ammonium-trichloro(dioxoethylene-o-o--)tellurate and Disease-Models--Animal

Topics: Adjuvants, Immunologic; Androgens; Animals; Antibodies, Anti-Idiotypic; Antiphospholipid Syndrome; Aspirin; Bone Marrow Transplantation; Bromocriptine; Cyclosporine; Disease Models, Animal; Estrogens; Ethylenes; Heparin; Hydroxyquinolines; Immunoglobulins, Intravenous; Immunosuppression Therapy; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lymphocyte Transfusion; Mice; T-Lymphocytes, Regulatory

Topics: Acquired Immunodeficiency Syndrome; Animals; Biological Factors; Clinical Trials as Topic; Colony-Stimulating Factors; Cytokines; Disease Models, Animal; Disease Susceptibility; Ethylenes; Genes, Viral; Haplorhini; Hematopoietic Stem Cells; HIV; HIV Antibodies; HIV Antigens; Humans; Mice; Receptors, HIV; Receptors, Virus; Recombinant Proteins; Retroviridae Infections; Ribavirin; Simian Immunodeficiency Virus; T-Lymphocytes; Viral Proteins

Topics: Acquired Immunodeficiency Syndrome; Animals; Biological Factors; Clinical Trials as Topic; Colony-Stimulating Factors; Cytokines; Disease Models, Animal; Disease Susceptibility; Ethylenes; Genes, Viral; Haplorhini; Hematopoietic Stem Cells; HIV; HIV Antibodies; HIV Antigens; Humans; Mice; Receptors, HIV; Receptors, Virus; Recombinant Proteins; Retroviridae Infections; Ribavirin; Simian Immunodeficiency Virus; T-Lymphocytes; Viral Proteins

Major depressive disorder (MDD) is a leading cause of morbidity, and the fourth leading cause of disease burden worldwide. While MDD is a treatable condition for many individuals, others suffer from treatment-resistant depression (TRD). Here, we suggest the immunomodulatory compound AS101 as novel therapeutic alternative. We previously showed in animal models that AS101 reduces anxiety-like behavior and elevates levels of the brain-derived neurotrophic factor (BDNF), a protein that has a key role in the pathophysiology of depression. To explore the potential antidepressant properties of AS101, we used the extensively characterized chronic mild stress (CMS) model, and the depressive rat line (DRL Finally, in Exp. 3 to attain insight into the mechanism we knocked down BDNF in the hippocampus, and demonstrated that the beneficial effect of AS101 was abrogated. Together with the previously established safety profile of AS101 in humans, these results may represent the first step towards the development of a novel treatment option for MDD and TRD.

Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Dentate Gyrus; Depressive Disorder; Disease Models, Animal; Drug Evaluation, Preclinical; Ethylenes; Exploratory Behavior; Gene Knockdown Techniques; Hippocampus; Immunologic Factors; Male; Motor Activity; Open Field Test; Rats; Rats, Sprague-Dawley; RNA Interference; RNA, Small Interfering; Stress, Physiological; Sucrose; Swimming

AS101 is an organotellurium compound with multifaceted immunoregulatory properties that is remarkable for its lack of toxicity. We tested the therapeutic effect of AS101 in experimental autoimmune uveitis (EAU), a model for human autoimmune uveitis. Unexpectedly, treatment with AS101 elicited Treg generation in vivo in otherwise unmanipulated mice. Mice immunized for EAU with the retinal antigen IRBP and treated with AS101 developed attenuated disease, as did AS101-treated recipients of retina-specific T cells activated in vitro. In both settings, eye-infiltrating effector T cells were decreased, whereas regulatory T (Treg) cells in the spleen were increased. Mechanistic studies in vitro revealed that AS101 restricted polarization of retina-specific T cells towards Th1 or Th17 lineage by repressing activation of their respective lineage-specific transcription factors and downstream signals. Retina-specific T cells polarized in vitro towards Th1 or Th17 in the presence of AS101 had impaired ability to induce EAU in naïve recipients. Finally, AS101 promoted differentiation of retina-specific T cells to Tregs in vitro independently of TGF-β. We conclude that AS101 modulates autoimmune T cells by inhibiting acquisition and expression of effector function and by promoting Treg generation, and suggest that AS101 could be useful as a therapeutic approach for autoimmune uveitis.

Topics: Animals; Autoimmune Diseases; Disease Models, Animal; Ethylenes; Mice; Mice, Transgenic; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells; Uveitis

In an endeavor to search for affordable and safer therapeutics against debilitating visceral leishmaniasis, we examined antileishmanial potential of ammonium trichloro [1,2-ethanediolato-O,O']-tellurate (AS101); a tellurium based non toxic immunomodulator. AS101 showed significant in vitro efficacy against both Leishmania donovani promastigotes and amastigotes at sub-micromolar concentrations. AS101 could also completely eliminate organ parasite load from L. donovani infected Balb/c mice along with significant efficacy against infected hamsters (˃93% inhibition). Analyzing mechanistic details revealed that the double edged AS101 could directly induce apoptosis in promastigotes along with indirectly activating host by reversing T-cell anergy to protective Th1 mode, increased ROS generation and anti-leishmanial IgG production. AS101 could inhibit IL-10/STAT3 pathway in L. donovani infected macrophages via blocking α4β7 integrin dependent PI3K/Akt signaling and activate host MAPKs and NF-κB for Th1 response. In silico docking and biochemical assays revealed AS101's affinity to form thiol bond with cysteine residues of trypanothione reductase in Leishmania promastigotes leading to its inactivation and inducing ROS-mediated apoptosis of the parasite via increased Ca

Topics: Animals; Cells, Cultured; Cricetinae; Disease Models, Animal; Ethylenes; Female; Host-Parasite Interactions; Integrins; Leishmania donovani; Leishmaniasis, Visceral; Male; Mice; Mice, Inbred BALB C; NADH, NADPH Oxidoreductases; Oxidation-Reduction; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction

Ammonium trichloro (dioxoethylene-O,O') tellurate (AS101) is a synthetic organotellurium compound with potent immunomodulatory and neuroprotective properties shown to inhibit the function of integrin αvβ3, a presynaptic cell-surface-adhesion receptor. As partial deletion of αvβ3 downregulated reuptake of serotonin by the serotonin transporter, we hypothesized that AS101 may influence pathways regulating anxiety. AS101 was tested in the modulation of anxiety-like behavior using the selectively bred Submissive (Sub) mouse strain that develop anxiety-like behavior in response to an i.p. injection. Mice were treated daily with AS101 (i.p., 125 or 200 μg/kg) or vehicle for 3 weeks, after which their anxiety-like behavior was measured in the elevated plus maze. Animals were then culled for the measurement of serum corticosterone levels by ELISA and hippocampal expression of brain-derived neurotrophic factor (BDNF) by RT-PCR. Chronic administration of AS101 significantly reduced anxiety-like behavior of Sub mice in the elevated plus maze, according to both time spent and entries to open arms, relative to vehicle-treated controls. AS101 also markedly reduced serum corticosterone levels of the treated mice and increased their hippocampal BDNF expression. Anxiolytic-like effects of AS101 may be attributed to the modulation of the regulatory influence integrin of αvβ3 upon the serotonin transporter, suggesting a multifaceted mechanism by which AS101 buffers the hypothalamic-pituitary-adrenal axis response to injection stress, enabling recovery of hippocampal BDNF expression and anxiety-like behavior in Sub mice. Further studies should advance the potential of AS101 in the context of anxiety-related disorders.

Topics: Ammonium Compounds; Animals; Anxiety; Brain-Derived Neurotrophic Factor; Corticosterone; Disease Models, Animal; Ethylenes; Hypothalamo-Hypophyseal System; Immunomodulation; Integrin alphaVbeta3; Mice; Neuroprotective Agents; Pituitary-Adrenal System; Tellurium

We reported that AS101 (organotellurium compound, trichloro(dioxoethylene-O,O') tellurate) inhibited the differentiation of Th17 cells and reduced the production of IL-17 and GM-CSF. In addition, AS101 promoted the production of IL-2 in activated T cells. Flow cytometric analysis showed that AS101 inhibited Th17 cell proliferation. AS101 blocked the activation of transcriptional factor NFAT, Stat3, and RORγt, and increased activation of Erk1/2, suggesting a mechanism of action of AS101. We further demonstrated that AS101 was effective in amelioration of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Finally, by real-time PCR analysis we showed that AS101 reduces the IL-17, IFN-γ, GM-CSF, and IL-6 mRNA expression in inflammatory cells of spinal cords. Additionally, flow cytometry analysis also indicated that the CD4+ T cells and IL-17 and GM-CSF-producing cells were reduced in the spinal cords of AS101 treated mice compared to those treated with PBS.

Topics: Animals; CD4-Positive T-Lymphocytes; Cell Polarity; Cell Proliferation; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Ethylenes; Female; Freund's Adjuvant; Immunologic Factors; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Oncogene Protein v-akt; Peptide Fragments; Signal Transduction; Spinal Cord; Th17 Cells

The histone deacetylase, SIRT1, plays a major role in glucose regulation and lipid metabolism. Ammonium Trichloro (dioxoethylene-o,o') Tellurate, AS101, is a potent in vitro and in vivo immunomodulator, with several potential therapeutic applications. AS101 administration resulted in upregulation of SIRT1 protein expression and activity. These effects were associated with decreased levels of serum insulin like growth factor-1 (IGF-1) and of insulin. The properties of AS101 prompted us to investigate its potential therapeutic role in rats with type 2 diabetes (T2D). T2D was induced by a high fat diet combined with a low dose of Streptozotocin (STZ). Treatment with AS101 before manifestation of hyperglycemia, resulted in increased insulin sensitivity, and decreased blood glucose levels, and prevented symptoms of diabetes including defective glucose clearance, fatty liver, and abnormal distribution of insulin-producing beta cells in the pancreas. Treatment after disease emergence resulted in partial restoration of normal glucose homeostasis. Diabetic rats showed a reduction in liver SIRT1 levels. In both treatment regimens the reduction in SIRT1 levels in the liver were blocked by AS101 consumption. Together, these findings demonstrate the therapeutic potential of AS101 for treating T2D, and for reversing impaired fat and glucose metabolism.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Ethylenes; Insulin Resistance; Insulin-Like Growth Factor I; Rats; Sirtuin 1; Tellurium

Fulminant hepatic failure is a dangerous condition, which occurs when large parts of the liver become damaged beyond repair, and the liver is no longer able to function. This syndrome is induced by inflammatory processes, resulting in acute liver failure. Recently, the organotellurium compound, trichloro(dioxoethylene-O,O(')) tellurate (AS101), has been found by our group to be able to directly inhibit caspases, due to its Te(IV)-thiol chemistry. The aim of this study was to examine the potential of AS101 as an anti-inflammatory and anti-apoptotic compound in vitro and in vivo following liver injury.. Propionibacterium acnes-primed LPS-induced liver injury was performed in Balb/c mice. ALT/AST, cytokines, caspase-1,-3 and-8 activities, and liver histology were assessed.. AS101 inhibited TNFalpha or anti-FAS-induced apoptotic processes in hepatocytes in vitro. A P. acnes+LPS in vivo liver injury model revealed lower serum ALT and AST and reduced necrosis and apoptosis in AS101-treated mice. IL-18 and IL-1beta reduced levels in AS101-treated mice were associated with caspase-1 activity inhibition. Our findings suggest IL-6, IL-17 and pSTAT3 as additional novel players in the pathogenicity of FHF. Inhibition of caspase-3, and-8 activities by AS101 treatment contributed to decreased hepatocyte death, resulting in increased survival.. We suggest that due to its interaction with key-target cysteine residues, AS101 mediates anti-inflammatory and anti-apoptotic effects in this FHF model, which may serve as a potent treatment for mitigation of hepatic damage.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Apoptosis; Aspartate Aminotransferases; Caspases; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cytokines; Disease Models, Animal; Ethylenes; Hepatitis; Hepatocytes; Lipopolysaccharides; Liver; Liver Failure; Mice; Mice, Inbred BALB C; Treatment Outcome

In Parkinson's disease (PD) dopaminergic neurons in the substantia nigra (SN) become dysfunctional and many ultimately die. We report that the tellurium immunomodulating compound ammonium trichloro(dioxoethylene-O,O'-)tellurate (AS101) protects dopaminergic neurons and improves motor function in animal models of PD. It is effective when administered systemically or by direct infusion into the brain. Multifunctional activities of AS101 were identified in this study. These were mainly due to the peculiar Tellur(IV)-thiol chemistry of the compound, which enabled the compound to interact with cysteine residues on both inflammatory and apoptotic caspases, resulting in their inactivation. Conversely, its interaction with a key cysteine residue on p21(ras), led to its activation, an obligatory activity for AS101-induced neuronal differentiation. Furthermore, AS101 inhibited IL-10, resulting in up-regulation of GDNF in the SN. This was associated with activation of the neuroprotective kinases Akt and mitogen-activated protein kinases, and up-regulation of the antiapoptotic protein Bcl-2. Inhibition of caspase-1 and caspase-3 activities were associated with decreased neuronal death and inhibition of IL-1beta. We suggest that, because multiple mechanisms are involved in the dysfunction and death of neurons in PD, use of a multifunctional compound, exerting antiapoptotic, anti-inflammatory, and neurotrophic-inducing capabilities may be potentially efficacious for the treatment of PD.

Topics: Adjuvants, Immunologic; Animals; Apoptosis; Cells, Cultured; Disease Models, Animal; Dopamine; Ethylenes; Inflammation; Male; Mice; Mice, Inbred C57BL; Motor Activity; Neurons; Parkinson Disease; Protective Agents; Rats; Rats, Sprague-Dawley; Tellurium

Ammonium trichloro(dioxoethylene-0,0') tellurate (AS101) is a non-toxic organotellurium compound with pleiotropic activities. It was recently shown to induce production of the neurotrophic factor glial cell line-derived neurotrophic factor and to rescue neuronal-like PC-12 cells from neurotrophic factor deprivation-induced apoptosis. In this study, we show that AS101 improves functional outcome and reduces brain damage in a mouse model of focal ischemic stroke. Both pre-stroke and post-stroke intraperitoneal treatments with AS101 reduced infarct size and edema and improved the neurological function of the animals. AS101 treatments reduced both apoptotic and inflammatory caspase activities, and also inhibited protein tyrosine nitration suggesting that AS101 suppresses oxidative stress. Studies of cultured neurons showed that AS101 confers protection against apoptosis induced by either glucose deprivation or the lipid peroxidation product 4-hydroxynonenal. Moreover, AS101 treatment reduced glutamate-induced intracellular calcium elevation, a major contributor to neuronal death in stroke. As AS101 has an excellent safety profile in humans, our pre-clinical data suggest a potential therapeutic benefit of AS101 in patients suffering from stroke and other neurodegenerative conditions.

Topics: Analysis of Variance; Animals; Animals, Newborn; Calcium; Caspases; Cell Survival; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Ethylenes; Glucose; Hypoxia; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Neurons; Neuroprotective Agents; Rats; Time Factors

The immunomodulator ammonium trichloro(dioxyethylene-0-0')tellurate (AS101) has been shown to possess antitumoral properties in several murine models. In the present study, we demonstrate a synergistic in vivo antitumor effect of AS101 and Taxol against early stage Madison 109 lung adenocarcinoma. Treatment with optimal doses of Taxol (25 and 17 mg/kg) and AS101 (0.5 mg/kg) resulted in 66.6 and 43.3% cures. We propose that the antitumor effect is the result of both a direct and indirect effect of the drugs on tumor cells. AS101 and Taxol directly inhibited clonogenicity of M109 cells in a synergistic dose-dependent manner. Exposure of M109 cells to clinically achievable concentrations of Taxol and AS101 produced a synergistic internucleosomal DNA fragmentation associated with programmed cell death. We suggest that AS101 renders tumor cells more susceptible to chemotherapy in general and to Taxol in particular, partly by increasing the wild-type p53 protein expression that is required for efficient execution of the death program. Moreover, we demonstrate a synergistic effect of AS101 and Taxol in increasing the tumoricidal activity of macrophages. This activity is produced by nitric oxide secretion. The synergistic antitumoral effects of AS101 and Taxol were partly ablated both in vitro and in vivo by inhibition of nitric oxide synthase. These findings indicate that AS101 in combination with Taxol may be a promising antitumor drug, and illustrate the mechanism of action of both drugs when acting synergistically. Phase II clinical trials have been initiated using AS101 in combination with Taxol.

Topics: Adenocarcinoma; Adjuvants, Immunologic; Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Division; Cytotoxicity, Immunologic; Disease Models, Animal; Drug Therapy, Combination; Ethylenes; Female; Lung Neoplasms; Macrophage Activation; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Nitric Oxide; Paclitaxel; Tumor Cells, Cultured; Tumor Suppressor Protein p53