It has been shown that oxidized low-density lipoprotein (ox-LDL), through the activation of glomerular cells, stimulates pathobiological processes involved in monocyte infiltration into the mesangium. The underlying molecular mechanisms are not fully understood. The present study showed that ox-LDL strongly induced AP-1 binding activity in rat mesangial cells (RMCs) in a dose- and time-dependent manner, reaching the maximal activation at 250 microg ml(-1) within 24 h. The results from mobility shift assays and Western blotting analysis revealed that this AP-1 binding increase involved c-Jun, but not c-Fos. Moreover, this ox-LDL-increased AP-1 binding was inhibited by several protein kinase (PK) inhibitors: the protein kinase C (PKC) inhibitor Bisindolylmaleimide I, the cAMP-dependent PK (PKA) inhibitor H89, and the tyrosine PK (PTK) inhibitor genistein. Protein phosphorylation represents mitogen-activated protein kinase (MAPK) activity. Therefore, we examined the role of ox-LDL on the activation of mesangial cell JNK/SAPK, the only recognized protein kinase that catalyses phosphorylation of c-Jun. The incubation of mesangial cells with ox-LDL induced phosphorylation of JNK1/SAPK dose dependently, with the maximal response at 150 microg ml(-1). This study demonstrates that multiple kinase activities are involved in the mechanism of ox-LDL-induced AP-1 activation in mesangial cells, and ox-LDL stimulates AP-1 through JNK-c-Jun other than MEK-c-Fos signalling pathway.

To guide the administration of fat emulsion in the nutritional support of acute renal failure (ARF), pharmacokinetic analysis with an one-compartment open model after bolus intravenous injection was performed to compare the elimination kinetics of long-chain triglycerides (LCT) and medium-chain triglycerides (MCT) in ischemic acute renal failure rats. Sprague-Dawley rats were randomized into four groups, namely LCT normal group, LCT ARF group, MCT normal group and MCT ARF group. The model of ischemic acute renal failure was induced by clamping the left renal artery for 60 min and contralateral nephrectomy. All the rats were fasted with water ad libitum for 10 h before 0.3 g/kg body weight of 10% Intralipid (LCT) or 10% Lipofundin (MCT: LCT = 50:50) was injected as a bolus to them via the tail vein. The serum triglyceride concentration was determined at 2, 10, 40, 70, 100, 130 and 160 min after intravenous injection for kinetic analysis. The results showed that the elimination rate constant (ke) of LCT ARF group was significantly decreased, while the half life period (t1/2) of it was significantly longer than those of LCT normal group. The ke and t1/2 of MCT showed no statistical difference between normal and ARF groups. In the normal group the ke of LCT was significantly decreased compared with MCT whereas the t1/2 was significantly prolonged. In the ARF group the ke of LCT was much less than that of MCT while the t1/2 was much longer. The serum insulin levels of both MCT groups were significantly higher than those of LCT groups. These results indicate that MCT will be eliminated more rapidly than LCT in ARF rats. MCT may also increase the secretion of insulin. In conclusion, MCT may be more favorable than LCT in the nutritional management of ARF.

Evidence suggested that the use of partial dopamine D2/D3 receptor agonists may be a better choice for the treatment of Parkinson's disease (PD), and the stimulation of 5-HT1A receptors (mainly via nondopaminergic mechanisms) alleviates motor and nonmotor disorders of PD, implying that the multitarget approach may provide a double bonus for the treatment of the disease. In this study, 20 novel 1-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazine derivatives were designed and synthesized using a bioisosterism approach, and their activities for D2/D3/5-HT1A receptors were further tested. The results showed that several compounds exhibited a multitarget combination of D2/5-HT1A agonism. Compounds 7b and 34c showed agonistic activities on D2/D3/5-HT1A receptor. The EC50 value of 7b for D2/D3/5-HT1A receptor were 0.9/19/2.3 nmol/L, respectively; and the EC50 value of 34c for D2/D3/5-HT1A receptor were 3.3/10/1.4 nmol/L, respectively. In addition, 34c exhibited good metabolic stability (the half-life T 1/2 = 159.7 minutes) in vitro, which is of great significance for the further exploration of multitarget anti-PD drugs.

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