Browsing by Author "Stosic-Grujicic, Stanislava (7004253020)"

The immunomodulatory potential of tiazofurin (TR) on experimental autoimmune encephalomyelitis (EAE) was investigated. Given continuously, TR dose-dependently suppressed the development of EAE in Dark Agouti (DA) rats immunized with either rat spinal cord homogenate (SCH) or myelin oligodendrocyte glycoprotein (MOG). Amelioration of clinical signs was also obtained when the drug was administered during the inductive phase only (day 0 to 8), or during the effector phase (day 10 to 20) of the disease. Efficacy of TR was further evaluated by adoptive transfer of the disease with myelin basic protein (MBP)-sensitized draining lymph node cells (DLNC). Cells from TR-protected rats failed to transfer the disease into naive syngeneic recipients; in addition, TR treatment of recipient rats that had received MBP-sensitized lymphoid cells diminished the adoptively transferred EAE. A reduction of clinical EAE in TR-treated rats was accompanied with the absence of mononuclear infiltration in the spinal cord and defective adhesive cell-cell interactions. The anti-MOG autoAb production was also decreased. Importantly, no evidence for a generalized impairment of the T cell activity, nor decreased in vitro proliferative antigen specific response of LNC from TR-treated animals was found. These results suggest that TR exerts its EAE protective and suppressive effects by limiting adhesive interactions involved in the autoimmune pathogenic process, and due to the lack of general immunosuppressive activity, it should be considered as a candidate drug for the treatment of neuroinflammatory diseases like multiple sclerosis (MS). © 2002 Elsevier Science B.V. All rights reserved.

The immunomodulatory potential of tiazofurin (TR) on experimental autoimmune encephalomyelitis (EAE) was investigated. Given continuously, TR dose-dependently suppressed the development of EAE in Dark Agouti (DA) rats immunized with either rat spinal cord homogenate (SCH) or myelin oligodendrocyte glycoprotein (MOG). Amelioration of clinical signs was also obtained when the drug was administered during the inductive phase only (day 0 to 8), or during the effector phase (day 10 to 20) of the disease. Efficacy of TR was further evaluated by adoptive transfer of the disease with myelin basic protein (MBP)-sensitized draining lymph node cells (DLNC). Cells from TR-protected rats failed to transfer the disease into naive syngeneic recipients; in addition, TR treatment of recipient rats that had received MBP-sensitized lymphoid cells diminished the adoptively transferred EAE. A reduction of clinical EAE in TR-treated rats was accompanied with the absence of mononuclear infiltration in the spinal cord and defective adhesive cell-cell interactions. The anti-MOG autoAb production was also decreased. Importantly, no evidence for a generalized impairment of the T cell activity, nor decreased in vitro proliferative antigen specific response of LNC from TR-treated animals was found. These results suggest that TR exerts its EAE protective and suppressive effects by limiting adhesive interactions involved in the autoimmune pathogenic process, and due to the lack of general immunosuppressive activity, it should be considered as a candidate drug for the treatment of neuroinflammatory diseases like multiple sclerosis (MS). © 2002 Elsevier Science B.V. All rights reserved.

The effect of interleukin-17 (IL-17) on production of nitric oxide (NO) in rodent astrocytes was investigated. While IL-17 by itself did not induce NO production, it caused a dose-dependent enhancement of IFN-γ-triggered NO synthesis in both mouse and rat primary astrocytes. In contrast, IL-17 was unable to stimulate NO synthesis in either murine or rat macrophages. IFN-γ-triggered expression of mRNA for iNOS, but not for its transcription factor interferon regulatory factor-1 (IRF-1), was markedly elevated in IL-17-treated astrocytes. The induction of iNOS mRNA by IL-17 in IFN-γ-pretreated astrocytes was abolished by antagonists of nuclear factor-κB (NF-κB) activation - a proteasome inhibitor MG132 and an antioxidant agent PDTC, as well as with specific p38 MAP kinase inhibitor SB203580. While IL-17 stimulated both IL-1β and IL-6 production in astrocytes, only IL-1 was partly responsible for IL-17-induced NO release. Finally, IL-17 synergized with exogenous IL-1β and TNF-α for astrocyte NO production. Having in mind a well-known neurotoxic action of NO, these results suggest a possible role for IL-17 in the inflammatory diseases of the CNS. © 2001 Elsevier Science B.V. All rights reserved.

The effect of interleukin-17 (IL-17) on production of nitric oxide (NO) in rodent astrocytes was investigated. While IL-17 by itself did not induce NO production, it caused a dose-dependent enhancement of IFN-γ-triggered NO synthesis in both mouse and rat primary astrocytes. In contrast, IL-17 was unable to stimulate NO synthesis in either murine or rat macrophages. IFN-γ-triggered expression of mRNA for iNOS, but not for its transcription factor interferon regulatory factor-1 (IRF-1), was markedly elevated in IL-17-treated astrocytes. The induction of iNOS mRNA by IL-17 in IFN-γ-pretreated astrocytes was abolished by antagonists of nuclear factor-κB (NF-κB) activation - a proteasome inhibitor MG132 and an antioxidant agent PDTC, as well as with specific p38 MAP kinase inhibitor SB203580. While IL-17 stimulated both IL-1β and IL-6 production in astrocytes, only IL-1 was partly responsible for IL-17-induced NO release. Finally, IL-17 synergized with exogenous IL-1β and TNF-α for astrocyte NO production. Having in mind a well-known neurotoxic action of NO, these results suggest a possible role for IL-17 in the inflammatory diseases of the CNS. © 2001 Elsevier Science B.V. All rights reserved.

To determine the mechanism underlying ribavirin induced amelioration of experimental autoimmune encephalomyelitis (EAE), cytokine profiles were evaluated in draining lymph node (DLN) cell culture supernatants and spinal cord obtained from EAE and/or ribavirin-treated EAE Dark Agouti rats. Administration of ribavirin to EAE rats markedly affected the production of pro-inflammatory cytokines IFN-γ, IL-1β and TNF-α in DLN and spinal cord, thus shifting the balance towards the anti-inflammatory cytokines IL-10 and TGF-β. These findings suggest that ribavirin attenuates EAE by limiting cytokine-mediated immunoinflammatory events leading to CNS destruction. The conducted experiments provide rationale for ribavirin to be considered as a candidate drug in the development of new therapeutic strategies for the treatment of autoimmune diseases in humans, such as multiple sclerosis. © 2008 Elsevier B.V. All rights reserved.

To determine the mechanism underlying ribavirin induced amelioration of experimental autoimmune encephalomyelitis (EAE), cytokine profiles were evaluated in draining lymph node (DLN) cell culture supernatants and spinal cord obtained from EAE and/or ribavirin-treated EAE Dark Agouti rats. Administration of ribavirin to EAE rats markedly affected the production of pro-inflammatory cytokines IFN-γ, IL-1β and TNF-α in DLN and spinal cord, thus shifting the balance towards the anti-inflammatory cytokines IL-10 and TGF-β. These findings suggest that ribavirin attenuates EAE by limiting cytokine-mediated immunoinflammatory events leading to CNS destruction. The conducted experiments provide rationale for ribavirin to be considered as a candidate drug in the development of new therapeutic strategies for the treatment of autoimmune diseases in humans, such as multiple sclerosis. © 2008 Elsevier B.V. All rights reserved.

Covalent attachment of NO to the first approved HIV protease inhibitor Saquinavir (Saq-NO) expands the therapeutic potential of the original drug. Apart from retained antiviral activity, the modified drug exerts strong antitumor effects and lower toxicity. In the present study, we have evaluated the sensitivity of different hematological malignancies to Saq-NO. Saq-NO efficiently diminished the viability of Jurkat, Raji, HL-60 and K562 cells. While Jurkat and Raji cells (established from pediatric patients) displayed abrogated proliferative potential, HL-60 and K652 cells (originated from adults) exposed to Saq-NO treatment underwent caspase dependent apoptosis. In addition, similar sensitivity to Saq-NO was observed in mononuclear blood cells obtained from pediatric patients with acute lymphoblastic leukemia (ALL) and adult patients with acute myeloid leukemia (AML). Western blot analysis indicated p70S6 kinase as a possible intracellular target of Saq-NO action. Moreover, the addition of a NO moiety to Lopinavir resulted in improved antitumor potential as compared to the parental compound, suggesting that NO-derived HIV protease inhibitors are a potential new source of anticancer drugs with unique mode of action. © 2015 Elsevier Ltd.

Covalent attachment of NO to the first approved HIV protease inhibitor Saquinavir (Saq-NO) expands the therapeutic potential of the original drug. Apart from retained antiviral activity, the modified drug exerts strong antitumor effects and lower toxicity. In the present study, we have evaluated the sensitivity of different hematological malignancies to Saq-NO. Saq-NO efficiently diminished the viability of Jurkat, Raji, HL-60 and K562 cells. While Jurkat and Raji cells (established from pediatric patients) displayed abrogated proliferative potential, HL-60 and K652 cells (originated from adults) exposed to Saq-NO treatment underwent caspase dependent apoptosis. In addition, similar sensitivity to Saq-NO was observed in mononuclear blood cells obtained from pediatric patients with acute lymphoblastic leukemia (ALL) and adult patients with acute myeloid leukemia (AML). Western blot analysis indicated p70S6 kinase as a possible intracellular target of Saq-NO action. Moreover, the addition of a NO moiety to Lopinavir resulted in improved antitumor potential as compared to the parental compound, suggesting that NO-derived HIV protease inhibitors are a potential new source of anticancer drugs with unique mode of action. © 2015 Elsevier Ltd.

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) and the helpful tool in preclinical testing of various substances considered for treatment of this human CNS disease. Ribavirin (R) and tiazofurin (T) are purine nucleoside analogues, with the broad spectrum of anti-viral, anti-tumoral and anti-inflammatory properties. We proposed that combined treatment with RT, administrated during the effector phase of EAE, would attenuate disease severity, both clinically and pathologically. Ribavirin was given daily at a dosage of 30 mg/kg and tiazofurin was given at a dosage of 10 mg/kg every other day for 15 days. We detected amelioration of clinical signs and faster recovery in the RT group compared to the control group. Immunohistochemical analyses revealed that RT treatment decrease the number of T cells, macrophages and microglia. In the controls, we detected reactive type of microglia, while in the RT group we noticed ramified/resting form. Demyelination areas and axonal damage were not recorded in the RT group, in contrast to the control group where multiple areas of demyelination zones and axonal loss were found. RT combination treatment suppresses ongoing EAE, prevents demyelination and axonal loss, and therefore may well be the potential therapy for the treatment of MS. © 2007 Elsevier B.V. All rights reserved.

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) and the helpful tool in preclinical testing of various substances considered for treatment of this human CNS disease. Ribavirin (R) and tiazofurin (T) are purine nucleoside analogues, with the broad spectrum of anti-viral, anti-tumoral and anti-inflammatory properties. We proposed that combined treatment with RT, administrated during the effector phase of EAE, would attenuate disease severity, both clinically and pathologically. Ribavirin was given daily at a dosage of 30 mg/kg and tiazofurin was given at a dosage of 10 mg/kg every other day for 15 days. We detected amelioration of clinical signs and faster recovery in the RT group compared to the control group. Immunohistochemical analyses revealed that RT treatment decrease the number of T cells, macrophages and microglia. In the controls, we detected reactive type of microglia, while in the RT group we noticed ramified/resting form. Demyelination areas and axonal damage were not recorded in the RT group, in contrast to the control group where multiple areas of demyelination zones and axonal loss were found. RT combination treatment suppresses ongoing EAE, prevents demyelination and axonal loss, and therefore may well be the potential therapy for the treatment of MS. © 2007 Elsevier B.V. All rights reserved.

The effects of tiazofurin (TR) on proliferation and cytokine-induced nitric oxide (NO) production in the L929 fibrosarcoma cell line and murine embryonic fibroblasts were investigated. Treatment with TR inhibited the growth of nonconfluent L929 cells in a dose-dependent manner. TR, at concentrations not affecting cell viability or proliferation, markedly decreased IFN-γ + LPS-induced expression of inducible NO synthase (iNOS) mRNA and, subsequently, NO production in confluent L929 cultures. However, TR did not interfere with the IFN-γ-triggered expression of mRNA for IRF-1, an important iNOS transcription factor, implying that TR interferes with some other intracellular pathway involved in iNOS induction triggered by IFN-γ + LPS. In contrast to the results obtained in L929 cells, iNOS mRNA expression induced by IFN-γ + LPS in murine embryonic fibroblasts was resistant to TR, indicating a tumor-selective action of this agent. © 2001 Elsevier Science B.V.

The effects of tiazofurin (TR) on proliferation and cytokine-induced nitric oxide (NO) production in the L929 fibrosarcoma cell line and murine embryonic fibroblasts were investigated. Treatment with TR inhibited the growth of nonconfluent L929 cells in a dose-dependent manner. TR, at concentrations not affecting cell viability or proliferation, markedly decreased IFN-γ + LPS-induced expression of inducible NO synthase (iNOS) mRNA and, subsequently, NO production in confluent L929 cultures. However, TR did not interfere with the IFN-γ-triggered expression of mRNA for IRF-1, an important iNOS transcription factor, implying that TR interferes with some other intracellular pathway involved in iNOS induction triggered by IFN-γ + LPS. In contrast to the results obtained in L929 cells, iNOS mRNA expression induced by IFN-γ + LPS in murine embryonic fibroblasts was resistant to TR, indicating a tumor-selective action of this agent. © 2001 Elsevier Science B.V.