1α,2α-Epoxy-3ß-hydroxy oleanolic acid derivatives regulation of the metabolism, haemolysis and ß-lactamase gene expression in vitro and their structure-microbicidal activity relationship.

Oleanolic acid (OA), one of the major pentacyclic triterpenes abundantly present in nature, is a promising compound with various biological activities, including anti-inflammatory, anti-ulcer, hepatoprotective, antidiabetic, fungicidal and antiparasitic properties. Therefore, a series of derivatives of 1α,2α-epoxy-3ß-hydroxyl oleanolic acid derivatives were designed and synthesized, and their antibacterial activities were investigated in vitro. Based on these results, the compounds with antibacterial activity were screened by RT-PCR to determine whether they can regulate the expression of genes related to metabolism, haemolysis, and ß-lactamase in vitro, and the structure-microbicidal activity relationship of each compound was analyzed. Our study shows that some of the modifications in the synthetic compounds, such as the introduction of an ortho-cyano-substituted benzyl group and a short chain alkyl ester at the 28-carboxyl, as well as the introduction of an acetyl group at the 3-hydroxyl group of ring A, could enhance antibacterial activity. This provides basic evidence for the optimization of 1α,2α-epoxy-3ß-hydroxyl oleanolic acid derivatives. The antibacterial mechanism of the active OA derivatives appears to involve the regulation of expression of metabolism-associated genes in Escherichia coli, haemolysis-associated genes in Bacillus subtilis, metabolism-related genes in Klebsiella pneumonia and ß-lactamase-associated genes in Acinetobacter baumannii. Some OA derivatives were bactericidal to three of the strains and appeared to regulate gene expression associated with metabolism, haemolysis, and ß-lactamase in vitro. These newly designed OA derivatives possess unique antibacterial activities and may be potentially useful for prophylactic or therapeutic intervention of bacterial infections.

Cadmium-induced splenic lymphocytes anoikis is not mitigated by activating Nrf2-mediated antioxidative defense response.

Cadmium (Cd) is a widely used heavy metal which is reported to exert extensive harm to the environment and human health. Owing to Cd being an element it is continuously enriched in the environment. The mechanism of splenic toxicity by Cd, however, is not yet clear. In order to explore the toxic mechanism of Cd exposure to the spleen, we added 0, 35, 70 and 140 mg/kg of Cd to the diet of chicken and fed them this diet for 90 days. Analysis of histopathological sections showed that Cd exposure damaged the spleen structure, the spleen red pulp, the white pulp boundary disappeared and the number of lymphocytes decreased significantly, suggesting that Cd exposure leads to organ injury to the spleen. Particularly, Cd-induced anoikis - a special form of programmed cell death caused by the loss of contact between cells and extracellular matrix and other cells - is associated with integrin-related cell detachment and activation of apoptotic signaling pathways. Moreover, Cd exposure leads to an increase in free radicals content and affects the activity of antioxidant enzymes resulting in oxidative stress. Simultaneously, Cd activated the body's antioxidant defense system mediated by the Nuclear factor related factor 2 (Nrf2) signaling pathway. Based on our results Cd-induced splenic lymphocytes anoikis is not mitigated by Nrf2-mediated antioxidative defense response.

Di-(2-ethylhexyl) phthalate induced nephrotoxicity in quail (Coturnix japonica) by triggering nuclear xenobiotic receptors and modulating the cytochrome P450 system.

Di-(2-ethylhexyl) phthalate (DEHP), a plasticizer that is mainly used in the production of polyvinyl alcohol-containing chloride products, has attracted attention due to potential threats to human health and the environment. Nevertheless, knowledge of DEHP-induced nephrotoxicity is still limited. To explore the mechanism of DEHP-induced nephrotoxicity, quail were treated with 0, 250, 500 and 1000 mg/kg DEHP by oral gavage for 45 days. Based on the results of histopathological analysis, DEHP exposure induced a disorganized renal structure, a partially dilated glomerulus and an atrophied Bowman's space. Renal tubular epithelial cells were unclear, and swelling of columnar epithelial cells was observed, suggesting that DEHP exposure caused renal disease and renal injury. Notably, DEHP interfered with the homeostasis of cytochrome P450 systems (CYP450s) by increasing the activities or contents of CYP450s (total CYP450, Cyt b5, ERND, APND, AH and NCR). The expression levels of certain CYP450 isoforms (CYP1A, CYP1B, CYP2C, CYP2D, CYP2J and CYP3A) were significantly downregulated in the kidney in DEHP-treated quail. Furthermore, DEHP induced the expression of nuclear receptors (AHR, CAR and PXR) in a dose-dependent manner. The results of this study suggested that DEHP-induced nephrotoxicity in quail was associated with the induction of nuclear xenobiotic receptor (NXR) responses and interference with CYP450 homeostasis. In conclusion, all data indicated that DEHP induced nephrotoxicity by triggering NXRs and modulating the cytochrome P450 system. The results of this study provide a new basis for understanding the nephrotoxicity of DEHP.