ABSTRACT
Bovine papillomavirus (BPV) is recognized as a causal agent of benign and malignant tumors in cattle. Thirteen types of BPV are currently characterized and classified into three distinct genera, associated with different pathological outcomes. The described BPV types as well as other putative ones have been demonstrated by molecular biology methods, mainly by the employment of degenerated PCR primers. Specifically, divergences in the nucleotide sequence of the L1 gene are useful for the identification and classification of new papillomavirus types. On the present work, a method based on the PCR-RFLP technique and DNA sequencing was evaluated as a screening tool, allowing for the detection of two relatively rare types of BPV in lesions samples from a six-year-old Holstein dairy cow, chronically affected with cutaneous papillomatosis. These findings point to the dissemination of BPVs with unclear pathogenic potential, since two relatively rare, new described BPV types, which were first characterized in Japan, were also detected in Brazil.
Subject(s)
Cattle Diseases/virology , Coinfection/veterinary , Deltapapillomavirus/genetics , Deltapapillomavirus/isolation & purification , Papillomavirus Infections/veterinary , Polymerase Chain Reaction/methods , Polymorphism, Restriction Fragment Length/genetics , Animals , Biopsy , Brazil , Cattle , Cattle Diseases/genetics , Cattle Diseases/pathology , Coinfection/genetics , Coinfection/pathology , Coinfection/virology , Papillomavirus Infections/genetics , Papillomavirus Infections/pathology , Papillomavirus Infections/virology , Phylogeny , Warts/pathology , Warts/virologyABSTRACT
Jun N-terminal kinase (JNK) is a stress-activated protein kinase that can be induced by inflammatory cytokines, bacterial endotoxin, osmotic shock, UV radiation, and hypoxia. We report the identification of an anthrapyrazolone series with significant inhibition of JNK1, -2, and -3 (K(i) = 0.19 microM). SP600125 is a reversible ATP-competitive inhibitor with >20-fold selectivity vs. a range of kinases and enzymes tested. In cells, SP600125 dose dependently inhibited the phosphorylation of c-Jun, the expression of inflammatory genes COX-2, IL-2, IFN-gamma, TNF-alpha, and prevented the activation and differentiation of primary human CD4 cell cultures. In animal studies, SP600125 blocked (bacterial) lipopolysaccharide-induced expression of tumor necrosis factor-alpha and inhibited anti-CD3-induced apoptosis of CD4(+) CD8(+) thymocytes. Our study supports targeting JNK as an important strategy in inflammatory disease, apoptotic cell death, and cancer.
Subject(s)
Anthracenes/pharmacology , Enzyme Inhibitors/pharmacology , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Pyrazolones , Adenosine Triphosphate/metabolism , Animals , Anthracenes/chemistry , Anthracenes/metabolism , Anthraquinones , Binding, Competitive , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Cell Differentiation/drug effects , Cells, Cultured , Cytokines/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Female , Gene Expression/drug effects , Humans , JNK Mitogen-Activated Protein Kinases , Jurkat Cells , Lymphocyte Activation/drug effects , Mice , Mice, Inbred C57BL , Molecular Structure , Monocytes/cytology , Monocytes/metabolism , Protein Kinase Inhibitors , Pyrazoles , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
The type two intramolecular Diels-Alder reaction (T2IMDA) is an efficient method for the formation of medium rings. The methodology is particularly effective for the construction of seven- and eight-membered rings. A strategy for the synthesis of functionalized cycloheptanes and cyclooctanes has been developed that involves a bridged to fused ring interchange. The T2IMDA provides a synthesis for rigid bridged bicyclic molecules that can be stereoselectively elaborated before ozonolysis of the bridgehead double bond. Following oxidative cleavage, aldol condensation provides fused bicyclic ring systems that otherwise are difficult to synthesize. This methodology is amenable to the synthesis of terpene natural products. This is demonstrated here through total syntheses of (+/-)-ledol and (+/-)-ledene and a formal synthesis of (+/-)-compressanolide.
