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1.
Front Immunol ; 10: 979, 2019.
Article in English | MEDLINE | ID: mdl-31191514

ABSTRACT

The study shows that treatment of NOD mice with either of two tellurium-based small molecules, AS101 [ammonium trichloro(dioxoethylene-o,o')tellurate] or SAS [octa-O-bis-(R,R)-tartarate ditellurane] could preserve ß cells function and mass. These beneficial effects were reflected in decreased incidence of diabetes, improved glucose clearance, preservation of body weight, and increased survival. The normal glucose levels were associated with increased insulin levels, preservation of ß cell mass and increased islet size. Importantly, this protective activity could be demonstrated when the compounds were administered either at the early pre-diabetic phase with no or initial insulitis, at the pre-diabetic stage with advanced insulitis, or even at the advanced, overtly diabetic stage. We further demonstrate that both tellurium compounds prevent migration of autoimmune lymphocytes to the pancreas, via inhibition of the α4ß7 integrin activity. Indeed, the decreased migration resulted in diminished pancreatic islets damage both with respect to their size, ß cell function, and caspase-3 activity, the hallmark of apoptosis. Most importantly, AS101 and SAS significantly elevated the number of T regulatory cells in the pancreas, thus potentially controlling the autoimmune process. We show that the compounds inhibit pancreatic caspase-1 activity followed by decreased levels of the inflammatory cytokines IL-1ß and IL-17 in the pancreas. These properties enable the compounds to increase the proportion of Tregs in the pancreatic lymph nodes. AS101 and SAS have been previously shown to regulate specific integrins through a unique redox mechanism. Our current results suggest that amelioration of disease in NOD mice by this unique mechanism is due to decreased infiltration of pancreatic islets combined with increased immune regulation, leading to decreased inflammation within the islets. As these tellurium compounds show remarkable lack of toxicity in clinical trials (AS101) and pre-clinical studies (SAS), they may be suitable for the treatment of type-1 diabetes.


Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Ethylenes/therapeutic use , Integrins/antagonists & inhibitors , Interleukin-1beta/antagonists & inhibitors , T-Lymphocytes, Regulatory/drug effects , Animals , Diabetes Mellitus, Type 1/immunology , Ethylenes/pharmacology , Female , Integrins/physiology , Interleukin-1beta/physiology , Mice , Mice, Inbred NOD , Pancreatitis/drug therapy , Th17 Cells/physiology
2.
Behav Pharmacol ; 28(6): 458-465, 2017 09.
Article in English | MEDLINE | ID: mdl-28590303

ABSTRACT

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 αvß3, a presynaptic cell-surface-adhesion receptor. As partial deletion of αvß3 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 αvß3 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.


Subject(s)
Anxiety/drug therapy , Ethylenes/pharmacology , Ammonium Compounds , Animals , Anxiety/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Corticosterone/analysis , Corticosterone/blood , Disease Models, Animal , Ethylenes/metabolism , Hypothalamo-Hypophyseal System/metabolism , Immunomodulation , Integrin alphaVbeta3/metabolism , Mice , Neuroprotective Agents , Pituitary-Adrenal System/metabolism , Tellurium
3.
Arch Microbiol ; 196(1): 51-61, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24322541

ABSTRACT

The antibacterial effects of a new organo-tellurium compound [Octa-O-bis-(R,R)-tartarate ditellurane (OTD)] on Escherichia coli isolates as a model are shown. OTD was found to be a bactericidal drug. It exhibits inhibition zones on a protein-rich agar medium but not in a protein-poor medium unless a thiol is added. When applied at the lag phase, OTD inhibits more efficiently than at the log phase. Thiols enhance the efficiency at the log phase. OTD inhibits biofilm formation of E. coli. X-ray microanalysis demonstrated damage caused to the Na⁺/K⁺ pumps and leakage of potassium and phosphorous. Scanning electron microscopy demonstrated an incomplete surface of the bacterial cell wall with a concavity in the center that looks like a hole. Transmission electron microscopy demonstrated severe damage, such as depletion, perforation, and holes in the inner membrane. These results indicate for the first time that the new tellurium compound has antibacterial activities.


Subject(s)
Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Organometallic Compounds/pharmacology , Tartrates/pharmacology , Biofilms/drug effects , Cell Wall/drug effects , Escherichia coli/growth & development , Microbial Sensitivity Tests , Microscopy, Electron, Scanning , Microscopy, Electron, Transmission
4.
J Interferon Cytokine Res ; 29(7): 393-8, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19450150

ABSTRACT

Sleep deprivation is a major health problem in modern society. Deprivation of rapid eye movement (REM) sleep is particularly damaging to cognition and to spatial memory; however, the mechanisms that mediate these deteriorations in function are not known. We explored the possibility that REM sleep deprivation may provoke major changes in the immune system by inducing inflammation. Rats were subjected to 72 h of REM sleep deprivation, and the plasma levels of proinflammatory cytokines (IL-1, IL-1beta, IL-6, IL-17A, and TNF-alpha), an anti-inflammatory cytokine (IL-10), the inflammatory markers homocysteine, corticosterone, and hyperthermia were measured immediately after the deprivation period, and 7 days later. The results indicate that REM sleep deprivation induced an inflammatory response. The levels of the proinflammatory cytokines and markers were significantly elevated in sleep-deprived rats as compared to control rats. After 7 days of recovery, the levels of some markers, including hyperthermia, remained higher in sleep-deprived rats versus the control animals. IL-17A appears to play a pivotal role in coordinating the inflammation. These data shed new light on the mechanism of sleep deprivation-induced inflammation.


Subject(s)
Inflammation , Interleukin-17/blood , Sleep Deprivation/immunology , Animals , Biomarkers/blood , Corticosterone/blood , Fever , Homocysteine/blood , Interleukin-17/classification , Male , Rats , Rats, Long-Evans , Up-Regulation
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