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We have shown elsewhere that equine-2 influenza virus (EIV; subtype H3N8) induced pronounced cell death in infected cells through apoptosis as demonstrated by DNA fragmentation assay and a combined TUNEL and immunostaining scheme. In this study, we investigated the mechanism of EIV-mediated cytotoxicity on a permissive mammalian epithelial cell line, Madin-Darby canine kidney (MDCK) cells. EIV infection increased the cellular levels of oxidative stress and c-Jun/AP-1 protein (which is known to be affected by oxidative stress), as well as its DNA binding activity. Increased production of TGF-beta1, an inducer of c-Jun N-terminal kinase or stress-activated protein kinase (JNK/SAPK) activation, was also detected in EIV-infected MDCK cells. It has been reported that TGF-beta may initiate a signaling cascade leading to JNK/SAPK activation. Addition of c-Jun antisense oligodeoxynucleotide, antioxidant N-acetyl-cysteine (NAC), JNK/SAPK inhibitor carvedilol, or TGF-beta-neutralizing antibody effectively blocked c-Jun/AP-1 upregulation and TGF-beta1 production mediated by EIV infection. These treatments also attenuated EIV-induced cytopathogenic effects (CPE) and apoptosis. Our results suggest that a stress-activated pathway is involved in apoptosis mediated by EIV infection. It is likely that EIV infection turns on the JNK/SAPK cascade, which modulates the activity of apoptosis-promoting regulatory factor c-Jun/AP-1 and epithelial growth inhibitory cytokine TGF-beta.

Polychlorinated biphenyls (PCBs) are a group of synthetic chemicals that induce and promote liver tumors in rodents. We previously showed hepatic nuclear factor kappaB (NF-kappaB) activation and increased hepatocyte proliferation in PCB-treated rats. In this study, the role of NF-kappaB in hepatocyte proliferation and apoptosis after PCB administration was analyzed in wild-type mice and in mice deficient in the NF-kappaB p50 subunit (p50-/-). In a 2-day study, mice received a single intraperitoneal (ip) injection of corn oil or PCB-153. Hepatic NF-kappaB DNA binding activity and cell proliferation were increased by PCB-153 in wild-type mice but not in p50-/- mice. In a 21-day study, mice received six ip injections of corn oil or PCB-153 (twice weekly for 3 weeks) and were euthanized 4 days after the last injection. In this study, NF-kappaB DNA binding activity was not increased after PCB-153 treatment in wild-type or p50-/- mice. Cell proliferation was significantly increased in the wild-type mice treated with PCB-153; in the p50-/- mice treated with PCB-153, cell proliferation was greater than in untreated mice but less than in wild-type mice treated with PCB-153. The livers of p50-/- mice showed greater apoptosis than those of wild-type mice; PCB-153 decreased apoptosis in p50-/- mice, with higher inhibition in the 21-day study than in the 2-day study. RNase protection assays indicated that PCB-153 decreased the mRNA level of cyclin A2, B1, B2, and C in the 2-day study, but not in the 21-day study; however, it did not affect cyclin D1 and D2 mRNA levels at either time point. Cyclin D1 protein levels were not affected by PCB-153. Taken together, these data indicate that the absence of the NF-kappaB p50 subunit alters the proliferative and apoptotic changes in mouse liver in the response to PCB-153.

PCBs are organic pollutants that persist and bioaccumulate in the environment. These chemicals induce and promote liver tumors in rodents. Previous studies have shown that they increase oxidative stress in the liver, including lipid peroxidation, oxidative DNA damage, and NF-κB activation. The objective of these studies was to determine if the promoting activities of PCBs could be inhibited by dietary antioxidants (vitamin E, selenium, or phytochemicals) or by knocking out the p50 subunit of NF-κB. In the antioxidant studies, female rats were first injected with DEN (150 mg/kg) and then administered 4 biweekly i.p. injections (300 μmol/kg/injection) of PCB-77, PCB-153, or vehicle; the number and volume of placental glutathione S-transferase (PGST)-positive foci were then quantified. Vitamin E did not influence the promoting activities of PCBs. Increasing dietary selenium above the recommended intake increased the number of foci induced but decreased their volume. Most of the phytochemicals examined (N-acetyl cysteine, β-carotene, resveratrol, EGCG) had no significant effect on the promoting activity of PCB-77. Ellagic acid increased and lycopene decreased the number of foci; ellagic acid, CoQ 10 , and curcumin decreased the volume of foci. In the NF-κB knockout study, male mice were first injected with DEN (90 mg/kg); controls not receiving DEN were also studied. Both p50 −/− and wild-type mice were then injected biweekly 20 times with PCB-153 (300 (μmol/kg). In DEN-treated and DEN + PCB-treated mice, the incidence of tumors was lower in the p50 −/− mice than in wild-type mice. In mice receiving PCB-153, the tumor incidence and tumor volume were higher. The volume of tumors that were positive for glutamine synthetase was increased in mice administered PCB-153. This study shows that the promotion of hepatocarcinogenesis by PCBs is largely unaffected by dietary antioxidants but is diminished when NF-κB activation is impaired by the absence of the p50 subunit.

Here, we demonstrate the assembly of a new stable lanthanide-based metal-organic framework (MOF), Eu(HDPB)(phen) (1) (HDPB = (1,1ʹ:3ʹ,1ʹʹ-terphenyl)-3,3ʹʹ,5,5ʹʹ-tetracarboxylic acid, phen = 1,10-phenanthroline), with a three-dimensional framework under solvothermal conditions. 1...