Reactive oxygen species (ROS) and oxidative stress increase susceptibility to neurodegeneration a... more Reactive oxygen species (ROS) and oxidative stress increase susceptibility to neurodegeneration and other age-related pathologies. We have previously demonstrated that an infusion prepared from Pulicaria incisa (Pi) has protective, anti-inflammatory, and antioxidative effects in glial cells. However, the neuroprotective activities of Pi infusion in cultured neurons and aging mice have never been studied. In the following study, the effects of Pi infusion were explored in a hydrogen peroxide (H2O2)-induced oxidative stress model in SH-SY5Y human neuroblastoma cells. Profiling of the infusion by gas chromatography–mass spectrometry identified chlorogenic acid, quercetin, and aucubin as some of its main constituents. H2O2-induced ROS accumulation and caspase 3 activity decreased SH-SY5Y viability and were prevented upon the pretreatment of cells with Pi infusion. Additionally, the Pi infusion upregulated cellular levels and the nuclear translocation of nuclear factor erythroid 2–relate...
We chose to focus our investigations on the effect of the active forms, TTF and AcA, rather than ... more We chose to focus our investigations on the effect of the active forms, TTF and AcA, rather than the whole (crude) extract. 1. To establish cultivation program designed to develop lead cultivar/s (which will be selected from the different Af accessions) with the highest yield of the active compounds TTF and/or achillolide A (AcA). These cultivar/s will be the source for the purification of large amounts of the active compounds when needed in the future for functional foods/drug development. This task was completed. 2. To determine the effect of the Af extract, TTF and AcA on neuronal vulnerability to oxidative stress in cultured neurons expressing FAD-linked mutants.Compounds were tested in N2a neuroblastoma cell line. In addition, we have tested the effects of TTF and AcA on signaling events promoted by H₂O₂ in astrocytes and by β-amyloid in neuronal N2a cells. 3. To determine the effect of the Af extract, TTF and AcA on neuropathology (amyloidosis and tau phosphorylation) in cultu...
Plant-derived substances have been shown to affect potential targets in inflammatory diseases. We... more Plant-derived substances have been shown to affect potential targets in inflammatory diseases. We have previously purified from the desert plant Achillea fragrantissima, a sesquiterpene lactone named achillolide A, and demonstrated its anti-inflammatory activities in cultured brain macrophages named microglial cells. In the present study, we further investigated achillolide A in alleviating atopic dermatitis, a chronic and recurring inflammatory skin disease. We investigated achillolide A for its in vivo anti-inflammatory activity using the oxazolone model of atopic dermatitis in mice, in which oxazolone induces ear swelling. Our results show that mice treated with achillolide A showed a significant decrease in the oxazolone-induced ear swelling. Since macrophages are inflammatory cells that play a pivotal role in the pathogenesis of atopic dermatitis, the anti-inflammatory effects of achillolide A were also studied in spleen cells. We demonstrated that achillolide A reduced the lev...
Proceedings of the National Academy of Sciences, 1998
Myasthenia gravis (MG) is a T cell-regulated, antibody-mediated autoimmune disease. Two peptides ... more Myasthenia gravis (MG) is a T cell-regulated, antibody-mediated autoimmune disease. Two peptides representing sequences of the human acetylcholine receptor α-subunit, p195–212 and p259–271, previously were shown to stimulate the proliferation of peripheral blood lymphocytes of patients with MG and were found to be immunodominant T cell epitopes in SJL and BALB/c mice, respectively. Single amino acid-substituted analogs of p195–212 and p259–271, as well as a dual analog composed of the tandemly arranged two single analogs, were shown to inhibit, in vitro and in vivo , MG-associated autoimmune responses. Stimulation of T cells through the antigen-specific T cell receptor activates tyrosine kinases and phospholipase C (PLC). Therefore, in attempts to understand the mechanism of action of the analogs, we first examined whether the myasthenogenic peptides trigger tyrosine phosphorylation and activation of phospholipase C. For that purpose, we measured generation of inositol phosphates an...
Cytokines have been suggested to be involved in the cross talk between the immune and the nervous... more Cytokines have been suggested to be involved in the cross talk between the immune and the nervous systems, under normal and pathological conditions. For example, the cytokine interleukin-2 was suggested to be involved in response to CNS trauma and spontaneous regeneration. Here, we examined whether mammalian CNS has an intrinsic potential to produce interleukin-2 and, if so, what its cellular origin is. mRNA sequences encoding for interleukin-2 were detected in brains of humans and rodents. Northern blot analysis revealed the presence of several interleukin-2 transcripts of different sizes in the brain, all recognized by lymphocyte-derived interleukin-2 cDNA probes. One of the transcripts, a high molecular weight form of approximately 5 kb, appeared to be unique to the brain. Reverse transcription and amplification by PCR of human fetal brain mRNA revealed one cDNA product that, upon sequence analysis, showed a high degree of homology with the human lymphocyte-derived interleukin-2 coding sequence. To identify the possible cellular source of the interleukin-2 transcripts within the mammalian brain, we similarly analyzed mRNA of rat brain cells in culture. Northern blot analysis revealed that astrocytes contain transcripts that hybridize with interleukin-2 cDNA probe. These findings point to the astrocytes as a possible source of brain interleukin-2.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the increased produc... more Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the increased production of autoantibodies and by T cell dysfunction associated with general clinical manifestations. A model of induced experimental SLE by the immunization with the human monoclonal anti-DNA 16/6Id(+) autoantibody and a model of the SLE-prone mice (NZB x NZW)F1 were used in the present study. Two peptides based on the complementarity determining regions (CDR) 1 and 3 of a murine monoclonal anti-DNA 16/6Id(+) autoantibody were shown to ameliorate spontaneous and induced SLE in mice. We demonstrate here that levels of matrix metalloproteinase (MMP)-3 and MMP-9 were elevated in plasma and kidneys of SLE-afflicted mice. Levels of both MMP-3 and MMP-9 were elevated in kidneys of mice with the 16/6Id induced experimental SLE already in the early phases of disease development. However, increased levels of only MMP-3 were detected in the plasma at the early stages of disease, while MMP-9 activity was elevated later, when clinical manifestations were already observed. Treatment of SLE-afflicted mice, with the CDR1-based peptide that ameliorates disease manifestations in mice, led to a reduction in MMP-9 activity and in MMP-3 protein levels both in plasma and in kidneys. We thus suggest that these enzymes may play a pathogenic role in the disease and may serve as markers for the determination of disease progression or amelioration.
Reactive oxygen species (ROS) and oxidative stress increase susceptibility to neurodegeneration a... more Reactive oxygen species (ROS) and oxidative stress increase susceptibility to neurodegeneration and other age-related pathologies. We have previously demonstrated that an infusion prepared from Pulicaria incisa (Pi) has protective, anti-inflammatory, and antioxidative effects in glial cells. However, the neuroprotective activities of Pi infusion in cultured neurons and aging mice have never been studied. In the following study, the effects of Pi infusion were explored in a hydrogen peroxide (H2O2)-induced oxidative stress model in SH-SY5Y human neuroblastoma cells. Profiling of the infusion by gas chromatography–mass spectrometry identified chlorogenic acid, quercetin, and aucubin as some of its main constituents. H2O2-induced ROS accumulation and caspase 3 activity decreased SH-SY5Y viability and were prevented upon the pretreatment of cells with Pi infusion. Additionally, the Pi infusion upregulated cellular levels and the nuclear translocation of nuclear factor erythroid 2–relate...
We chose to focus our investigations on the effect of the active forms, TTF and AcA, rather than ... more We chose to focus our investigations on the effect of the active forms, TTF and AcA, rather than the whole (crude) extract. 1. To establish cultivation program designed to develop lead cultivar/s (which will be selected from the different Af accessions) with the highest yield of the active compounds TTF and/or achillolide A (AcA). These cultivar/s will be the source for the purification of large amounts of the active compounds when needed in the future for functional foods/drug development. This task was completed. 2. To determine the effect of the Af extract, TTF and AcA on neuronal vulnerability to oxidative stress in cultured neurons expressing FAD-linked mutants.Compounds were tested in N2a neuroblastoma cell line. In addition, we have tested the effects of TTF and AcA on signaling events promoted by H₂O₂ in astrocytes and by β-amyloid in neuronal N2a cells. 3. To determine the effect of the Af extract, TTF and AcA on neuropathology (amyloidosis and tau phosphorylation) in cultu...
Plant-derived substances have been shown to affect potential targets in inflammatory diseases. We... more Plant-derived substances have been shown to affect potential targets in inflammatory diseases. We have previously purified from the desert plant Achillea fragrantissima, a sesquiterpene lactone named achillolide A, and demonstrated its anti-inflammatory activities in cultured brain macrophages named microglial cells. In the present study, we further investigated achillolide A in alleviating atopic dermatitis, a chronic and recurring inflammatory skin disease. We investigated achillolide A for its in vivo anti-inflammatory activity using the oxazolone model of atopic dermatitis in mice, in which oxazolone induces ear swelling. Our results show that mice treated with achillolide A showed a significant decrease in the oxazolone-induced ear swelling. Since macrophages are inflammatory cells that play a pivotal role in the pathogenesis of atopic dermatitis, the anti-inflammatory effects of achillolide A were also studied in spleen cells. We demonstrated that achillolide A reduced the lev...
Proceedings of the National Academy of Sciences, 1998
Myasthenia gravis (MG) is a T cell-regulated, antibody-mediated autoimmune disease. Two peptides ... more Myasthenia gravis (MG) is a T cell-regulated, antibody-mediated autoimmune disease. Two peptides representing sequences of the human acetylcholine receptor α-subunit, p195–212 and p259–271, previously were shown to stimulate the proliferation of peripheral blood lymphocytes of patients with MG and were found to be immunodominant T cell epitopes in SJL and BALB/c mice, respectively. Single amino acid-substituted analogs of p195–212 and p259–271, as well as a dual analog composed of the tandemly arranged two single analogs, were shown to inhibit, in vitro and in vivo , MG-associated autoimmune responses. Stimulation of T cells through the antigen-specific T cell receptor activates tyrosine kinases and phospholipase C (PLC). Therefore, in attempts to understand the mechanism of action of the analogs, we first examined whether the myasthenogenic peptides trigger tyrosine phosphorylation and activation of phospholipase C. For that purpose, we measured generation of inositol phosphates an...
Cytokines have been suggested to be involved in the cross talk between the immune and the nervous... more Cytokines have been suggested to be involved in the cross talk between the immune and the nervous systems, under normal and pathological conditions. For example, the cytokine interleukin-2 was suggested to be involved in response to CNS trauma and spontaneous regeneration. Here, we examined whether mammalian CNS has an intrinsic potential to produce interleukin-2 and, if so, what its cellular origin is. mRNA sequences encoding for interleukin-2 were detected in brains of humans and rodents. Northern blot analysis revealed the presence of several interleukin-2 transcripts of different sizes in the brain, all recognized by lymphocyte-derived interleukin-2 cDNA probes. One of the transcripts, a high molecular weight form of approximately 5 kb, appeared to be unique to the brain. Reverse transcription and amplification by PCR of human fetal brain mRNA revealed one cDNA product that, upon sequence analysis, showed a high degree of homology with the human lymphocyte-derived interleukin-2 coding sequence. To identify the possible cellular source of the interleukin-2 transcripts within the mammalian brain, we similarly analyzed mRNA of rat brain cells in culture. Northern blot analysis revealed that astrocytes contain transcripts that hybridize with interleukin-2 cDNA probe. These findings point to the astrocytes as a possible source of brain interleukin-2.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the increased produc... more Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the increased production of autoantibodies and by T cell dysfunction associated with general clinical manifestations. A model of induced experimental SLE by the immunization with the human monoclonal anti-DNA 16/6Id(+) autoantibody and a model of the SLE-prone mice (NZB x NZW)F1 were used in the present study. Two peptides based on the complementarity determining regions (CDR) 1 and 3 of a murine monoclonal anti-DNA 16/6Id(+) autoantibody were shown to ameliorate spontaneous and induced SLE in mice. We demonstrate here that levels of matrix metalloproteinase (MMP)-3 and MMP-9 were elevated in plasma and kidneys of SLE-afflicted mice. Levels of both MMP-3 and MMP-9 were elevated in kidneys of mice with the 16/6Id induced experimental SLE already in the early phases of disease development. However, increased levels of only MMP-3 were detected in the plasma at the early stages of disease, while MMP-9 activity was elevated later, when clinical manifestations were already observed. Treatment of SLE-afflicted mice, with the CDR1-based peptide that ameliorates disease manifestations in mice, led to a reduction in MMP-9 activity and in MMP-3 protein levels both in plasma and in kidneys. We thus suggest that these enzymes may play a pathogenic role in the disease and may serve as markers for the determination of disease progression or amelioration.
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Papers by Anat Elmann