The Experts below are selected from a list of 90 Experts worldwide ranked by ideXlab platform
Benjamin Sredni - One of the best experts on this subject based on the ideXlab platform.
-
Tellurium Compound provides pro apoptotic signaling in drug resistant multiple myeloma
Leukemia & Lymphoma, 2021Co-Authors: Benjamin Sredni, Eti Zigmanhoffman, Benjamin Meilik, E Naparstek, Boris TartakovskyAbstract:Multiple Myeloma, effectively treated by chemotherapeutic drugs, relapses due to drug resistance. We tested here the capacity of mesenchymal stromal cells, from the bone marrow of patients or from adipose tissue of healthy individuals, to induce drug resistance in Myeloma cell lines. We show that drug resistance can be achieved by factors secreted by the various MSC's. Mass spectrometry analysis of MSC's conditioned media revealed that fibronectin, was particularly instrumental in providing anti-apoptotic signals to MM cells. Moreover, we demonstrate that SAS ([octa-O-bis-(R,R)tartarate ditellurane]), an immunomodulator Tellurium Compound, is not only able of blocking the physical interaction between MM cells and fibronectin but is also capable of re-sensitizing the cells to the chemotherapeutic drugs. Finally, we show that this re-sensitization is coupled with the blocking of pAKT induction, in MM cells, by the MSC's. These results indicate that SAS may be useful in the treatment of drug resistant MM.
-
the immunomodulatory Tellurium Compound ammonium trichloro dioxoethylene o o tellurate reduces anxiety like behavior and corticosterone levels of submissive mice
Behavioural Pharmacology, 2017Co-Authors: Moshe Gross, Benjamin Sredni, Dvora Kenigsbuchsredni, Emanuel Stanciu, Albert PinhasovAbstract: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.
-
the small Tellurium Compound as101 ameliorates rat crescentic glomerulonephritis association with inhibition of macrophage caspase 1 activity via very late antigen 4 inactivation
Frontiers in Immunology, 2017Co-Authors: Yafit Hachmo, Yona Kalechman, Itai Skornick, Uzi Gafter, Rachel R Caspi, Benjamin SredniAbstract:Crescentic glomerulonephritis (CGN) is the most aggressive form of GN and, if untreated, patients can progress to end-stage renal failure within weeks of presentation. The α4β1 integrin (VLA-4) is an adhesion molecule of fundamental importance to the recruitment of leucocytes in inflammation. We addressed the role of VLA-4 in mediating progressive renal injury in a rat model of CGN using a small Tellurium Compound. AS101 [ammonium trichloro(dioxoethylene-o,o')tellurate]. This Compound has been previously shown to uniquely inhibit VLA-4 activity by redox inactivation of adjacent thiols in the exofacial domain of VLA-4. The study shows that administration of AS101 either before or after Glomerular-basement-membrane anti serum injection, ameliorates crescent formation or preserves renal function. This was associated with profound inhibition of critical inflammatory mediators, accompanied by decreased glomerular infiltration of macrophages. Mechanistic studies demonstrated vla-4 inactivation on glomerular macrophages both in vitro and in vivo as well as inhibition of caspase-1 activity. Importantly, this cysteine protease activity modification was dependent on VLA-4 inactivation and was associated with the anti-inflammatory activity of AS101. We propose that inactivation of macrophage VLA-4 by AS101 in vivo results in a decrease of inflammatory cytokines and chemokines produced in the glomeruli of diseased rats, resulting in decreased further macrophage recruitment and decreased extracellular matrix expansion. Thus, AS101, which is currently in clinical trials for other indications, might be beneficial for treatment of CGN.
-
ligand substitution reactions of the Tellurium Compound as 101 in physiological aqueous and alcoholic solutions
Inorganic Chemistry, 2016Co-Authors: Alon Silberman, Benjamin Sredni, Michael Albeck, Amnon AlbeckAbstract:Since its first crystallization, the aqueous structure of the Tellurium-containing experimental drug AS-101 has never been studied. We show that, under the aqueous conditions in which it is administered, AS-101 is subjected to an immediate ligand-substitution reaction with water, yielding a stable hydrolyzed oxide anion product that is identified, for the first time, to be TeOCl3–. Studying the structure of AS-101 in propylene glycol (PG), an alcoholic solvent often used for the topical and oral administration of AS-101, revealed the same phenomenon of ligand-substitution reaction between the alcoholic ligands. Upon exposure to water, the PG-substituted product is also hydrolyzed to the same Tellurium(IV) oxide form, TeOCl3–.
-
the effect of the novel Tellurium Compound as101 on autoimmune diseases
Autoimmunity Reviews, 2014Co-Authors: Gilad Halpert, Benjamin SredniAbstract:Abstract Tellurium is a rare element, which has been regarded as a non-essential trace element despite its relative abundance in the human body. The chemistry of Tellurium supports a plethora of activities, but its biochemistry is not clearly established to date. The small Tellurium IV Compound, ammonium trichloro (dioxoethylene- o,o ′)tellurate (AS101) developed and initially investigated by us, is currently being evaluated in Phase II clinical trials in psoriasis patients. AS101 is the first Tellurium Compound to be tested for clinical efficacy. This Compound is a potent immunomodulator both in vitro and in vivo with a variety of potential therapeutic applications. The present review will focus on the immunomodulatory properties of AS101, and specifically, its effects in mitigating autoimmune diseases. AS101 has several activities that act on the immune system, including: 1) its ability to reduce IL-17 levels and to inhibit the function of Th17 cells; 2) its specific unique redox-modulating activities enabling the inhibition of specific leukocyte integrins such as α4β1 and α4β7, that are pivotal for diapedesis of macrophages and CD4 + T inflammatory/auto-reactive cells into the autoimmune tissues; and 3) its ability to enhance the activity of regulatory T cells (Treg). These activities coupled with its excellent safety profile suggest that AS101 may be a promising candidate for the management of autoimmune diseases.
Michael Albeck - One of the best experts on this subject based on the ideXlab platform.
-
ligand substitution reactions of the Tellurium Compound as 101 in physiological aqueous and alcoholic solutions
Inorganic Chemistry, 2016Co-Authors: Alon Silberman, Benjamin Sredni, Michael Albeck, Amnon AlbeckAbstract:Since its first crystallization, the aqueous structure of the Tellurium-containing experimental drug AS-101 has never been studied. We show that, under the aqueous conditions in which it is administered, AS-101 is subjected to an immediate ligand-substitution reaction with water, yielding a stable hydrolyzed oxide anion product that is identified, for the first time, to be TeOCl3–. Studying the structure of AS-101 in propylene glycol (PG), an alcoholic solvent often used for the topical and oral administration of AS-101, revealed the same phenomenon of ligand-substitution reaction between the alcoholic ligands. Upon exposure to water, the PG-substituted product is also hydrolyzed to the same Tellurium(IV) oxide form, TeOCl3–.
-
multifunctional activity of a small Tellurium redox immunomodulator Compound as101 on dextran sodium sulfate induced murine colitis
Journal of Biological Chemistry, 2014Co-Authors: Gilad Halpert, Y Kalechman, Michael Albeck, Tom Eitan, Elena Voronov, Ron N Apte, Lea Rathwolfson, Benjamin SredniAbstract:Inflammatory bowel diseases (IBDs) are a group of idiopathic, chronic immune-mediated diseases characterized by an aberrant immune response, including imbalances of inflammatory cytokine production and activated innate and adaptive immunity. Selective blockade of leukocyte migration into the gut is a promising strategy for the treatment of IBD. This study explored the effect of the immunomodulating Tellurium Compound ammonium trichloro (dioxoethylene-o,o′) tellurate (AS101) on dextran sodium sulfate (DSS)-induced murine colitis. Both oral and intraperitoneal administration of AS101 significantly reduced clinical manifestations of IBD. Colonic inflammatory cytokine levels (IL-17 and IL-1β) were significantly down-regulated by AS101 treatment, whereas IFN-γ was not affected. Neutrophil and α4β7+ macrophage migration into the tissue was inhibited by AS101 treatment. Adhesion of mesenteric lymph node cells to mucosal addressin cell adhesion molecule (MAdCAM-1), the ligand for α4β7 integrin, was blocked by AS101 treatment both in vitro and in vivo. DSS-induced destruction of colonic epithelial barrier/integrity was prevented by AS101, via up-regulation of colonic glial-derived neurotrophic factor, which was found previously to regulate the intestinal epithelial barrier through activation of the PI3K/AKT pathway. Indeed, the up-regulation of glial-derived neurotrophic factor by AS101 was associated with increased levels of colonic pAKT and BCL-2 and decreased levels of BAX. Furthermore, AS101 treatment reduced colonic permeability to Evans blue and decreased colonic TUNEL+ cells. Our data revealed multifunctional activities of AS101 in the DSS-induced colitis model via anti-inflammatory and anti-apoptotic properties. We suggest that treatment with the small, nontoxic molecule AS101 may be an effective early therapeutic approach for controlling human IBD.
-
the anti inflammatory effects of the Tellurium redox modulating Compound as101 are associated with regulation of nfκb signaling pathway and nitric oxide induction in macrophages
Journal of Inflammation, 2010Co-Authors: Miri Brodsky, Michael Albeck, Gilad Halpert, Benjamin SredniAbstract: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. 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. 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
Journal of Hepatology, 2009Co-Authors: Miri Brodsky, Michael Albeck, Shira Hirsh, Benjamin SredniAbstract: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 TNFα 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-1β 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.
-
A potential antimicrobial treatment against ESBL-producing Klebsiella pneumoniae using the Tellurium Compound AS101
Archives of Microbiology, 2009Co-Authors: Miriam Daniel-hoffmann, Benjamin Sredni, Michael Albeck, Yeshayahu NitzanAbstract:Due to the extensive spread of antibiotic-resistant Klebsiella pneumoniae , the non-toxic immunomodulator, ammonium trichloro (dioxoethylene- o , o ′) tellurate (AS101), was introduced for the first time in this study. Eleven strains of K. pneumoniae were tested: five were extended spectrum beta lactamase (ESBL)-producing strains and six were non-ESBL-producing strains. The MIC and MBC of ten strains were 9 μg/ml AS101 and 18 μg/ml for one strain. AS101 treatment inhibited bacterial growth in a dose-dependent manner on protein-rich media. No inhibition by AS101 was observed on poorer media. In combination with β-mercaptoethanol (2-ME) or cysteamine, AS101 inhibited bacterial growth in both types of media. Growth inhibition was also shown following AS101 treatment at both lag and log phases. Our data indicate that AS101 enters the bacterium through its porins, causing bacterial destruction. The mechanism of cell death was characterized using several techniques: (a) scanning electron microscopy showed that bacteria treated with AS101 or in combination with cysteamine exhibited evidence of cell-wall damage; (b) X-ray microanalysis demonstrated damage to Na/K pumps; and (c) transmission electron microscopy demonstrated cell lysis. These phenomena suggest that AS101 has antibacterial potential against K. pneumoniae infections.
Gilad Halpert - One of the best experts on this subject based on the ideXlab platform.
-
the effect of the novel Tellurium Compound as101 on autoimmune diseases
Autoimmunity Reviews, 2014Co-Authors: Gilad Halpert, Benjamin SredniAbstract:Abstract Tellurium is a rare element, which has been regarded as a non-essential trace element despite its relative abundance in the human body. The chemistry of Tellurium supports a plethora of activities, but its biochemistry is not clearly established to date. The small Tellurium IV Compound, ammonium trichloro (dioxoethylene- o,o ′)tellurate (AS101) developed and initially investigated by us, is currently being evaluated in Phase II clinical trials in psoriasis patients. AS101 is the first Tellurium Compound to be tested for clinical efficacy. This Compound is a potent immunomodulator both in vitro and in vivo with a variety of potential therapeutic applications. The present review will focus on the immunomodulatory properties of AS101, and specifically, its effects in mitigating autoimmune diseases. AS101 has several activities that act on the immune system, including: 1) its ability to reduce IL-17 levels and to inhibit the function of Th17 cells; 2) its specific unique redox-modulating activities enabling the inhibition of specific leukocyte integrins such as α4β1 and α4β7, that are pivotal for diapedesis of macrophages and CD4 + T inflammatory/auto-reactive cells into the autoimmune tissues; and 3) its ability to enhance the activity of regulatory T cells (Treg). These activities coupled with its excellent safety profile suggest that AS101 may be a promising candidate for the management of autoimmune diseases.
-
multifunctional activity of a small Tellurium redox immunomodulator Compound as101 on dextran sodium sulfate induced murine colitis
Journal of Biological Chemistry, 2014Co-Authors: Gilad Halpert, Y Kalechman, Michael Albeck, Tom Eitan, Elena Voronov, Ron N Apte, Lea Rathwolfson, Benjamin SredniAbstract:Inflammatory bowel diseases (IBDs) are a group of idiopathic, chronic immune-mediated diseases characterized by an aberrant immune response, including imbalances of inflammatory cytokine production and activated innate and adaptive immunity. Selective blockade of leukocyte migration into the gut is a promising strategy for the treatment of IBD. This study explored the effect of the immunomodulating Tellurium Compound ammonium trichloro (dioxoethylene-o,o′) tellurate (AS101) on dextran sodium sulfate (DSS)-induced murine colitis. Both oral and intraperitoneal administration of AS101 significantly reduced clinical manifestations of IBD. Colonic inflammatory cytokine levels (IL-17 and IL-1β) were significantly down-regulated by AS101 treatment, whereas IFN-γ was not affected. Neutrophil and α4β7+ macrophage migration into the tissue was inhibited by AS101 treatment. Adhesion of mesenteric lymph node cells to mucosal addressin cell adhesion molecule (MAdCAM-1), the ligand for α4β7 integrin, was blocked by AS101 treatment both in vitro and in vivo. DSS-induced destruction of colonic epithelial barrier/integrity was prevented by AS101, via up-regulation of colonic glial-derived neurotrophic factor, which was found previously to regulate the intestinal epithelial barrier through activation of the PI3K/AKT pathway. Indeed, the up-regulation of glial-derived neurotrophic factor by AS101 was associated with increased levels of colonic pAKT and BCL-2 and decreased levels of BAX. Furthermore, AS101 treatment reduced colonic permeability to Evans blue and decreased colonic TUNEL+ cells. Our data revealed multifunctional activities of AS101 in the DSS-induced colitis model via anti-inflammatory and anti-apoptotic properties. We suggest that treatment with the small, nontoxic molecule AS101 may be an effective early therapeutic approach for controlling human IBD.
-
the anti inflammatory effects of the Tellurium redox modulating Compound as101 are associated with regulation of nfκb signaling pathway and nitric oxide induction in macrophages
Journal of Inflammation, 2010Co-Authors: Miri Brodsky, Michael Albeck, Gilad Halpert, Benjamin SredniAbstract: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. 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. 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.
Miri Brodsky - One of the best experts on this subject based on the ideXlab platform.
-
the anti inflammatory effects of the Tellurium redox modulating Compound as101 are associated with regulation of nfκb signaling pathway and nitric oxide induction in macrophages
Journal of Inflammation, 2010Co-Authors: Miri Brodsky, Michael Albeck, Gilad Halpert, Benjamin SredniAbstract: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. 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. 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
Journal of Hepatology, 2009Co-Authors: Miri Brodsky, Michael Albeck, Shira Hirsh, Benjamin SredniAbstract: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 TNFα 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-1β 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.
-
the synthetic Tellurium Compound as101 is a novel inhibitor of il 1beta converting enzyme
Journal of Interferon and Cytokine Research, 2007Co-Authors: Miri Brodsky, Michael Albeck, Sigal Yosef, Rushkin Galit, Dan L Longo, Amnon Albeck, Benjamin SredniAbstract: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.
Uzi Gafter - One of the best experts on this subject based on the ideXlab platform.
-
the small Tellurium Compound as101 ameliorates rat crescentic glomerulonephritis association with inhibition of macrophage caspase 1 activity via very late antigen 4 inactivation
Frontiers in Immunology, 2017Co-Authors: Yafit Hachmo, Yona Kalechman, Itai Skornick, Uzi Gafter, Rachel R Caspi, Benjamin SredniAbstract:Crescentic glomerulonephritis (CGN) is the most aggressive form of GN and, if untreated, patients can progress to end-stage renal failure within weeks of presentation. The α4β1 integrin (VLA-4) is an adhesion molecule of fundamental importance to the recruitment of leucocytes in inflammation. We addressed the role of VLA-4 in mediating progressive renal injury in a rat model of CGN using a small Tellurium Compound. AS101 [ammonium trichloro(dioxoethylene-o,o')tellurate]. This Compound has been previously shown to uniquely inhibit VLA-4 activity by redox inactivation of adjacent thiols in the exofacial domain of VLA-4. The study shows that administration of AS101 either before or after Glomerular-basement-membrane anti serum injection, ameliorates crescent formation or preserves renal function. This was associated with profound inhibition of critical inflammatory mediators, accompanied by decreased glomerular infiltration of macrophages. Mechanistic studies demonstrated vla-4 inactivation on glomerular macrophages both in vitro and in vivo as well as inhibition of caspase-1 activity. Importantly, this cysteine protease activity modification was dependent on VLA-4 inactivation and was associated with the anti-inflammatory activity of AS101. We propose that inactivation of macrophage VLA-4 by AS101 in vivo results in a decrease of inflammatory cytokines and chemokines produced in the glomeruli of diseased rats, resulting in decreased further macrophage recruitment and decreased extracellular matrix expansion. Thus, AS101, which is currently in clinical trials for other indications, might be beneficial for treatment of CGN.
-
inhibition of interleukin 10 by the immunomodulator as101 reduces mesangial cell proliferation in experimental mesangioproliferative glomerulonephritis association with dephosphorylation of stat3
Journal of Biological Chemistry, 2004Co-Authors: Yona Kalechman, Uzi Gafter, Ilya Freidkin, Michael Albeck, Talia Weinstein, Avry Chagnac, Ana Tobar, Benjamin SredniAbstract:Abstract Mesangial cell (MC) proliferation is essential for the pathogenesis and progression of glomerular disease. Using an acute model of mesangial proliferative glomerulonephritis (Thy1 GN), we show that neutralization of interleukin (IL)-10 greatly ameliorated the disease as expressed by both decreased MC expansion and proteinuria. Treatment with the Tellurium Compound AS101 (ammonium trichloro(dioxoethylene-o,o′)tellurate) resulted in favorable effects provided that the Compound was administered 24 h before insult, whereas partial effects were obtained when administered after insult. We identified STAT3 as playing a pivotal role in IL-10-induced MC proliferation in vitro and in vivo. IL-10 activates MC STAT3 in vitro as expressed by its phosphorylation and nuclear translocation. The role of STAT3 in MC proliferation induced by IL-10 was deduced from results showing that IL-10-induced proliferation was abrogated if MC transfected with STAT3 antisense oligonucleotides were used or if cells were incubated with inhibitors of STAT3. AS101 deactivates STAT3 in control but not in MC transfected with IL-10 antisense oligonucleotides. Inactivation of STAT3 prevents reduction of MC proliferation by AS101. We further demonstrate the role of STAT3 in the regulation of cell cycle and survival regulatory proteins by AS101 in MC via inhibition of IL-10. IL-10 increased MC expression of Bcl-2 and Bcl-X1 and simultaneously decreased the levels of p27kip1. These survival factors were decreased by AS101 in a STAT3- and IL-10-dependent manner, whereas p27kip1 was similarly increased. In Thy1 GN, phosphorylated STAT3 in glomerular MC peaked at day 6 and correlated with MC expansion. Neutralization of IL-10 or its inhibition by AS101 abolished phosphorylation of STAT3. This effect positively correlated with amelioration of the disease. These in vitro and in vivo studies indicate that the autocrine MC growth factor IL-10 induces MC proliferation via STAT3. We suggest that IL-10 or its downstream target STAT3 might be therapeutic targets for kidney diseases induced by mesangial proliferation.
