RESUMO
The chemical reactivity of acyl glucuronide (AG) has been thought to be associated with the toxic properties of drugs containing carboxylic acid moieties, but there has been no direct evidence showing that AG formation is related to the observed toxicity. In the present study, the cytotoxicity of AGs, especially that associated with the inflammatory response, was investigated. The changes in the mRNA and protein expression levels of interleukin 8 (IL-8) and monocyte chemoattractant protein (MCP)-1 induced by the treatment of human peripheral blood mononuclear cells (PBMCs) with diclofenac (Dic), probenecid (Pro), tolmetin (Tol), ibuprofen (Ibu), naproxen (Nap), and their AGs were investigated by real-time reverse transcription polymerase chain reaction, and the viabilities of CD3+, CD14+, and CD19+ cells were measured by flow cytometry. Treatment with Dic-AG, Pro-AG, and Tol-AG significantly increased the expression levels of IL-8 and MCP-1. In addition, Dic-AG, Pro-AG, and Tol-AG significantly decreased the viability of CD14+ cells. Of these three AGs, Dic-AG showed the most potent changes, followed by Tol-AG and Pro-AG. Treatment with Ibu-AG and Nap-AG affected neither the expression levels of IL-8 and MCP-1 nor the viability of CD14+ cells. None of the drugs affected the CD3+ and CD19+ cell populations. Dic-AG increased the phosphorylation of p38 mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK)1/2. The pretreatment of peripheral blood mononuclear cells (PBMCs) with SB203580 (p38 inhibitor) significantly suppressed the Dic-AG-induced expression of inflammatory factors and cytotoxicity of CD14+ cells. In conclusion, AGs induce inflammatory responses and cytotoxicity against CD14+ cells via the p38 MAPK pathway. These factors may be useful biomarkers for evaluating the toxicity of AGs.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inflamação/tratamento farmacológico , Antígenos CD/genética , Antígenos CD/metabolismo , Linhagem Celular Tumoral , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , RNA Mensageiro/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
CH4 conversion is one of the most challenging chemical reactions due to its inertness in terms of physical and chemical properties. We have achieved photo-induced C-H bond breaking of CH4 and successive C-O bond formation to form CH3OH concomitant with HCHO by an organometallic Ru complex with O2.
RESUMO
We herein report a new synthetic method for the preparation of α-hydroxyketones by the dioxygenation of alkynes. The reaction proceeds at room temperature under the action of Fe porphyrin and pinacolborane under air as a green oxidant to produce α-hydroxyketones. The mild reaction conditions allow chemoselective oxidation with functional group tolerance. Terminal alkynes in addition to internal alkynes are applicable, affording unsymmetrical α-hydroxyketones that are difficult to obtain by any reported dioxygenation of unsaturated C-C bonds.
RESUMO
The cell surface glycoprotein CD44 has various types of splicing variants, which contribute to its multiple distinct cellular functions. Recently, it was reported that the CD44v8-10 isoform interacts with the system Xc(-) transporter-related protein (xCT), and inhibits the accumulation of reactive oxygen species by promoting the synthesis of the antioxidant glutathione in human tumour cells. In this study, we investigated the expression and function of CD44 variants and xCT in canine tumours. From semi-quantitative reverse transcription polymerase chain reaction analysis, the mRNA expression of the CD44v8-10 isoform was observed in canine tumour tissues as well as human cases. The overexpression of CD44v8-10 may promote the synthesis of glutathione and enhance the resistance to radiation of canine breast tumour cells. Furthermore, canine xCT mRNA expression was significantly upregulated in the canine breast tumour tissues as compared to the normal tissues surrounding the tumours. To investigate the function of canine xCT, we treated canine tumour cells with the xCT inhibitor sulfasalazine. Consequently, the sulfasalazine-treated cells were more sensitive to oxidative stress than the non-treated cells. Taken together, these results suggested that CD44v8-10 and xCT play important roles in the therapy resistance of canine tumours as well as human tumours.