Julia Mazar - Academia.edu (original) (raw)
Papers by Julia Mazar
Tissue damage associated with trauma might release a sufficient autoantigen substrate to break im... more Tissue damage associated with trauma might release a sufficient autoantigen substrate to break immune tolerance. In a previous study, we showed that the leukopenia observed following severe inflammation is related to adenosine A1-receptor (A1R) desensitization and A2AR upregulation. We hypothesized that, under destructive pathological conditions this mechanism is beneficial in reducing prevalence of autoimmunity. In this study, we aim to evaluate the protective role of A1R and A2AR in prevention of autoimmune diseases. We used two murine models of autoimmune diseases: type 1 diabetes (T1D) induced by low-dose streptozotocin and pristane-induced lupus (PIL) and on neutrophils we studied NETosis regulation by adenosine. In both the T1D and PIL models, A1R-KO mice were predisposed to the development of autoimmunity. In the PIL model, in WT mice, parallel to the decline of A1R mRNA levels, lymphocytes number dropped (-85%) 6h after pristane injection. WT mice remained without any sign of disease at 36 weeks. In contrast, following pristane 43% of A1R-KO mice suffered from lupus-like disease. Compared to A1R-KO, in WT mice at 10 days A2AR mRNA levels were significantly higher. Similar to PIL, in T1D model the presence of A1R and A2AR was protective. In addition, we found that A1R increases and A2AR suppresses NETosis. We suggest that adenosine-dependent immune suppression and reduction in neutrophil extracellular traps (NETs) limits the reactive T-cells and development of anti-double strand DNA (dsDNA) antibodies that promote autoimmunity. A 1 and A 2A adenosine receptors play a protective role to reduce prevalence of autoimmunity following tissue damage
Blood
Mimosine, a non-protein amino acid, acts as a reversible inhibitor of DNA replication, and is wid... more Mimosine, a non-protein amino acid, acts as a reversible inhibitor of DNA replication, and is widely used to synchronize cells at G1 phase of the cell cycle. We tested the possibility that mimosine might have an apoptotic effect on two types of AML cells: the monoblastic U-937 and the promyelocytic HL-60 cell lines. We show that mimosine induces apoptosis in both cell lines, with U-937 cells being more sensitive. The apoptotic effect of mimosine was antagonized by the addition of exogenous iron, indicating that it may act through iron chelation. Its mode of action was thus compared to that of desferrioxamine (DFO), a therapeutic iron chelating agent. Mimosine and DFO differed in their sensitivity to the suppressive effect of exogenous sources of iron in the form of hemin and ferrous sulfate suggesting different targets of action. Addition of another metal ion cupric sulfate was also able to antagonize the apoptotic effect of mimosine, undermining the notion that apoptosis is mediate...
Blood
Many types of antitumor therapy in general and AML in particular exert their effect by activating... more Many types of antitumor therapy in general and AML in particular exert their effect by activating apoptosis. Apoptosis of AML cells can be induced by cytostatic drugs, corticosteroids, and radiation. Recently, the role of different proteases as possible targets for chemotherapy was described. N-tosyl-L-phenylalanine chloromethyl ketone (TPCK), a chymotrypsin-like protease (CLP) inhibitor was shown to exert a dual effect on leukemic cells: proapoptotic and antiapoptotic. In the present study the mechanism of its proapoptotic effect was addressed. It was found that the CLP inhibitors, TPCK and 3,4 dichloroisicoumarine induced apoptosis in a time- and concentration-dependent manner. Apoptosis was accompanied by a decrease in mitochondrial membrane potential, cytochrome c release, caspase-3 (but not caspase-8) activation, PS flip-flop (measured by Annexin-V staining followed by flow cytometry analysis) and chromatin condensation, but not fragmentation (detected by acridine orange/ethidi...
Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis
Background CD40 belongs to the tumor necrosis factor receptor family and its ligation is a centra... more Background CD40 belongs to the tumor necrosis factor receptor family and its ligation is a central event in major inflammatory and immune reactions. We have previously demonstrated that CD40 ligation upregulates the secretion of mononuclear chemokines from peritoneal mesothelial cells (PMC), and that blocking the CD40 ligand (CD154) reduced the mononuclear infiltrate in a model of peritonitis. Objective To characterize the kinetics of CD154 expression on peritoneal leukocytes and examine the correlation of this occurrence with the mononuclear transition at the resolution phase of peritonitis. Methods Leukocytes were collected from the effluent of 11 patients during episodes of peritonitis while undergoing peritoneal dialysis (PD). The effluent was then analyzed by flow cytometry to characterize CD154 expression. Results CD154 expression on peritoneal mononuclear cells gradually increased during the resolution phase of peritonitis, peaking first on T cells (CD4+ and CD8+ cells at 20 ...
Blood
Inherited factor VII (FVII) deficiency is the most common among the autosomal recessive rare blee... more Inherited factor VII (FVII) deficiency is the most common among the autosomal recessive rare bleeding disorders, with an estimated prevalence of 1:300,000 in European countries. Affected individuals display a wide range of clinical phenotypes, ranging from mild non spontaneous bleeding to life threatening (i.e. central nervous system[CNS] bleeding, gastrointestinal [GI] bleeding or haemarthrosis), whereas up to one-third of individuals with a FVII deficiency are asymptomatic and are mainly diagnosed during family studies or after screening for surgery. Unfortunately, the residual activity of FVII does not predict the individual propensity to bleed, and even in individuals with the same mutation, differences in clotting phenotypes can be seen. As our tertiary center serves a unique population in the Negev, we aimed at studying the prevalence and phenotype of FVII deficiency within the last decade. Methods: We searched all electronic records for the last 10 years depicting rare bleedi...
Journal of leukocyte biology, Jan 11, 2017
SIRS is associated with lymphopenia, and prolonged lymphopenia of septic patients has been associ... more SIRS is associated with lymphopenia, and prolonged lymphopenia of septic patients has been associated with increased mortality risk. We hypothesize that elevated adenosine during SIRS down-regulates Gi-coupled A1R, which signals an effect that sensitizes a cAMP-dependent lymphotoxic response. In this study, we evaluate the role of adenosine in SIRS-mediated lymphopenia and impaired IL-15 production. Cecal ligation and puncture was used to induce sepsis-associated SIRS in mice. BMDCs were cultured and used to measure the effect of adenosine on IL-15. We found that A1R mRNA levels were significantly down-regulated and A1R-dependent Gi activity was abolished in T cells of septic mice. In accordance, cAMP was elevated in isolated T cells from cecal ligation and puncture compared with sham-treated mice. Similar to septic mice, leukopenia was evident in sham A1R-KO mice, after treatment with the A1R antagonist (8-cyclopentyl-1,3-dipropylxanthine), or after A1R desensitization. In contrast...
Biochemical Society Transactions, 2000
The Biological bulletin, 2011
Synaptic vesicles contain a variety of proteins and lipids that mediate fusion with the pre-synap... more Synaptic vesicles contain a variety of proteins and lipids that mediate fusion with the pre-synaptic membrane. Although the structures of many synaptic vesicle proteins are known, an overall picture of how they are organized at the vesicle surface is lacking. In this paper, we describe a better method for the isolation of squid synaptic vesicles and characterize the results. For highly pure and intact synaptic vesicles from squid optic lobe, glycerol density gradient centrifugation was the key step. Different electron microscopic methods show that vesicle membrane surfaces are largely covered with structures corresponding to surface proteins. Each vesicle contains several stalked globular structures that extend from the vesicle surface and are consistent with the V-ATPase. BLAST search of a library of squid expressed sequence tags identifies 10 V-ATPase subunits, which are expressed in the squid stellate ganglia. Negative-stain tomography demonstrates directly that vesicles flatten ...
Kidney International, 2005
Kidney International, 2006
Journal of Biological Chemistry, 2009
International Immunopharmacology, 2014
Under stressful conditions such as ischemia, sepsis, and severe trauma, adenosine levels are elev... more Under stressful conditions such as ischemia, sepsis, and severe trauma, adenosine levels are elevated and protect the tissue by interaction with G coupled receptors. In a model of peritonitis, we previously found that pharmacological preconditioning (PPC) of mice with a selective adenosine A 1 receptor (A 1 R) agonist, 2-chloro-N(6)-cyclopentyladenosine (CCPA), induced the A 2A R which reduces cytokine secretion and leukocyte recruitment. In our present study we determined whether mice PPC will moderate cellular immune response by the same mechanism. Similar to the effect on inflammation, PPC reduced the response to lymphocyte mitogens and allogeneic MLR response. The inhibitory effect of PPC on the immune response was A 1 R and A 2A R dependent as illustrated by experiments with antagonists of these receptors and mice with knock down (KO) receptors. In MLR with PPC splenocytes we found reduced levels of pro-inflammatory cytokines (IFN-γ, IL-15, TNF-α) and elevation of IL-10, as well as elevation of regulatory T-cell. Our data indicate that PPC is able to remarkably suppress cellular immune response due to the sensitization A 2A R. This effect of PPC sheds light on the protective role of adenosine in ischemic preconditioning and makes this treatment candidate for the prevention of graft rejection.
Cytokine, 2006
The possibility that islets play a role in graft rejection during islet transplantation for type-... more The possibility that islets play a role in graft rejection during islet transplantation for type-1 diabetes patients holds promise for ex vivo islet manipulation and for specific anti-rejection therapy. Interleukin (IL)-15 is a T cell growth factor and chemoattractant that is expressed by non-T cells. Intragraft expression of IL-15 is elevated during acute rejection in patients and in mice, and systemic blockade of IL-15 in mice prolongs allograft survival. However, the source of IL-15 in these conditions is undetermined. Since epithelial cell-derived IL-15 promotes lymphocyte proliferation in culture, we sought to determine whether islet-derived IL-15 promotes rejection in mice. We designed antisense oligodeoxyribonucleotide molecules that target mouse IL-15. Uptake of FITC-labeled antisense molecules and efficacy of IL-15 inhibition in IFNgamma-stimulated islets were evaluated. Islets exhibited typical cytoplasmatic distribution of antisense molecules and produced IL-15 levels that were comparable to non-stimulated cells. Antisense-treated islet allografts, that were transplanted across multiple minor-histocompatibility-antigen mismatched strains of mice, were accepted at a higher rate than control-antisense treated islets or untreated islets (88.9% vs. 37.5% and 20%, respectively). Our results suggest that islet-derived IL-15 may be involved in acute islet allograft rejection.
Apoptosis, 2008
Mimosine, a non-protein amino acid, is mainly known for its action as a reversible inhibitor of D... more Mimosine, a non-protein amino acid, is mainly known for its action as a reversible inhibitor of DNA replication and, therefore, has been widely used as a cell cycle synchronizing agent. Recently, it has been shown that mimosine also induces apoptosis, as mainly reflected in its ability to elicit characteristic nuclear changes. The present study elucidates the mechanism underlying mimosine's apoptotic effects, using the U-937 leukemia cell line. We now demonstrate that in isolated rat liver mitochondria, mimosine induces mitochondrial swelling that can be inhibited by cyclosporine A, indicative of permeability transition (PT) mega-channel opening. Mimosine-induced apoptosis was accompanied by formation of hydrogen peroxide and a decrease in reduced glutathione levels. The apoptotic process was partially inhibited by cyclosporine A and substantially blocked by the antioxidant N-acetylcysteine, suggesting an essential role for reactive oxygen species formation during the apoptotic processes. The apoptosis induced by mimosine was also accompanied by a decrease in mitochondrial membrane potential, cytochrome c release and caspase 3 and 9 activation. Our results thus imply that mimosine activates apoptosis through mitochondrial activation and formation of H2O2, both of which play functional roles in the induction of cell death.
Anesthesiology, 2005
Background Ketamine is an anesthetic drug. Subanesthetic doses of ketamine have been shown to red... more Background Ketamine is an anesthetic drug. Subanesthetic doses of ketamine have been shown to reduce interleukin-6 concentrations after surgery and to reduce mortality and the production of tumor necrosis factor alpha and interleukin 6 in septic animals. Similarly, adenosine was shown to reduce tumor necrosis factor alpha and mortality of septic animals. The aim of this study was to determine whether adenosine mediates the antiinflammatory effects of ketamine. Methods Sepsis was induced in mice by lipopolysaccharide or Escherichia coli inoculation. Leukocyte recruitment and cytokine concentrations were used as inflammation markers. Adenosine concentrations were assayed by high-performance liquid chromatography, and the involvement of adenosine in the effects of ketamine was demonstrated by adenosine receptor agonists and antagonists. Results Ketamine markedly reduced mortality from sepsis, leukocyte recruitment, and tumor necrosis factor-alpha and interleukin-6 concentrations. Ketam...
Anesthesia & Analgesia, 2006
Ketamine was reported to decrease cytokine production and improve survival after Escherichia coli... more Ketamine was reported to decrease cytokine production and improve survival after Escherichia coli-induced sepsis. We examined whether ketamine decreased interleukin (IL)-6 production and improved survival after 1) burn injury or 2) burn injury combined with sepsis (E. coli) at 24 h. Ketamine (10 mg/kg) or saline was given at 1 h after burn injury (G 1, 2, 5, 6), 24 h after burn injury (G 3, 4), or at E. coli inoculation (G 7, 8). Mortality was recorded for 7 days and IL-6 was measured in serum at 6 h after burn (G 1-2), 30 h after burn (G 3-4), or 6 h after sepsis (30 h after burn) (G 5-8). Burn injury only: Ketamine given immediately (1 h) after burn injury but not 24 h after, decreased the burn-induced increase of IL-6 but did not improve survival. Burn injury + sepsis: Ketamine given immediately after burn injury did not significantly decrease the sepsis-induced increase of IL-6 or improve survival. In contrast, ketamine given immediately after sepsis significantly improved survival (46.1% versus 13.3%, P = 0.008) and decreased IL-6 production (72,640 +/- 40,990 vs 332,300 +/- 32,300 pg/mL, P = 0.008). We conclude that ketamine therapy improves survival in burn injury followed by sepsis. This beneficial effect is probably achieved through interference with the inflammatory cascade, as evidenced by attenuation of the proinflammatory marker IL-6.
Cellular Microbiology, 2009
Tissue damage associated with trauma might release a sufficient autoantigen substrate to break im... more Tissue damage associated with trauma might release a sufficient autoantigen substrate to break immune tolerance. In a previous study, we showed that the leukopenia observed following severe inflammation is related to adenosine A1-receptor (A1R) desensitization and A2AR upregulation. We hypothesized that, under destructive pathological conditions this mechanism is beneficial in reducing prevalence of autoimmunity. In this study, we aim to evaluate the protective role of A1R and A2AR in prevention of autoimmune diseases. We used two murine models of autoimmune diseases: type 1 diabetes (T1D) induced by low-dose streptozotocin and pristane-induced lupus (PIL) and on neutrophils we studied NETosis regulation by adenosine. In both the T1D and PIL models, A1R-KO mice were predisposed to the development of autoimmunity. In the PIL model, in WT mice, parallel to the decline of A1R mRNA levels, lymphocytes number dropped (-85%) 6h after pristane injection. WT mice remained without any sign of disease at 36 weeks. In contrast, following pristane 43% of A1R-KO mice suffered from lupus-like disease. Compared to A1R-KO, in WT mice at 10 days A2AR mRNA levels were significantly higher. Similar to PIL, in T1D model the presence of A1R and A2AR was protective. In addition, we found that A1R increases and A2AR suppresses NETosis. We suggest that adenosine-dependent immune suppression and reduction in neutrophil extracellular traps (NETs) limits the reactive T-cells and development of anti-double strand DNA (dsDNA) antibodies that promote autoimmunity. A 1 and A 2A adenosine receptors play a protective role to reduce prevalence of autoimmunity following tissue damage
Blood
Mimosine, a non-protein amino acid, acts as a reversible inhibitor of DNA replication, and is wid... more Mimosine, a non-protein amino acid, acts as a reversible inhibitor of DNA replication, and is widely used to synchronize cells at G1 phase of the cell cycle. We tested the possibility that mimosine might have an apoptotic effect on two types of AML cells: the monoblastic U-937 and the promyelocytic HL-60 cell lines. We show that mimosine induces apoptosis in both cell lines, with U-937 cells being more sensitive. The apoptotic effect of mimosine was antagonized by the addition of exogenous iron, indicating that it may act through iron chelation. Its mode of action was thus compared to that of desferrioxamine (DFO), a therapeutic iron chelating agent. Mimosine and DFO differed in their sensitivity to the suppressive effect of exogenous sources of iron in the form of hemin and ferrous sulfate suggesting different targets of action. Addition of another metal ion cupric sulfate was also able to antagonize the apoptotic effect of mimosine, undermining the notion that apoptosis is mediate...
Blood
Many types of antitumor therapy in general and AML in particular exert their effect by activating... more Many types of antitumor therapy in general and AML in particular exert their effect by activating apoptosis. Apoptosis of AML cells can be induced by cytostatic drugs, corticosteroids, and radiation. Recently, the role of different proteases as possible targets for chemotherapy was described. N-tosyl-L-phenylalanine chloromethyl ketone (TPCK), a chymotrypsin-like protease (CLP) inhibitor was shown to exert a dual effect on leukemic cells: proapoptotic and antiapoptotic. In the present study the mechanism of its proapoptotic effect was addressed. It was found that the CLP inhibitors, TPCK and 3,4 dichloroisicoumarine induced apoptosis in a time- and concentration-dependent manner. Apoptosis was accompanied by a decrease in mitochondrial membrane potential, cytochrome c release, caspase-3 (but not caspase-8) activation, PS flip-flop (measured by Annexin-V staining followed by flow cytometry analysis) and chromatin condensation, but not fragmentation (detected by acridine orange/ethidi...
Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis
Background CD40 belongs to the tumor necrosis factor receptor family and its ligation is a centra... more Background CD40 belongs to the tumor necrosis factor receptor family and its ligation is a central event in major inflammatory and immune reactions. We have previously demonstrated that CD40 ligation upregulates the secretion of mononuclear chemokines from peritoneal mesothelial cells (PMC), and that blocking the CD40 ligand (CD154) reduced the mononuclear infiltrate in a model of peritonitis. Objective To characterize the kinetics of CD154 expression on peritoneal leukocytes and examine the correlation of this occurrence with the mononuclear transition at the resolution phase of peritonitis. Methods Leukocytes were collected from the effluent of 11 patients during episodes of peritonitis while undergoing peritoneal dialysis (PD). The effluent was then analyzed by flow cytometry to characterize CD154 expression. Results CD154 expression on peritoneal mononuclear cells gradually increased during the resolution phase of peritonitis, peaking first on T cells (CD4+ and CD8+ cells at 20 ...
Blood
Inherited factor VII (FVII) deficiency is the most common among the autosomal recessive rare blee... more Inherited factor VII (FVII) deficiency is the most common among the autosomal recessive rare bleeding disorders, with an estimated prevalence of 1:300,000 in European countries. Affected individuals display a wide range of clinical phenotypes, ranging from mild non spontaneous bleeding to life threatening (i.e. central nervous system[CNS] bleeding, gastrointestinal [GI] bleeding or haemarthrosis), whereas up to one-third of individuals with a FVII deficiency are asymptomatic and are mainly diagnosed during family studies or after screening for surgery. Unfortunately, the residual activity of FVII does not predict the individual propensity to bleed, and even in individuals with the same mutation, differences in clotting phenotypes can be seen. As our tertiary center serves a unique population in the Negev, we aimed at studying the prevalence and phenotype of FVII deficiency within the last decade. Methods: We searched all electronic records for the last 10 years depicting rare bleedi...
Journal of leukocyte biology, Jan 11, 2017
SIRS is associated with lymphopenia, and prolonged lymphopenia of septic patients has been associ... more SIRS is associated with lymphopenia, and prolonged lymphopenia of septic patients has been associated with increased mortality risk. We hypothesize that elevated adenosine during SIRS down-regulates Gi-coupled A1R, which signals an effect that sensitizes a cAMP-dependent lymphotoxic response. In this study, we evaluate the role of adenosine in SIRS-mediated lymphopenia and impaired IL-15 production. Cecal ligation and puncture was used to induce sepsis-associated SIRS in mice. BMDCs were cultured and used to measure the effect of adenosine on IL-15. We found that A1R mRNA levels were significantly down-regulated and A1R-dependent Gi activity was abolished in T cells of septic mice. In accordance, cAMP was elevated in isolated T cells from cecal ligation and puncture compared with sham-treated mice. Similar to septic mice, leukopenia was evident in sham A1R-KO mice, after treatment with the A1R antagonist (8-cyclopentyl-1,3-dipropylxanthine), or after A1R desensitization. In contrast...
Biochemical Society Transactions, 2000
The Biological bulletin, 2011
Synaptic vesicles contain a variety of proteins and lipids that mediate fusion with the pre-synap... more Synaptic vesicles contain a variety of proteins and lipids that mediate fusion with the pre-synaptic membrane. Although the structures of many synaptic vesicle proteins are known, an overall picture of how they are organized at the vesicle surface is lacking. In this paper, we describe a better method for the isolation of squid synaptic vesicles and characterize the results. For highly pure and intact synaptic vesicles from squid optic lobe, glycerol density gradient centrifugation was the key step. Different electron microscopic methods show that vesicle membrane surfaces are largely covered with structures corresponding to surface proteins. Each vesicle contains several stalked globular structures that extend from the vesicle surface and are consistent with the V-ATPase. BLAST search of a library of squid expressed sequence tags identifies 10 V-ATPase subunits, which are expressed in the squid stellate ganglia. Negative-stain tomography demonstrates directly that vesicles flatten ...
Kidney International, 2005
Kidney International, 2006
Journal of Biological Chemistry, 2009
International Immunopharmacology, 2014
Under stressful conditions such as ischemia, sepsis, and severe trauma, adenosine levels are elev... more Under stressful conditions such as ischemia, sepsis, and severe trauma, adenosine levels are elevated and protect the tissue by interaction with G coupled receptors. In a model of peritonitis, we previously found that pharmacological preconditioning (PPC) of mice with a selective adenosine A 1 receptor (A 1 R) agonist, 2-chloro-N(6)-cyclopentyladenosine (CCPA), induced the A 2A R which reduces cytokine secretion and leukocyte recruitment. In our present study we determined whether mice PPC will moderate cellular immune response by the same mechanism. Similar to the effect on inflammation, PPC reduced the response to lymphocyte mitogens and allogeneic MLR response. The inhibitory effect of PPC on the immune response was A 1 R and A 2A R dependent as illustrated by experiments with antagonists of these receptors and mice with knock down (KO) receptors. In MLR with PPC splenocytes we found reduced levels of pro-inflammatory cytokines (IFN-γ, IL-15, TNF-α) and elevation of IL-10, as well as elevation of regulatory T-cell. Our data indicate that PPC is able to remarkably suppress cellular immune response due to the sensitization A 2A R. This effect of PPC sheds light on the protective role of adenosine in ischemic preconditioning and makes this treatment candidate for the prevention of graft rejection.
Cytokine, 2006
The possibility that islets play a role in graft rejection during islet transplantation for type-... more The possibility that islets play a role in graft rejection during islet transplantation for type-1 diabetes patients holds promise for ex vivo islet manipulation and for specific anti-rejection therapy. Interleukin (IL)-15 is a T cell growth factor and chemoattractant that is expressed by non-T cells. Intragraft expression of IL-15 is elevated during acute rejection in patients and in mice, and systemic blockade of IL-15 in mice prolongs allograft survival. However, the source of IL-15 in these conditions is undetermined. Since epithelial cell-derived IL-15 promotes lymphocyte proliferation in culture, we sought to determine whether islet-derived IL-15 promotes rejection in mice. We designed antisense oligodeoxyribonucleotide molecules that target mouse IL-15. Uptake of FITC-labeled antisense molecules and efficacy of IL-15 inhibition in IFNgamma-stimulated islets were evaluated. Islets exhibited typical cytoplasmatic distribution of antisense molecules and produced IL-15 levels that were comparable to non-stimulated cells. Antisense-treated islet allografts, that were transplanted across multiple minor-histocompatibility-antigen mismatched strains of mice, were accepted at a higher rate than control-antisense treated islets or untreated islets (88.9% vs. 37.5% and 20%, respectively). Our results suggest that islet-derived IL-15 may be involved in acute islet allograft rejection.
Apoptosis, 2008
Mimosine, a non-protein amino acid, is mainly known for its action as a reversible inhibitor of D... more Mimosine, a non-protein amino acid, is mainly known for its action as a reversible inhibitor of DNA replication and, therefore, has been widely used as a cell cycle synchronizing agent. Recently, it has been shown that mimosine also induces apoptosis, as mainly reflected in its ability to elicit characteristic nuclear changes. The present study elucidates the mechanism underlying mimosine's apoptotic effects, using the U-937 leukemia cell line. We now demonstrate that in isolated rat liver mitochondria, mimosine induces mitochondrial swelling that can be inhibited by cyclosporine A, indicative of permeability transition (PT) mega-channel opening. Mimosine-induced apoptosis was accompanied by formation of hydrogen peroxide and a decrease in reduced glutathione levels. The apoptotic process was partially inhibited by cyclosporine A and substantially blocked by the antioxidant N-acetylcysteine, suggesting an essential role for reactive oxygen species formation during the apoptotic processes. The apoptosis induced by mimosine was also accompanied by a decrease in mitochondrial membrane potential, cytochrome c release and caspase 3 and 9 activation. Our results thus imply that mimosine activates apoptosis through mitochondrial activation and formation of H2O2, both of which play functional roles in the induction of cell death.
Anesthesiology, 2005
Background Ketamine is an anesthetic drug. Subanesthetic doses of ketamine have been shown to red... more Background Ketamine is an anesthetic drug. Subanesthetic doses of ketamine have been shown to reduce interleukin-6 concentrations after surgery and to reduce mortality and the production of tumor necrosis factor alpha and interleukin 6 in septic animals. Similarly, adenosine was shown to reduce tumor necrosis factor alpha and mortality of septic animals. The aim of this study was to determine whether adenosine mediates the antiinflammatory effects of ketamine. Methods Sepsis was induced in mice by lipopolysaccharide or Escherichia coli inoculation. Leukocyte recruitment and cytokine concentrations were used as inflammation markers. Adenosine concentrations were assayed by high-performance liquid chromatography, and the involvement of adenosine in the effects of ketamine was demonstrated by adenosine receptor agonists and antagonists. Results Ketamine markedly reduced mortality from sepsis, leukocyte recruitment, and tumor necrosis factor-alpha and interleukin-6 concentrations. Ketam...
Anesthesia & Analgesia, 2006
Ketamine was reported to decrease cytokine production and improve survival after Escherichia coli... more Ketamine was reported to decrease cytokine production and improve survival after Escherichia coli-induced sepsis. We examined whether ketamine decreased interleukin (IL)-6 production and improved survival after 1) burn injury or 2) burn injury combined with sepsis (E. coli) at 24 h. Ketamine (10 mg/kg) or saline was given at 1 h after burn injury (G 1, 2, 5, 6), 24 h after burn injury (G 3, 4), or at E. coli inoculation (G 7, 8). Mortality was recorded for 7 days and IL-6 was measured in serum at 6 h after burn (G 1-2), 30 h after burn (G 3-4), or 6 h after sepsis (30 h after burn) (G 5-8). Burn injury only: Ketamine given immediately (1 h) after burn injury but not 24 h after, decreased the burn-induced increase of IL-6 but did not improve survival. Burn injury + sepsis: Ketamine given immediately after burn injury did not significantly decrease the sepsis-induced increase of IL-6 or improve survival. In contrast, ketamine given immediately after sepsis significantly improved survival (46.1% versus 13.3%, P = 0.008) and decreased IL-6 production (72,640 +/- 40,990 vs 332,300 +/- 32,300 pg/mL, P = 0.008). We conclude that ketamine therapy improves survival in burn injury followed by sepsis. This beneficial effect is probably achieved through interference with the inflammatory cascade, as evidenced by attenuation of the proinflammatory marker IL-6.
Cellular Microbiology, 2009