Antiviral effect of hyperthermic treatment in rhinovirus infection.
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Human rhinoviruses (HRV) are recognized as the major etiologic agents for the common cold. Starting from the observation that local hyperthermic treatment is beneficial in patients with natural and experimental common colds, we have studied the effect of brief hyperthermic treatment (HT) on HRV replication in HeLa cells. We report that a 20-min HT at 45 degrees C is effective in suppressing HRV multiplication by more than 90% when applied at specific stages of the virus replication cycle. Synthesis of virus proteins is not affected by HT, indicating that the target for treatment is a posttranslational event. The antiviral effect is a transient cell-mediated event and is associated with the synthesis of the 70-kDa heat shock protein hsp70. Unlike poliovirus, rhinovirus infection does not inhibit the expression of hsp70 induced by heat. The possibility that hsp70 could play a role in the control of rhinovirus replication is suggested by the fact that a different class of HSP inducers, the cyclopentenone prostaglandins PGA1 and delta 12-PGJ2, were also effective in inhibiting HRV replication in HeLa cells. Inhibition of hsp70 expression by actinomycin D prevented the antiviral activity of prostaglandins in HRV-infected cells. These results indicate that the beneficial effect of respiratory hyperthermia may be mediated by the induction of a cytoprotective heat shock response in rhinovirus-infected cells. (+info)
Formation of reactive cyclopentenone compounds in vivo as products of the isoprostane pathway.
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Cyclopentenone prostaglandins A2 and J2 are reactive compounds that possess unique biological activities. However, the extent to which they are formed in vivo remains unclear. In this study, we explored whether D2/E2-isoprostanes undergo dehydration in vivo to form A2/J2-isoprostanes. Oxidation of arachidonic acid in vitro generated a series of compounds that were confirmed to be A2/J2-isoprostanes by mass spectrometric analyses. A2/J2-isoprostanes were detected in vivo esterified to lipids in livers from normal rats at a level of 5. 1 +/- 2.3 ng/g, and levels increased dramatically by a mean of 24-fold following administration of CCl4. An A2-isoprostane, 15-A2t-isoprostane, was obtained and found to readily undergo Michael addition with glutathione and to adduct covalently to protein. A2/J2-isoprostanes could not be detected in the circulation, even following CCl4 administration, which we hypothesized might be explained by rapid formation of adducts. This was supported by finding that essentially all the radioactivity excreted into the urine following infusion of radiolabeled 15-A2t-isoprostane into a human volunteer was in the form of a polar conjugate(s). These data identify a new class of reactive compounds that are produced in vivo as products of the isoprostane pathway that can exert biological effects relevant to the pathobiology of oxidant injury. (+info)
Endothelial cell apoptosis induced by the peroxisome proliferator-activated receptor (PPAR) ligand 15-deoxy-Delta12, 14-prostaglandin J2.
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15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) is a bioactive prostanoid produced by dehydration and isomerization of PGD2, a cyclooxygenase product. It was recently shown to activate the nuclear peroxisome proliferator-activated receptor gamma (PPARgamma), a critical transcription factor involved in adipocyte and monocyte differentiation. In this report, we show that 15d-PGJ2 is a potent inducer of caspase-mediated endothelial cell apoptosis. PPARalpha, -delta, and -gamma were expressed by endothelial cells, which, when treated with 15d-PGJ2, induced receptor translocation into the nucleus, and an increase in PPAR response element-driven reporter gene expression. Ciglitizone, a selective activator of PPARgamma, also induced transcriptional activation and endothelial cell apoptosis. Endothelial apoptosis induced by 15d-PGJ2 was inhibited by treatment of cells with an oligonucleotide decoy to a consensus PPAR response element sequence. Furthermore, overexpression of the PPARgamma isotype induced endothelial cell apoptosis, which was further potentiated by 15d-PGJ2 treatment. We conclude that 15d-PGJ2 induces endothelial cell apoptosis via a PPAR-dependent pathway. The PPAR pathway may be a therapeutic target for numerous pathologies in which excessive angiogenesis is implicated. (+info)
Antitumor activity of 13,14-dihydro-15-deoxy-delta7-prostaglandin-A1-methyl ester integrated into lipid microspheres against human ovarian carcinoma cells resistant to cisplatin in vivo.
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One of the delta7-prostaglandin A1 derivatives with unique antitumor activities, 13,14-dihydro-15-deoxy-delta7-prostaglandin-A1-methyl ester, was integrated into lipid microspheres (Lipo-TEI9826) and examined for its antitumor effect in vitro and in vivo. The in vitro relative resistance of human ovarian cancer, A2780CP, to cisplatin (CDDP) and Lipo-TEI9826 was 27.3 and 2.0, respectively, compared with A2780, the parent cell line of A2780CP. In in vivo experiments, when A2780CP and the parent cell line A2780 were inoculated into nude mice, A2780CP grew two times more rapidly than did A2780. The growth of A2780CP tumor was not suppressed by CDDP, whereas that of the A2780 tumor was significantly suppressed. Nevertheless, the growth of both the A2780 and the A2780CP inoculated tumors was significantly inhibited by treatment with Lipo-TEI9826 at any time after the initial treatment, compared with the lipid microspheres only. These results show that Lipo-TEI9826 may be an effective antitumor agent and capable of overcoming CDDP resistance. (+info)
Induction of ferritin and heat shock proteins by prostaglandin A1 in human monocytes. Evidence for transcriptional and post-transcriptional regulation.
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Prostaglandins of the A type (PGA) exert a cytoprotective activity during hyperthermia and virus infection. This effect is associated with induction of heat shock proteins (HSP) in mammalian cells. We now report that, in human monocytes, PGA1 is able to induce the synthesis of the iron-binding, redox-regulated protein ferritin. L-chain ferritin induction is consequent to a substantial increase in the accumulation of L-chain ferritin transcripts in PGA1-treated cells, whereas H-chain ferritin is regulated post-transcriptionally, consequently to reduction of iron-regulatory protein binding to iron-responsive elements in ferritin mRNA. Ferritin induction is specific for cyclopentenone prostaglandins (PGA1, PGA2, PGJ2, Delta12-PGJ2), whereas other arachidonic acid (AA) metabolites have no effect. In human monocytes, PGA1 also induces heat shock gene transcription via heat shock factor activation, as well as the synthesis of the oxidative-stress protein heme oxygenase (HOS). Differently from HSP, the induction of ferritin by PGA1 is specific for monocytes. Monocytes/macrophages play a pivotal role in inflammation, controlling iron metabolism and releasing a variety of mediators, including proinflammatory reactive oxygen species (ROS), cytokines and AA metabolites. As ferritin, together with hsp70 and HO, plays a key role in protection from oxidant damage, these results suggest that PGA1 may have cytoprotective activity also during oxidative injury. (+info)
15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway.
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Prostaglandin J(2) (PGJ(2)) and its metabolites Delta(12)-PGJ(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) are naturally occurring derivatives of prostaglandin D(2) that have been suggested to exert antiinflammatory effects in vivo. 15d-PGJ(2) is a high-affinity ligand for the peroxisome proliferator-activated receptor gamma (PPARgamma) and has been demonstrated to inhibit the induction of inflammatory response genes, including inducible NO synthase and tumor necrosis factor alpha, in a PPARgamma-dependent manner. We report here that 15d-PGJ(2) potently inhibits NF-kappaB-dependent transcription by two additional PPARgamma-independent mechanisms. Several lines of evidence suggest that 15d-PGJ(2) directly inhibits NF-kappaB-dependent gene expression through covalent modifications of critical cysteine residues in IkappaB kinase and the DNA-binding domains of NF-kappaB subunits. These mechanisms act in combination to inhibit transactivation of the NF-kappaB target gene cyclooxygenase 2. Direct inhibition of NF-kappaB signaling by 15d-PGJ(2) may contribute to negative regulation of prostaglandin biosynthesis and inflammation, suggesting additional approaches to the development of antiinflammatory drugs. (+info)
Inactivation of wild-type p53 tumor suppressor by electrophilic prostaglandins.
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The electrophilic eicosanoids prostaglandins A(1) or A(2) impaired p53-dependent transcription of endogenous genes and exogenous p53-luciferase reporter plasmids in RKO and HCT 116 colon cancer cells. Cellular accumulation of genetically wild-type, but transcriptionally silent p53 varied as a function of exposure time and concentration of prostaglandins A(1) and A(2). Prostaglandins A(1) and A(2) induced a conformational change in wild-type p53 that corresponded with its inactivation and its aberrant redistribution from the cytosol to the nucleus. Derangement of its transcriptional activity manifested as inhibition of p53-mediated apoptosis by etoposide, a representative antineoplastic agent. We conclude that electrophilic eicosanoids impair the role of wild-type p53 as a guardian of genomic integrity by a process distinct from somatic mutation or viral oncoprotein binding. This process may pertain to malignant and premalignant conditions, such as colon carcinoma and adenoma, which often harbor a genetically wild-type, but inactive form of p53 tumor suppressor. (+info)
Effect of the novel prostaglandin A1 derivative TEI-6363 on ROS17/2.8 cell differentiation in vitro.
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The effect of TEI-6363 (5-[E-4-N,N-dimethylaminophenylmethylene]-4-hydroxy-2-[1-methyl imidazole-2-ilthio]-4-[4-phenylbutyl]-2-cyclopentenone), a chemically synthesized prostaglandin A1 derivative, on cell proliferation and osteoblastic differentiation was investigated concurrently. ROS17/2.8 cells (a rat osteosarcoma-derived cell line) were treated with TEI-6363 at two concentrations, 10(-7) and 10(-6) M, and viable cells were counted to assess cytotoxic effects and determine the growth curve. After 96 h of treatment, there was no evidence of any effect of TEI-6363 on cell viability at either concentration. However, a clear inhibitory effect on cell proliferation was observed after treatment with 10(-6) M TEI-6363 for 24 h or longer. A pulse-treatment experiment showed that TEI-6363 induced the inhibition of proliferating ROS17/2.8 cells 24 h after addition. The inhibition of proliferation was associated with G1-arrest demonstrated by flow cytometric analysis, and incorporation of [3H]thymidine by ROS17/2.8 cells was decreased. Osteoblastic differentiation (assessed on the basis of increased alkaline phosphatase activity and collagen synthesis) was induced by TEI-6363 treatment at 10(-6) M following G1-arrest and inhibition of cell proliferation. These results suggest that TEI-6363 arrested the cell cycle of ROS17/2.8 cells at the G1 phase and induced osteoblastic differentiation. These results did not appear to be dependent on a marked cytotoxic effect. (+info)