support the likelihood of ebselen, depending on the concentration employed, reduces viability of rat hippocampal astrocytes via its action on the mitochondrial activity. These may be early effects that do not involve caspase-3 activation. We conclude that, depending on the concentration used, ebselen might exert deleterious actions on astrocyte physiology that could compromise cell function.

Physicochemical and Biochemical Profiling of Diphenyl Diselenide

The objective of the present study was to evaluate the physicochemical and biochemical profiling of diphenyl diselenide (PhSe)₂, a selenoorganic compound with biological activity. Experimental protocols were established for chemical stability in isotonic phosphate buffer (PBS) pH 7.4 and in simulated gastric and intestinal fluids, biological stability (bovine serum albumin (BSA) and plasma), solubility in PBS pH 7.4, distribution coefficient (Log D) in octanol/PBS, and determination of free (PhSe)₂ concentrations in BSA and plasma by using liquid chromatography with ultraviolet detection and tandem mass spectrometry. (PhSe)₂ was found to be chemically stable and not susceptible to degradation in plasma. The aqueous solubility was 0.98 ± 0.072 μM and the Log D in octanol/PBS system was found to be 3.13. The percentage of unbound fractions of (PhSe)₂ obtained by equilibrium dialysis from BSA and plasma incubated with 100 μM (PhSe)₂ were 0.69 ± 0.12 and 0.44 ± 0.09 %, respectively. The findings indicated that (PhSe)₂ presents chemical and biological stability. Though, the compound showed low aqueous solubility, high Log D value and high binding to plasmatic protein. These data contribute to the knowledge of the toxicokinetic properties of (PhSe)₂ and further explain its low bioavailability in experimental models.

RETRACTED: Seleno-cyclodextrin sensitises human breast cancer cells to TRAIL-induced apoptosis through DR5 induction and NF-κB suppression

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/policies/article-withdrawal). This article has been retracted at the request of This article has been retracted at the request of the authors and the Editor-in-Chief. The authors contacted the Editors of the European Journal of Cancer regarding oversights or labelling errors introduced in Fig. 2 and Fig.7 during data processing. The authors provided the raw data, however the Editors conclude that the raw data management cannot be relied upon and the article needs to be retracted.

High-throughput screen identifies novel inhibitors of cancer biomarker α-methylacyl coenzyme A racemase (AMACR/P504S).

α-methylacyl coenzyme A racemase (AMACR) is a metabolic enzyme whose overexpression has been shown to be a diagnostic indicator of prostatic adenocarcinoma and other solid tumors. Here, we confirm that attenuation of AMACR expression diminishes the growth of prostate cancer cell lines by using stably expressed short-hairpin RNA constructs. This observation strongly suggests that the AMACR enzyme may be a target for therapeutic inhibition in prostate cancer. To this end, we report here a novel assay capable of screening libraries of diverse small molecules for inhibitors of AMACR activity. This assay facilitated the screening of approximately 5,000 unique compounds and the discovery of 7 distinct chemical entities capable of inhibiting AMACR at low micromolar concentrations. The most potent inhibitor discovered is the seleno-organic compound ebselen oxide [inhibitory concentration (IC(50)): 0.80 μmol/L]. The parent compound, ebselen (IC(50): 2.79 μmol/L), is a covalent inactivator of AMACR (K(I)((inact)): 24 μmol/L). Two of the AMACR inhibitors are selectively toxic to prostate cancer cell lines (LAPC4/LNCaP/PC3) that express AMACR compared to a normal prostate fibroblast cell line (WPMY1) that does not express the protein. This report shows the first high-throughput screen for the discovery of novel AMACR inhibitors, characterizes the first nonsubstrate-based inhibitors, and validates that AMACR is a viable chemotherapeutic target in vitro.

Susceptibility of mice to bacterial and fungal infections after intragastric administration of ebselen.

The seleno-organic compound ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) has anti-inflammatory activity and exhibits glutathione peroxidase-like activity in-vitro. Ebselen inhibited candidacidal activity over the same range of concentrations as it inhibited the production of microbicidal H2O2 by human neutrophils and macrophage-like cells. Therefore, the long-term administration of ebselen might be expected to induce an immunocompromised state in the host. To examine such a possibility, mice (5-weeks-old ddY, male) were given daily intragastric doses of 0, 10 or 100 mg/kg-1 ebselen for 21 days and then infected intraperitoneally with Candida albicans (10(8) cells/mouse), Pseudomonas aeruginosa (1.5 x 10(7) cells/mouse) or methicillin-resistant Staphylococcus aureus (5 x 10(8) cells/mouse). Ebselen at none of the tested doses affected the increase in body weight of mice during administration of the drug. No evidence was obtained that mice became more susceptible to the various microorganisms after the administration of ebselen at any tested dose.