Advanced Oxidation Protein Products Regulate the Pharmacokinetics of Aloe-emodin,Emodin,Rhein,and Chrysophanol in Chronic Kidney Disease Rats

Background:As accelerators and products of the progression of chronic kidney disease(CKD),advanced oxidation protein products(AOPPs)affect the function of the liver.Huang Gan granules(HGGs)are commonly used to prevent the progression of CKD,but the pharmacokinetics of aloe-emodin,emodin,rhein,and chrysophanol in HGGs in CKD remain unknown.Objective:To investigate the influence and its molecular mechanism of AOPPs on the in vivo pharmacokinetics of aloe-emodin,emodin,rhein,and chrysophanol in HGGs.Methods:We constructed 5/6 nephrectomised(5/6 nx),adenine-induced(adenine)and AOPP-treated rat models.After oral administration of HGG,the concentrations of aloe-emodin,emodin,rhein,and chrysophanol in the plasma samples were detected by high-performance liquid chromatography(HPLC),and their pharmacokinetics were analysed with the PKSolver software.The plasma concentrations of IL-6 and TNF-αare detected by enzyme linked immunosorbent assay(ELISA).The RT-PCR was performed in the HepG2 cells to explore the effect of TNF-αand IL-6 on the mRNA expression of CYP1A2 and CYP3A4.Result:The results showed that the method was suitable for the quantification of four anthraquinones in plasma and excreta samples with satisfactory linear(R R^(2)>0.9931),precision(<9.4%)and accuracy(±10%).In 5/6 nx,adenine and AOPPs-treated rats,the concentrations of TNF-αand IL-6 were increased.In 5/6 nx and adenine rats,the pharmacokinetic parameters(t_(1/2),MRT_(0-∞)and AUC_(0-∞))of aloe-emodin,emodin,rhein,and chryso-phanol were,respectively,significantly increased and correlated with the concentration of AOPPs.In AOPPs-treated rats,the concentration of AOPPs was significantly increased and the pharmacokinetic parameters of four anthraquinones were also increased.Conclusion:In summary,inflammatory cytokine production may be one of the important causes in AOPPs’regulat-ing the pharmacokinetic of aloe-emodin,emodin,rhein,and chrysophanol in the CKD rats.Studies of aloe-emodin,emodin,rhein,and chrysophanol in CKD facilitate the appropriate prescription of HGGs in the clinical.

Advanced oxidation protein products induce monocyte chemoattractant protein-1 expression via p38 mitogen-activated protein kinase activation in rat vascular smooth muscle cells

Background Advanced oxidation protein products （AOPPs） are new uremic toxins reported by Witko-Sarsat in 1996, which are associated with the pathogenesis of atherosclerosis. However, the mechanisms by which AOPPs enhance atherosclerosis have not been fully understood. Monocyte chemoattractant protein-1 （MCP-1） is a chemokine which stimulates migration of monocytes and plays a critical role in the development of atherosclerosis. In this study, we investigated the effect of AOPPs on MCP-1 expression in cultured vascular smooth muscle cells （VSMCs）.

p53 antibodies,metallothioneins,and oxidative stress markers in chronic ulcerative colitis with dysplasia

AIM:To investigate the role of p53 antibodies (p53Abs),metallothioneins (MTs) and oxidative stress markers in the early detection of dysplasia in chronic ulcerative colitis (UC).METHODS:The study included 30 UC patients,15 without dysplasia (group Ⅱ) and 15 with dysplasia (group Ⅲ),in addition to 15 healthy volunteers (group Ⅰ,control subjects).The enzyme-linked immunosorbent assay technique was used to measure serum p53Abs and MTs,while advanced oxidation protein products (AOPPs),and reduced glutathione (GSH) levels were measured by spectrophotometric method in all subjects.RESULTS:In group Ⅱ and group Ⅲ compared to group Ⅰ,there were significant increases in serum levels of AOPPs (145.94 ± 29.86 μmol/L and 192.21 ± 46.71 μmol/L vs 128.95 ± 3.06 μmol/L,P < 0.002 and P <0.001,respectively),MTs (8.18 ± 0.35 μg/mL and 9.20 ± 0.58 μg/mL vs 6.12 ± 0.25 μg/mL,P < 0.05 and P < 0.05,respectively),and p53Abs (20.19 ± 3.20 U/mL and 34.66 ± 1.34 U/mL vs 9.42 ± 1.64 U/mL,P < 0.001 and P < 0.001,respectively).There were significantly higher levels of AOPPs (P < 0.05) and p53Abs (P < 0.001) in UC patients with dysplasia compared to those without dysplasia,while MTs showed no significant difference between the 2 groups (P > 0.096).In contrast,GSH levels showed a significant decrease in both patients' groups (1.87 ± 0.02 μmol/mL and 1.37 ± 0.09 μmol/mL vs 2.49 ± 0.10 μmol/mL,P < 0.05 and P < 0.05 in groups Ⅱ and Ⅲ,respectively) compared with group Ⅰ,and the levels were significantly lower in group Ⅲ than group Ⅱ (P < 0.05).There was a positive correlation between AOPPs and both MTs (r=0.678,P < 0.001) and p53Abs (r=0.547,P < 0.001),and also between p53Abs and MTs (r=0.739,P < 0.001).There was a negative correlation between AOPPs and GSH (r =-0.385,P < 0.001),and also between GSH and both MTs (r=-0.662,P < 0.001) and p53Abs (r=-0.923,P < 0.001).CONCLUSION:Oxidative stress and oxidative cellular damage play an important role in the pathogenesis of chronic UC and the associated carcinogenetic process.p53Abs levels could help in early detection of dysplasia in these conditions.

Role of reactive oxygen species in the renal fibrosis

Renal fibrosis is a common pathway of progressive renal diseases leading to end-stage renal disease regardless of the etiology. Accumulating evidence indicates that oxidative stress, resulting in generation of reactive oxygen species （ROS）, plays a critical role in the initiation and progression of fibrotic diseases. Nicotinamide adenine dinucleotide phosphate （NADPH） oxidase is the predominant enzyme source for ROS generation and is now recognized as a key mediator of cell proliferation and matrix accumulation in renal disease. Multiple stimuli and agonists, such as transforming growth factor , tumor necrosis factor, platelet derived growth factor, angiotensin II, hyperglycemia, oxidized low-density lipoprotein and albumin have been shown to alter the activity or expression of the NADPH oxidase and ultimately increase ROS production. ROS directly incites damage to biologically important macromolecules and leads to generation of the so-called advanced oxidation protein products （AOPPs） and advanced glycation end products, which are not only markers of oxidative stress but also cause renal injury. Targeting NADPH oxidase and/or reducing AOPPs production miaht be a novel strateav for the theraoeutic intervention of varietv of fibrotic kidney disorders.