tellurium and Disease-Models--Animal

Primary demyelination is an important component of a number of human diseases and toxic neuropathies. Animal models of primary demyelination are useful for isolating processes involved in myelin breakdown and remyelination because the complicating events associated with axonal degeneration and regeneration are not present. The tellurium neuropathy model has proven especially useful in this respect. Tellurium specifically blocks synthesis of cholesterol, a major component of PNS myelin. The resulting cholesterol deficit in myelin-producing Schwann cells rapidly leads to sychronous primary demyelination of the sciatic nerve, which is followed by rapid synchronous remyelination when tellurium exposure is discontinued. Known alterations in gene expression for myelin proteins and for other proteins involved in the sequence of events associated with demyelination and subsequent remyelination in the PNS are reviewed, and new data regarding gene expression changes during tellurium neuropathy are presented and discussed.

Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Gene Expression Regulation; Humans; Macrophages; Myelin Proteins; Myelin Sheath; Peripheral Nervous System; RNA, Messenger; Tellurium

Fluorescence located in 1500-1700 nm (denoted as the near-infrared IIb window, NIR-IIb) has drawn great interest for bioimaging, owing to its ultrahigh tissue penetration depth and spatiotemporal resolution. Therefore, NIR-IIb fluorescent probes with high photoluminescence quantum yield (PLQY) and stability along with high biocompatibility are urgently pursued. Herein, a novel NIR-IIb fluorescent probe of Au-doped Ag

Topics: Animals; Biocompatible Materials; Cell Line; Cell Survival; Disease Models, Animal; Gold; Hindlimb; Humans; Ischemia; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Quantum Dots; Signal-To-Noise Ratio; Silver; Spectroscopy, Near-Infrared; Tellurium

Two-dimensional nanomaterial-based photothermal therapy (PTT) is currently under intensive investigation as a promising approach toward curative cancer treatment. However, high toxicity, moderate efficacy, and low uniformity in shape remain critical unresolved issues that hamper their clinical application. Thus, there is an urgent need for developing versatile nanomaterials to meet clinical expectations. To achieve this goal, we developed a stable, highly uniform in size, and nontoxic nanomaterials made of tellurium-selenium (TeSe)-based lateral heterojunction. Systemic delivery of TeSe nanoparticles in mice showed highly specific accumulation in tumors relative to other healthy tissues. Upon exposure to light, TeSe nanoparticles nearly completely eradicated lung cancer and hepatocellular carcinoma in preclinical models. Consistent with tumor suppression, PTT altered the tumor microenvironment and induced immense cancer cell apoptosis. Together, our findings demonstrate an exciting and promising PTT-based approach for cancer eradication.

Topics: Animals; Antineoplastic Agents; Biomarkers; Cell Line, Tumor; Chemical Phenomena; Disease Models, Animal; Drug Carriers; Fluorescent Antibody Technique; Humans; Metal Nanoparticles; Mice; Selenium; Tellurium; Xenograft Model Antitumor Assays

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

Endometriosis is difficult to treat since the side effects of the current therapeutic method and the high recurrence rate; thus, newer and safer therapeutic approaches are urgently needed. This work investigates the enhanced permeability and retention effect of CdTe quantum dots (QDs) and hollow gold nanospheres (HAuNS) in endometriosis to increase the delivery of HAuNS into lesion cells. The surface of HAuNS is successfully conjugated with a TNYL peptide that has specific affinity for the EphB4 receptor, which is a member of the Eph family of receptor tyrosine kinases. It is found that the EphB4 receptor is overexpressed in endometriosis lesions. The data indicate that both QDs and HAuNS can efficiently accumulate in endometriotic lesions through permeable vessels and the TNYL-conjugated HAuNS (TNYL-HAuNS) accumulate more via the interaction with EphB4. The specific photothermal ablation therapy based on TNYL-HAuNS significantly inhibits the growth of the endometriotic volume and induces the atrophy and degeneration of ectopic endometrium with no detectable toxicity to the normal organs. The level of TNF-α and estradiol also significantly decreases in the endometriotic lesions, indicating that the treatment enables a recovery from hormonal imbalance and inflammatory injury. This work can be a valuable reference for future endometriosis therapy.

Topics: Ablation Techniques; Animals; Cadmium Compounds; Disease Models, Animal; Endometriosis; Female; Gold; Hyperthermia, Induced; Mice; Nanospheres; Peptides; Phototherapy; Quantum Dots; Receptor, EphB4; Tellurium; Tissue Distribution; Treatment Outcome

Organic Te(IV) compounds (organotelluranes) differing in their labile ligands exhibited anti-integrin activities in vitro and anti-metastatic properties in vivo. They underwent ligand substitution with l-cysteine, as a thiol model compound. Unlike inorganic Te(IV) compounds, the organotelluranes did not form a stable complex with cysteine, but rather immediately oxidized it. The organotelluranes inhibited integrin functions, such as adhesion, migration, and metalloproteinase secretion mediation in B16F10 murine melanoma cells. In comparison, a reduced derivative with no labile ligand inhibited adhesion of B16F10 cells to a significantly lower extent, thus pointing to the importance of the labile ligands of the Te(IV) atom. One of the organotelluranes inhibited circulating cancer cells in vivo, possibly by integrin inhibition. Our results extend the current knowledge on the reactivity and mechanism of organotelluranes with different labile ligands and highlight their clinical potential.

Topics: Animals; Antineoplastic Agents; Cell Adhesion; Cell Line, Tumor; Cell Movement; Disease Models, Animal; Integrin alpha4beta1; Integrins; Liver Neoplasms; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred C57BL; Organometallic Compounds; Protein Binding; Tellurium; Transplantation, Homologous

Data on the in vivo myocardial kinetics of (123)I-metaiodobenzylguanidine ((123)I-MIBG) are scarce and have always been obtained using planar acquisitions. To clarify the normal kinetics of (123)I-MIBG in vivo over time, we designed an experimental protocol using a 3-dimensional (3D) dynamic approach with a cadmium zinc telluride (CZT) camera.. We studied 6 anesthetized pigs (mean body weight, 37 ± 4 kg). Left ventricular myocardial perfusion and sympathetic innervation were assessed using (99m)Tc-tetrofosmin (26 ± 6 MBq), (123)I-MIBG (54 ± 14 MBq), and a CZT camera. A normal perfusion/function match on gated SPECT was the inclusion criterion. A dynamic acquisition in list mode started simultaneously with the bolus injection of (123)I-MIBG, and data were collected every 5 min for the first 20 min and then at acquisition steps of 30, 60, 90, and 120 min. Each step was reconstructed using dedicate software and reframed (60 s/frame). On the reconstructed transaxial slice that best showed the left ventricular cavity, regions of interest were drawn to obtain myocardial and blood pool activities. Myocardial time-activity curves were generated by interpolating data between contiguous acquisition steps, corrected for radiotracer decay and injected dose, and fitted to a bicompartmental model. Time to myocardial maximum signal intensity (MSI), MSI value, radiotracer retention index (RI, myocardial activity/blood pool integral), and washout rate were calculated. The mediastinal signal was measured and fitted to a linear model.. The myocardial MSI of (123)I-MIBG was reached within 5.57 ± 4.23 min (range, 2-12 min). The mean MSI was 0.426% ± 0.092%. Myocardial RI decreased over time and reached point zero at 176 ± 31 min (range, 140-229 min). The ratio between myocardial and mediastinal signal at 15 and 125 min and extrapolated at 176 and 4 h was 5.45% ± 0.61%, 4.33% ± 1.23% (not statistically significant vs. 15 min), 3.95% ± 1.46% (P < 0.03 vs. 125 min), and 3.63% ± 1.64% (P < 0.03 vs. 176 min), respectively. Mean global washout rate at 125 min was 15% ± 14% (range, 0%-34%), and extrapolated data at 176 min and 4 h were 18% ± 18% (range, 0.49%-45%) and 25% ± 23% (range, 1.7%-56.2%; not statistically significant vs. 176 min), respectively.. 3D dynamic analysis of (123)I-MIBG suggests that myocardial peak uptake is reached more quickly than previously described. Myocardial RI decreases over time and, on average, is null about 3 h after injection. The combination of an early peak and variations in delayed myocardial uptake could result in a wide physiologic range of washout rates. Mediastinal activity appears to be constant over time and significantly lower than previously described in planar studies, resulting in a higher heart-to-mediastinum ratio.

Topics: 3-Iodobenzylguanidine; Animals; Cadmium; Disease Models, Animal; Heart; Heart Ventricles; Imaging, Three-Dimensional; Iodine Radioisotopes; Models, Statistical; Myocardium; Organophosphorus Compounds; Organotechnetium Compounds; Oxygen Consumption; Perfusion; Radiopharmaceuticals; Swine; Sympathetic Nervous System; Tellurium; Time Factors; Tomography, Emission-Computed, Single-Photon; Zinc

Systemic sclerosis (SSc) is a connective tissue disorder characterized by skin and visceral fibrosis, microvascular damage, and autoimmunity. HOCl-induced mouse SSc is a murine model that mimics the main features of the human disease, especially the activation and hyperproliferation rate of skin fibroblasts. We demonstrate here the efficiency of a tellurium-based catalyst 2,3-bis(phenyltellanyl)naphthoquinone ((PHTE)(2)NQ) in the treatment of murine SSc, through its selective cytotoxic effects on activated SSc skin fibroblasts. SSc mice treated with (PHTE)(2)NQ displayed a significant decrease in lung and skin fibrosis and in alpha-smooth muscle actin (α-SMA) expression in the skin compared with untreated mouse SSc animals. Serum concentrations of advanced oxidation protein products, nitrate, and anti-DNA topoisomerase I autoantibodies were increased in SSc mice, but were significantly reduced in SSc mice treated with (PHTE)(2)NQ. To assess the mechanism of action of (PHTE)(2)NQ, the cytotoxic effect of (PHTE)(2)NQ was compared in normal fibroblasts and in mouse SSc skin fibroblasts. ROS production is higher in mouse SSc fibroblasts than in normal fibroblasts, and was still increased by (PHTE)(2)NQ to reach a lethal threshold and kill mouse SSc fibroblasts. Therefore, the effectiveness of (PHTE)(2)NQ in the treatment of mouse SSc seems to be linked to the selective pro-oxidative and cytotoxic effects of (PHTE)(2)NQ on hyperproliferative fibroblasts.

Topics: Actins; Animals; Autoantibodies; Cells, Cultured; Disease Models, Animal; DNA Topoisomerases, Type I; Female; Fibroblasts; Fibrosis; Glutathione; Hydrogen Peroxide; Hypochlorous Acid; In Vitro Techniques; Mice; Mice, Inbred BALB C; Naphthoquinones; Nitric Oxide; Organometallic Compounds; Reactive Oxygen Species; Scleroderma, Systemic; Skin; Tellurium

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

Organotellurides are newly described redox-catalyst molecules with original pro-oxidative properties. We have investigated the in vitro and in vivo antitumoral effects of the organotelluride catalyst LAB027 in a mouse model of colon cancer and determined its profile of toxicity in vivo. LAB027 induced an overproduction of H(2)O(2) by both human HT29 and murine CT26 colon cancer cell lines in vitro. This oxidative stress was associated with a decrease in proliferation and survival rates of the two cell lines. LAB027 triggered a caspase-independent, ROS-mediated cell death by necrosis associated with mitochondrial damages and autophagy. LAB027 also synergized with the cytotoxic drug oxaliplatin to augment its cytostatic and cytotoxic effects on colon cancer cell lines but not on normal fibroblasts. The opposite effects of LAB027 on tumor and on non-transformed cells were linked to differences in the modulation of reduced glutathione metabolism between the two types of cells. In mice grafted with CT26 tumor cells, LAB027 alone decreased tumor growth compared with untreated mice, and synergized with oxaliplatin to further decrease tumor development compared with mice treated with oxaliplatin alone. LAB027 an organotelluride catalyst compound synergized with oxaliplatin to prevent both in vitro and in vivo colon cancer cell proliferation while decreasing the in vivo toxicity of oxaliplatin. No in vivo adverse effect of LAB027 was observed in this model.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspases; Catalysis; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Disease Models, Animal; Glutathione; Humans; Hydrogen Peroxide; Mice; Naphthoquinones; Organometallic Compounds; Organoplatinum Compounds; Oxaliplatin; Oxidation-Reduction; Oxidative Stress; Tellurium; Transplantation, Heterologous

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

Ingestion of tellurium (Te), a toxic element, produces paralysis of the hind limbs in weanling rats that is due to temporary, segmental demyelination of the sciatic nerves bilaterally. Weanling rats were fed a 1.1% elemental Te diet and sacrificed at various time points for histological and magnetic resonance (MR) analysis of the sciatic nerves. No controls exhibited impairments of the hind limbs, whereas Te-treated animals became progressively impaired with increased Te exposure. Toluidine blue-stained nerve sections of Te-treated animals showed widened endoneurial spaces, disrupted myelin sheaths, swollen Schwann cells, and a few instances of axonal degeneration. Te decreased healthy myelin by 68% and increased percent extracellular matrix by 45% on day 7. MR experiments showed a decrease in the area of the short T2 component, an increase in average T1, and an increase in the position of the intermediate T2 component in Te-treated nerves. The correlation coefficient for healthy myelin and average T1 was 0.88 and that for healthy myelin and the area underneath the short T2 component was 0.77. The area of the short T2 component has been postulated as the best measure of the process of demyelination.

Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Magnetic Resonance Imaging; Peripheral Nervous System Diseases; Radiography; Rats; Rats, Inbred Lew; Sciatic Nerve; Tellurium

Changes in the magnetic resonance (MR) parameters of demyelinated neural tissue were measured in vitro using an experimental animal model. A tellurium (Te) diet was applied to weanling rats to induce the demyelination process in the sciatic nerve. The quantitative MR parameters, such as T(1), T(2) relaxation time constants and magnetization transfer (MT) were measured each day after applying the Te diet (up to 7 days) and were found to be substantially different from those of normal nerves. An increase in the average T(1) and T(2) was observed along with a decrease in the MT ratio (MTR) and the quantitative MT parameter M(0B), which describes the semisolid pool of protons. Most of the MR parameters correlated very well with the myelin fraction of neural tissue evaluated by quantitative histopathology. The T(2) relaxation spectrum provided the most efficient quantitative assessment of changes in neural tissue microstructure and its analysis resulted in a powerful tool to distinguish the processes of demyelination and inflammation. In comparison, the MT measurements were less successful.

Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Image Interpretation, Computer-Assisted; In Vitro Techniques; Magnetic Resonance Imaging; Rats; Rats, Inbred Lew; Reproducibility of Results; Sciatic Nerve; Sciatic Neuropathy; Sensitivity and Specificity; Tellurium

We have used an experimental model of tellurium(Te)-induced demyelinating neuropathy in the rat to study cellular mechanisms involved in regulating Schwann cell (SC) numbers during remyelination. Starting at postnatal day 21, weaned rats were fed a diet containing 1.1% elemental Te. Following 7 days of Te treatment and at several time points of post-tellurium treatment (PTe), the animals were processed for ultrastructural analysis, SC nuclei quantification and teased fibre preparations. It is well-established that Te induces a transient demyelinating/remyelinating sequence in sciatic nerves. The loss of the myelin sheath in this neuropathy produces active proliferation and overproduction of immature SCs. By electron microscopy analysis most mitotic SCs were located along demyelinated segments. Quantitative determination of SC nuclei per transverse section of sciatic nerve revealed a dramatic increase of SCs at 2 days PTe relative to control nerves. The number of SC nuclei then decreased progressively during the long-term period of recovery studied (330 days PTe). In Te-treated rats, SCs undergoing cell death were regularly found within the nerve fibre compartment, especially on demyelinated segments. Dying cells exhibited morphological features of apoptosis and appeared enclosed by lamellar processes of adjacent healthy SCs in extracellular compartments. Both healthy immature SCs and endoneurial macrophages were involved in the phagocytosis of apoptotic SCs. Particularly during remyelination, supernumerary endoneurial SCs were observed surrounding myelinated fibres. These cells progressively became atrophic with a morphological phenotype similar so that of "onion bulb" cells. On the other hand, teased fibre measurements revealed a remarkable permanent internodal shortening in remyelinated fibres from Te-treated sciatic nerves. These results indicate that a portion of redundant immature SCs are susceptible to elimination by apoptosis. However, other distinct biological mechanisms such as the persistence of supernumerary SCs in the endoneurium and the shortening of internodal lengths are also involved in regulating SC numbers during the remyelination stage.

Topics: Animals; Apoptosis; Cell Nucleus; Demyelinating Diseases; Disease Models, Animal; Male; Microscopy, Electron; Myelin Sheath; Ranvier's Nodes; Rats; Rats, Sprague-Dawley; Schwann Cells; Tellurium

Topics: Animals; Coronary Disease; Disease Models, Animal; Dogs; Fatty Acids; Heart; Isotopes; Microspheres; Radioisotopes; Radionuclide Imaging; Scandium; Tellurium; Tin

Topics: Cerebral Cortex; Disease Models, Animal; Inclusion Bodies; Lipidoses; Lysosomes; Microscopy, Electron; Neurons; Phentermine; Tellurium

Topics: Animals; Brain Diseases; Cell Membrane; Cerebral Cortex; Cytoplasmic Granules; Disease Models, Animal; Lipidoses; Microscopy, Electron; Mitochondria; Nerve Degeneration; Pigments, Biological; Rats; Spectrophotometry, Atomic; Tellurium