The anti-inflammatory effects of the tellurium redox modulating compound, AS101, are associated with regulation of NFkappaB signaling pathway and nitric oxide induction in macrophages.

BACKGROUND: LPS-activated macrophages produce mediators which are involved in inflammation and tissue injury, and especially those associated with endotoxic shock. The non toxic tellurium compound ammonium tri-chloro(dioxoethylene-O,O'-)tellurate, AS101, has been recently shown to exert profound anti-inflammatory properties in animal models, associated with its Te(IV) redox chemistry. This study explores the anti-inflammatory properties of AS101 with respect to modulation of inflammatory cytokines production and regulation of iNOS transcription and expression in activated macrophages via targeting the NFkB complex. RESULTS: AS101 decreased production of IL-6 and in parallel down-regulated LPS-induced iNOS expression and NO secretion by macrophages. AS101 reduced IkB phosphorylation and degradation, and reduced NFkB nuclear translocalization, albeit these effects were exerted at different kinetics. Chromatin immunoprecipitation assays showed that AS101 treatment attenuated p50-subunit ability to bind DNA at the NFkB consensus site in the iNOS promotor following LPS induction. CONCLUSIONS: Besides AS101, the investigation of therapeutic activities of other tellurium(IV) compounds is scarce in the literature, although tellurium is the fourth most abundant trace element in the human body. Since IKK and NFkB may be regulated by thiol modifications, we may thus envisage, inview of our integrated results, that Te(IV) compounds, may have important roles in thiol redox biological activity in the human body and represent a new class of anti-inflammatory compounds.

Resolution of inflammation-related apoptotic processes by the synthetic tellurium compound, AS101 following liver injury.

BACKGROUND/AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Octa-O-bis-(R,R)-Tartarate Ditellurane (SAS) - a novel bioactive organotellurium(IV) compound: synthesis, characterization, and protease inhibitory activity.

Octa-O-bis-(R,R)-Tartarate Ditellurane (SAS) is a new Te(IV) compound, comprised of two tellurium atoms, each liganded by four oxygen atoms from two carboxylates and two alkoxides of two tartaric acids. Unlike many other Te(IV) compounds, SAS was highly stable in aqueous solution. It interacted with thiols to form an unstable Te(SR)(4) product. The product of the interaction of SAS with cysteine was isolated and characterized by mass spectroscopy and elemental analysis. SAS selectively inactivated cysteine proteases, but it did not inactivate other families of proteolytic enzymes. It displayed selectivity towards the cysteine protease cathepsin B, a human enzyme of pharmaceutical interest, with a second order rate constant k(i)/K(i)=5900 M(-1) s(-1).

The synthetic tellurium compound, AS101, is a novel inhibitor of IL-1beta converting enzyme.

The organotellurium compound, trichloro(dioxoethylene-O,O') tellurate (AS101) has been shown previously to exert diverse biologic activities both in vitro and in vivo. This compound was recently found to react with thiols and to catalyze their oxidation. This property of AS101 raises the possibility that it may serve as a cysteine protease inhibitor. In the present study, using a substrate-specific enzymatic assay, we show that treatment of caspase-1 (interleukin-1beta [IL-1beta] converting enzyme [ICE]) with AS101 inhibits its enzymatic activity in a dose-dependent manner. Moreover, the results show that AS101 treatment causes a significant reduction in the active form of IL-18 and IL-1beta in peripheral blood mononuclear cells (PBMC) and in human HaCat keratinocytes. We further demonstrate that the inhibitory effect of AS101 does not involve nitric oxide (NO) or interferon-gamma (IFN-gamma), two possible regulators of IL-18 production, and does not occur at the mRNA level, suggesting a posttranscriptional mechanism of action. More importantly, AS101 downregulates IL-18 and IL-1beta serum levels in a mouse model of lipopolysaccharide (LPS)-induced sepsis, resulting in increased survival. Recent studies emphasize the pathophysiologic role of IL-18 and IL-1beta in a variety of inflammatory diseases. Thus, their blockage by the nontoxic compound, AS101, currently used in clinical studies, may provide clinical advantage in the treatment of these diseases.

Multifunctional tellurium molecule protects and restores dopaminergic neurons in Parkinson's disease models.

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.