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...
It is now widely accepted that injured nerves, like any other injured tissue, need assistance fro... more It is now widely accepted that injured nerves, like any other injured tissue, need assistance from their extracellular milieu in order to heal. We compared the postinjury activities of thrombin and gelatinases, two types of proteolytic activities known to be critically involved in tissue healing, in nonregenerative (rat optic nerve) and regenerative (fish optic nerve and rat sciatic nerve) neural tissue. Unlike gelatinases, whose induction pattern was comparable in all three nerves, thrombin-like activity differed clearly between regenerating and nonregenerating nervous systems. Postinjury levels of this latter activity seem to dictate whether it will display beneficial or detrimental effects on the capacity of the tissue for repair. The results of this study further highlight the fact that tissue repair and nerve regeneration are closely linked and that substances that are not unique to the nervous system, but participate in wound healing in general, are also crucial for regeneration or its failure in the nervous system.-Friedmann, I., Faber-Elman, A., Yoles, E., Schwartz, M. Injury-induced gelatinase and thrombin-like activities in regenerating and nonregenerating nervous systems.
Morphogenesis and tissue repair require appropriate cross-talk between the cells and their surrou... more Morphogenesis and tissue repair require appropriate cross-talk between the cells and their surrounding milieu, which includes extracellular components and soluble factors, e.g., cytokines and growth factors. The present work deals with this commuinicalion needed for recovery after axotonly in the central nervous system (CNS). The failure of CNS axons to regenerate after axonal injury has been attributed, in part, to astrocyte failure to repopuilate the injury site. The goal of this work was to provide an in vitro model to mimic the in vivo response of astrocytes to nerve injury and to find ways to modulate this response and create a milieu that favors astrocyte migration and repopulation of the injury site. In an astrocyte scratch wound model, we blocked astrocyte migration by tmnor necrosis factor a (TNF-a). This effect could not be reversed by astrocyte migration-inducing factors such as transforming growth factor i (TGF-1) or by any of the tested extracellular matrix (ECM) coniponents (laininin and fibronectin) except for vitronectin (Vn). Vn, added together with TNF-a, counteracted the TNFa blockage and allowed a massive migration of astrocytes (not due to cell proliferation) beyond that allowed by Vn only. Heparan sulfate proteoglycans (HSPG) were shown to be involved in the migration. The results may be relevant to regeneration of CNS axons, and may also provide an example that an extracellular component (Vn) can overcome and neutralize a negative effect of a growth factor/cytokine (TNF-a) and can act in synergy with other features of this cytokine to promote a necessary function (e.g., cell migration) that is otherwise inhibited.-Faber-Elman, A., Lavie, V., Schvartz, I., Shaltiel, S., Schwartz, M. Vitronectin overrides a negative effect of TNF-a on astrocyte migration.
Israel 3Corresponding author Communicated by M.Oren A covalent dimer ofinterleukin (IL)-2, produc... more Israel 3Corresponding author Communicated by M.Oren A covalent dimer ofinterleukin (IL)-2, produced in vitro by the action of a nerve-derived transglutaminase, has been shown previously to be cytotoxic to mature rat brain oligodendrocytes. Here we report that this cytotoxic effect operates via programmed cell death (apoptosis) and that the p53 tumor suppressor gene is involved directly in the process. The apoptotic death of mature rat brain oligodendrocytes in culture following treatment with dimeric IL-2 was demonstrated by chromatin condensation and internucleosomal DNA fragmentation. The peak of apoptosis was observed 16-24 h after treatment, while the commitment to death was already observed after 3-4 h. An involvement of p53 in this process was indicated by the shift in location of constitutively expressed endogenous p53 from the cytoplasm to the nucleus, as early as 15 min after exposure to dimeric IL-2. Moreover, infection with a recombinant retrovirus encoding a C-terminal p53 miniprotein, shown previously to act as a dominant negative inhibitor of endogenous wild-type p53 activity, protected these cells from apoptosis.
Glutamate toxicity is a major contributor to the pathophysiology of numerous neurodegenerative di... more Glutamate toxicity is a major contributor to the pathophysiology of numerous neurodegenerative diseases including amyotrophic lateral sclerosis and Alzheimer's disease. Therefore, protecting neuronal cells against glutamate-induced cytotoxicity might be an effective approach for the treatment of these diseases. We have previously purified from the medicinal plant Achillea fragrantissima two bioactive compounds which were not studied before: the sesquiterpene lactone achillolide A and the flavonoid 3,5,4′-trihydroxy-6,7,3′-trimethoxyflavone (TTF). We have shown that these compounds protect astrocytes from oxidative stress-induced cell death and inhibit microglial activation. The current study examined for the first time their effects on differentiated mouse neuroblastoma N2a cells and on glutamate toxicity. We have found that, although these compounds belong to different chemical families, they protect neuronal cells from glutamate toxicity. We further demonstrate that this protective effect might be, at least partially, due to inhibitory effects of these compounds on the levels of reactive oxygen species produced following treatment with glutamate.
Activated microglial cells release various mediators, which cause neuronal cell death and have be... more Activated microglial cells release various mediators, which cause neuronal cell death and have been implicated in different neurological disorders. The present study demonstrates that an infusion prepared from the plant Pulicaria incisa (Pi) inhibits microglial activation and down-regulates levels of the inflammatory cytokines interleukin (IL)-1β, IL-6, and of the toxic mediators nitric oxide and glutamate. The infusion was also shown to have antioxidant properties in cell-free assays (e.g., differential pulse voltammetry) and in a cellular assay, in which the infusion attenuated the induced accumulation of intracellular reactive oxygen species (ROS). We found that Pi infusion is rich in polyphenols, especially chlorogenic acids and ferulic acids, which might be responsible for the observed activities. It is proposed that Pi infusion be further evaluated for use as a functional beverage for the prevention and/or treatment of chronic diseases, especially neurodegenerative disorders in which microglial activation and oxidative stress play important roles.
Colored shade nets, which have been developed during the last decade to filter selected spectral ... more Colored shade nets, which have been developed during the last decade to filter selected spectral regions of sunlight, concomitantly with inducing light scattering, are designed to specifically modify plant behavior. Crops grown under various colored (photo-selective) shade nets (ChromatiNets™) were found to improve their fruit yield and fruit quality. In the study described here, we have found that pepper grown in an arid region under red and yellow shade nets, had a significant higher yield compared with black nets of the same shading factors, without reducing fruit size. In addition, the export-quality fruit yield was also significantly increased under the red and yellow shade nets. Our results from 2007 further showed that the photo-selective nets, especially the yellow shade net, maintained better the pepper fruit quality, as was evaluated by several quality parameters. Most prominently, it lowered the decay incidence at the end of storability and shelf-life simulation. The results suggest the advantage of growing pepper under light-dispersive photo-selective shade nets, rather than the traditional black nets, for improving productivity, quality and probably also, shelf-life. The latter requires further verification.
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.
The poor ability of mammalian central nervous system (CNS) axons to regenerate has been attribute... more The poor ability of mammalian central nervous system (CNS) axons to regenerate has been attributed, in part, to astrocyte behavior after axonal injury. This behavior is manifested by the limited ability of astrocytes to migrate and thus repopulate the injury site. Here, the migratory behavior of astrocytes in response to injury of CNS axons in vivo was simulated in vitro using a scratch-wounded astrocytic monolayer and soluble substances derived from injured rat optic nerves. The soluble substances, applied to the scratch-wounded astrocytes, blocked their migration whereas some known wound-associated factors such as transforming growth factor- 1 (TGF- 1), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), transforming growth factor-␣ (TGF-␣), and heparin-binding epidermal growth factor in combination with insulin-like growth factor-1 (HB-EGF ϩ IGF-1) stimulated intensive migration with consequent closure of the wound. Migration was not dominated by proliferating cells. Both bFGF and HB-EGF ϩ IGF-1, but not TGF- 1, could overcome the blocking effect of the optic nerve-derived substances on astrocyte migration. The induced migration appeared to involve proteoglycans. It is suggestive that appropriate choice of growth factors at the appropriate postinjury period may compensate for the endogenous deficiency in glial supportive factors and/or presence of glial inhibitory factors in the CNS.
Myasthenia gravis (MG) is a T cell-regulated antibody-mediated autoimmune disease. Immunization w... more Myasthenia gravis (MG) is a T cell-regulated antibody-mediated autoimmune disease. Immunization with two myasthenogenic peptides, p195-212 and p259-271, that are sequences of the human acetylcholine receptor α subunit was shown to induce experimental autoimmune MG (EAMG)associated immune responses. A peptide composed of the two altered peptide ligands (APL) of the myasthenogenic peptides (designated as dual APL) inhibited, in vitro and in vivo, those responses. The objectives of this study were to examine (i) whether in vivo T cell activation by p259-271 affects the cytokine profile and the T cell migration ability, and (ii) whether the latter are immunomodulated by in vivo administration of the dual APL. Our results showed that immunization of mice with p259-271 enriched the population of lymph node and spleen cells with subsets of T cells with strong adhesiveness towards E-and P-selectins. This enrichment was associated with an acquisition of a T h 1-type cytokine profile. Treatment of the immunized mice with the dual APL interfered with both the migratory potential of the autoreactive T cells, and the production of the T h 1-type cytokines IL-2 and IFN-γ (known to play a pathogenic role in MG and EAMG). T cells derived from APL-treated mice acquired a T h 3-type cytokine profile, characterized by the secretion of the immunosuppresive cytokine transforming growth factor-β. Thus, our results suggest that T cell selectin ligands and T cell-derived cytokines are involved in the induction and immunomodulation of EAMG-and MG-associated T cell responses.
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...
It is now widely accepted that injured nerves, like any other injured tissue, need assistance fro... more It is now widely accepted that injured nerves, like any other injured tissue, need assistance from their extracellular milieu in order to heal. We compared the postinjury activities of thrombin and gelatinases, two types of proteolytic activities known to be critically involved in tissue healing, in nonregenerative (rat optic nerve) and regenerative (fish optic nerve and rat sciatic nerve) neural tissue. Unlike gelatinases, whose induction pattern was comparable in all three nerves, thrombin-like activity differed clearly between regenerating and nonregenerating nervous systems. Postinjury levels of this latter activity seem to dictate whether it will display beneficial or detrimental effects on the capacity of the tissue for repair. The results of this study further highlight the fact that tissue repair and nerve regeneration are closely linked and that substances that are not unique to the nervous system, but participate in wound healing in general, are also crucial for regeneration or its failure in the nervous system.-Friedmann, I., Faber-Elman, A., Yoles, E., Schwartz, M. Injury-induced gelatinase and thrombin-like activities in regenerating and nonregenerating nervous systems.
Morphogenesis and tissue repair require appropriate cross-talk between the cells and their surrou... more Morphogenesis and tissue repair require appropriate cross-talk between the cells and their surrounding milieu, which includes extracellular components and soluble factors, e.g., cytokines and growth factors. The present work deals with this commuinicalion needed for recovery after axotonly in the central nervous system (CNS). The failure of CNS axons to regenerate after axonal injury has been attributed, in part, to astrocyte failure to repopuilate the injury site. The goal of this work was to provide an in vitro model to mimic the in vivo response of astrocytes to nerve injury and to find ways to modulate this response and create a milieu that favors astrocyte migration and repopulation of the injury site. In an astrocyte scratch wound model, we blocked astrocyte migration by tmnor necrosis factor a (TNF-a). This effect could not be reversed by astrocyte migration-inducing factors such as transforming growth factor i (TGF-1) or by any of the tested extracellular matrix (ECM) coniponents (laininin and fibronectin) except for vitronectin (Vn). Vn, added together with TNF-a, counteracted the TNFa blockage and allowed a massive migration of astrocytes (not due to cell proliferation) beyond that allowed by Vn only. Heparan sulfate proteoglycans (HSPG) were shown to be involved in the migration. The results may be relevant to regeneration of CNS axons, and may also provide an example that an extracellular component (Vn) can overcome and neutralize a negative effect of a growth factor/cytokine (TNF-a) and can act in synergy with other features of this cytokine to promote a necessary function (e.g., cell migration) that is otherwise inhibited.-Faber-Elman, A., Lavie, V., Schvartz, I., Shaltiel, S., Schwartz, M. Vitronectin overrides a negative effect of TNF-a on astrocyte migration.
Israel 3Corresponding author Communicated by M.Oren A covalent dimer ofinterleukin (IL)-2, produc... more Israel 3Corresponding author Communicated by M.Oren A covalent dimer ofinterleukin (IL)-2, produced in vitro by the action of a nerve-derived transglutaminase, has been shown previously to be cytotoxic to mature rat brain oligodendrocytes. Here we report that this cytotoxic effect operates via programmed cell death (apoptosis) and that the p53 tumor suppressor gene is involved directly in the process. The apoptotic death of mature rat brain oligodendrocytes in culture following treatment with dimeric IL-2 was demonstrated by chromatin condensation and internucleosomal DNA fragmentation. The peak of apoptosis was observed 16-24 h after treatment, while the commitment to death was already observed after 3-4 h. An involvement of p53 in this process was indicated by the shift in location of constitutively expressed endogenous p53 from the cytoplasm to the nucleus, as early as 15 min after exposure to dimeric IL-2. Moreover, infection with a recombinant retrovirus encoding a C-terminal p53 miniprotein, shown previously to act as a dominant negative inhibitor of endogenous wild-type p53 activity, protected these cells from apoptosis.
Glutamate toxicity is a major contributor to the pathophysiology of numerous neurodegenerative di... more Glutamate toxicity is a major contributor to the pathophysiology of numerous neurodegenerative diseases including amyotrophic lateral sclerosis and Alzheimer's disease. Therefore, protecting neuronal cells against glutamate-induced cytotoxicity might be an effective approach for the treatment of these diseases. We have previously purified from the medicinal plant Achillea fragrantissima two bioactive compounds which were not studied before: the sesquiterpene lactone achillolide A and the flavonoid 3,5,4′-trihydroxy-6,7,3′-trimethoxyflavone (TTF). We have shown that these compounds protect astrocytes from oxidative stress-induced cell death and inhibit microglial activation. The current study examined for the first time their effects on differentiated mouse neuroblastoma N2a cells and on glutamate toxicity. We have found that, although these compounds belong to different chemical families, they protect neuronal cells from glutamate toxicity. We further demonstrate that this protective effect might be, at least partially, due to inhibitory effects of these compounds on the levels of reactive oxygen species produced following treatment with glutamate.
Activated microglial cells release various mediators, which cause neuronal cell death and have be... more Activated microglial cells release various mediators, which cause neuronal cell death and have been implicated in different neurological disorders. The present study demonstrates that an infusion prepared from the plant Pulicaria incisa (Pi) inhibits microglial activation and down-regulates levels of the inflammatory cytokines interleukin (IL)-1β, IL-6, and of the toxic mediators nitric oxide and glutamate. The infusion was also shown to have antioxidant properties in cell-free assays (e.g., differential pulse voltammetry) and in a cellular assay, in which the infusion attenuated the induced accumulation of intracellular reactive oxygen species (ROS). We found that Pi infusion is rich in polyphenols, especially chlorogenic acids and ferulic acids, which might be responsible for the observed activities. It is proposed that Pi infusion be further evaluated for use as a functional beverage for the prevention and/or treatment of chronic diseases, especially neurodegenerative disorders in which microglial activation and oxidative stress play important roles.
Colored shade nets, which have been developed during the last decade to filter selected spectral ... more Colored shade nets, which have been developed during the last decade to filter selected spectral regions of sunlight, concomitantly with inducing light scattering, are designed to specifically modify plant behavior. Crops grown under various colored (photo-selective) shade nets (ChromatiNets™) were found to improve their fruit yield and fruit quality. In the study described here, we have found that pepper grown in an arid region under red and yellow shade nets, had a significant higher yield compared with black nets of the same shading factors, without reducing fruit size. In addition, the export-quality fruit yield was also significantly increased under the red and yellow shade nets. Our results from 2007 further showed that the photo-selective nets, especially the yellow shade net, maintained better the pepper fruit quality, as was evaluated by several quality parameters. Most prominently, it lowered the decay incidence at the end of storability and shelf-life simulation. The results suggest the advantage of growing pepper under light-dispersive photo-selective shade nets, rather than the traditional black nets, for improving productivity, quality and probably also, shelf-life. The latter requires further verification.
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.
The poor ability of mammalian central nervous system (CNS) axons to regenerate has been attribute... more The poor ability of mammalian central nervous system (CNS) axons to regenerate has been attributed, in part, to astrocyte behavior after axonal injury. This behavior is manifested by the limited ability of astrocytes to migrate and thus repopulate the injury site. Here, the migratory behavior of astrocytes in response to injury of CNS axons in vivo was simulated in vitro using a scratch-wounded astrocytic monolayer and soluble substances derived from injured rat optic nerves. The soluble substances, applied to the scratch-wounded astrocytes, blocked their migration whereas some known wound-associated factors such as transforming growth factor- 1 (TGF- 1), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), transforming growth factor-␣ (TGF-␣), and heparin-binding epidermal growth factor in combination with insulin-like growth factor-1 (HB-EGF ϩ IGF-1) stimulated intensive migration with consequent closure of the wound. Migration was not dominated by proliferating cells. Both bFGF and HB-EGF ϩ IGF-1, but not TGF- 1, could overcome the blocking effect of the optic nerve-derived substances on astrocyte migration. The induced migration appeared to involve proteoglycans. It is suggestive that appropriate choice of growth factors at the appropriate postinjury period may compensate for the endogenous deficiency in glial supportive factors and/or presence of glial inhibitory factors in the CNS.
Myasthenia gravis (MG) is a T cell-regulated antibody-mediated autoimmune disease. Immunization w... more Myasthenia gravis (MG) is a T cell-regulated antibody-mediated autoimmune disease. Immunization with two myasthenogenic peptides, p195-212 and p259-271, that are sequences of the human acetylcholine receptor α subunit was shown to induce experimental autoimmune MG (EAMG)associated immune responses. A peptide composed of the two altered peptide ligands (APL) of the myasthenogenic peptides (designated as dual APL) inhibited, in vitro and in vivo, those responses. The objectives of this study were to examine (i) whether in vivo T cell activation by p259-271 affects the cytokine profile and the T cell migration ability, and (ii) whether the latter are immunomodulated by in vivo administration of the dual APL. Our results showed that immunization of mice with p259-271 enriched the population of lymph node and spleen cells with subsets of T cells with strong adhesiveness towards E-and P-selectins. This enrichment was associated with an acquisition of a T h 1-type cytokine profile. Treatment of the immunized mice with the dual APL interfered with both the migratory potential of the autoreactive T cells, and the production of the T h 1-type cytokines IL-2 and IFN-γ (known to play a pathogenic role in MG and EAMG). T cells derived from APL-treated mice acquired a T h 3-type cytokine profile, characterized by the secretion of the immunosuppresive cytokine transforming growth factor-β. Thus, our results suggest that T cell selectin ligands and T cell-derived cytokines are involved in the induction and immunomodulation of EAMG-and MG-associated T cell responses.
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