1. To investigate Genkwa Flos hepatotoxicity, a cell metabolomics strategy combined with serum pharmacology was performed on human HL-7702 liver cells in this study.
2. Firstly, cell viability and biochemical indicators were determined and the cell morphology was observed to confirm the cell injury and develop a cell hepatotoxicity model. Then, with the help of cell metabolomics based on UPLC-MS, the Genkwa Flos group samples were completely separated from the blank group samples in the score plots and seven upregulated as well as two down-regulated putative biomarkers in the loading plot were identified and confirmed. Besides, two signal molecules and four enzymes involved in biosynthesis pathway of lysophosphatidylcholine and the sphingosine kinase/sphingosine-1-phosphate pathway were determined to investigate the relationship between Genkwa Flos hepatotoxicity and these two classic pathways. Finally, the metabolic pathways related to specific biomarkers and two classic metabolic pathways were analyzed to explain the possible mechanism of Genkwa Flos hepatotoxicity.
3. Based on the results, lipid peroxidation and oxidative stress, phospholipase A2/lysophosphatidylcholine pathway, the disturbance of sphingosine-1-phosphate metabolic profile centered on sphingosine kinase/sphingosine-1-phosphate pathway and fatty acid metabolism might be critical participators in the progression of liver injury induced by Genkwa Flos. 相似文献
BackgroundPeriodontitis is associated with the pathogenesis of atherosclerotic plaque, and hypersensitive C reactive protein (hs-CRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) are the serum biomarkers of the stability of atherosclerotic plaque. Whether periodontitis is associated with the serum level of hs-CRP and Lp-PLA2 of acute ischemic stroke remains unclear.Material and MethodsWe recruited 103 cases with acute ischemic stroke within 7 days after stroke onset. Pocket depth and clinical attachment loss were assessed by oral examination to define the severe periodontitis. Demographic information including gender, age and body weight index, income level, education level, past medical history include smoking history, drinking history, ischemic stroke history, coronary heart disease, hypertension, diabetes and hyperlipidemia were collected, and serum biomarkers including white blood cell (WBC), fibrinogen, total cholesterol (TC), triglyceride (TG), lower density lipoprotein (LDL-C), high density lipoprotein (HDL-C), hs-CRP, HemoglobinA1c (HbAlc), Homocysteine (HCY) and Lp-PLA2 were tested.Results65 (63.1%) cases were diagnosed as severe periodontitis. Severe periodontitis group showed more male, age, drinking history, higher levels of hs-CRP and Lp-PLA2. Multivariate logistic regression showed that severe periodontitis was were significantly associated with hs-CRP (OR = 2.367, 95%CI: 1.182–4.738; P = .015) and Lp-PLA2 (OR = 2.577, 95% CI: 1.010–6.574; P = .048).ConclusionsSevere periodontitis is independently associated with the serum Level of hs-CRP and Lp-PLA2 in patients with acute ischemic stroke. Whether the improvement of periodontitis could decrease the occurrence and re-occurrence of ischemic stroke by stablizating atherosclerotic plaque need be further studied in future. 相似文献
Flavocoxid (Limbrel), a proprietary mixture of flavonoid molecules (baicalin and catechin), was tested against a traditional nonsteroidal anti-inflammatory drug, naproxen, for the management of the signs and symptoms of moderate osteoarthritis (OA) in humans. Discomfort and global disease activity were used as the primary end points, and safety assessments were also taken for both treatments as a secondary endpoint. In this double-blind study, 103 subjects were randomly assigned to receive either flavocoxid [500 mg twice daily (BID)] or naproxen (500 mg BID) in a 1-month onset of action trial. Outcome measures included the short Western Ontario and McMaster University Osteoarthritis Index, subject Visual Analogue Scale for discomfort and global response, and investigator Visual Analogue Scale for global response and fecal occult blood. Both flavocoxid and naproxen showed significant reduction in the signs and symptoms of knee OA (P ≤ .001). There were no statistically detectable differences between the flavocoxid and naproxen groups with respect to any of the outcome variables. Similarly, there were no statistically detectable differences between the groups with respect to any adverse event, although there was a trend toward a higher incidence of edema and nonspecific musculoskeletal discomfort in the naproxen group. In this short-term pilot study, flavocoxid was as effective as naproxen in controlling the signs and symptoms of OA of the knee and would present a safe and effective option for those individuals on traditional nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors. A low incidence of adverse events was reported for both groups. 相似文献
We used molecular modeling to examine the binding of 1, 2-dioctanoyl-sn-glycero-3-phosphocholine (a lecithin), 1-octanoyl-sn-glycero-3-phosphocholine (a lysolecithin) and their tetrahedral intermediates in the catalytic site of phospholipase A2 (PLA2). We performed energy minimization on each complex, computed the binding energy, determined the relative binding energy among the complexes and calculated the difference in inter- and intramolecular energies of the components in the complexes. We found that the calculated orientation of the sn-1 ester bond of lysolecithin in the active site is similar to that of the sn-2 ester bond in lecithin, thus permitting PLA2 to hydrolyze lysolecithin using the same mechanism as it uses to hydrolyze lecithin. On the other hand, the binding of lecithin is energetically more favorable by 4.5 kcal/mol than the binding of lysolecithin to the enzyme, and the binding of the lecithin tetrahedral intermediate is also energetically more favorable by 19.7 kcal/mol than the binding of the lysolecithin tetrahedral intermediate to the enzyme, which explains why lecithin is a better substrate than lysolecithin in the catalytic site. These results indicate that the activation energy for the hydrolysis of lysolecithin is higher than that for lecithin, consistent with the observed slower rate for the hydrolysis of lysolecithin. 相似文献
1. Global myocariial ischaemia (MI) for periods greater tan 5 min caused an inhibition of phosphatidylinositol specific phospholipase C (PtdIns-PLC) activity. 2. Two min reperfusion following a 20 min MI period, a time point associated with reperfusion-induced arrhythmias, resulted in an activation of PtdIns-PLC activity, dependent on endogenous noradrenaline and mediated via al-adrenoceptors. 3. This 2 min reperfusion response, in contrast to healthy myocardium, resulted in: (i) enhanced PtdIns-PLC activity; (ii) increased sensitivity to endogenous noradrenaline; (iii) rapid increases in inositol(1,4,5)trisphosphate (Ins(1,4,5)P3); and (iv) PLC hydrolysis primarily of PtdIns(4,5)P2, such that the majority of InsP isomers derive from Ins(1,4,5)P3. 4. Together, these data suggest a functional role for Ins(1,4,5)P3 under postischaemic reperfusion conditions, and provide a possible link between al-adrenoceptor stimulation of the PtdIns turnover pathway and reperfusion injury. 相似文献
The edema-producing activity of NNAVPLA2, an acidic phospholipase A2 (PLA2) enzyme from Naja naja atra venom (NNAV), was less potent than that of TMVPLA2 II, a basic PLA; from Trimeresurus mucrosquamatus venom (TMV). These edema-forming effects were greatly suppressed by pretreatment of rats with diphenhydramine/ methysergide or compound 48/80, which reduced the tissue content of histamine and serotonin. Heparin abolished and suppressed the paw edema caused by protamine and TMVPLA2 II, respectively, but had no effect on the NNAVPLA2-induced response. In isolated rat peritoneal mast cells, both PLA2 concentration dependently induced the release of histamine and β-glueuronidase. Again, TMVPLA2 II was more potent than NNAVPLA2. This degranulation effect of mast cells caused by TMVPLA2 II and protamine was inhibited by heparin, while that caused by NNAVPLA2 was unaffected. The edema-forming and mast cell degranulation effects were greatly decreased in both PBPB-modified NNAVPLA2 and PBPB-modified TMVPLA2 II, in which the catalytic activity of the enzymes was completely lost. PBPB-modified TMVPLA2 II-induced paw edema was also suppressed by heparin. Furthermore, this edematous response was totally reversed in rat pretreated with aspirin in combination with diphenhydramine and methysergide. These results suggest that the edema-forming effect of PLA2 is probably dependent on the presence of catalytic, positive charge and pharmacological sites on its molecule. 相似文献
1. Phospholipase A2 (PLA2) cleaves phospholipids to produce a lyso-phospholipid and free fatty acid and, in view of the biological activity of the products, PLA2 may play a role in many disease states. Lyso-phospholipids and free arachidonic acid increase in ischaemic myocardium, indicating that ischaemia activates the enzyme. 2. Plasma PLA2 activity was measured in patients with acute myocardial infarction, based on the release of labelled arachidonic acid from Escherichia coli cell membrane. Fourteen males (peak serum creatine phosphokinase (CK) above twice upper normal) were studied on day 1 (within 6 h of chest pain onset), days 2-4, and days 6-9. Normal age matched males (n = 13) were also studied. 3. Plasma PLA2 in patients with uncomplicated myocardial infarction (n = 12) was, initially, 1.14 +/- 0.10 (s.e.m.) nmol/min per mL plasma, similar to that in the normal group (1.52 +/- 0.14). On days 2-4, PLA2 activity increased to 1.94 +/- 0.18 (P less than 0.001) and this activity was correlated with the earlier peak CK level (P less than 0.02). On days 6-9, PLA2 activity was 1.49 +/- 0.13 while in two patients who developed complications and underwent open-heart surgery between the last two measurements, there were further increases to 4.22 and 4.04 nmol/min per mL. 4. The increase in plasma PLA2 in uncomplicated myocardial infarction is likely to be due to release from the damaged myocardium; whether it contributes to pathophysiology is uncertain. 相似文献
The effect of histamine on the phosphoinositide turnover andintracellular free calcium activity [Ca2+]i was examined inhuman glomerular epithelial cells in culture. Addition of histamineto glomerular epithelial cells resulted in formation of inositolphosphates in a time- and dose-dependent manner. A transientmaximum of inositol trisphosphate (InsP3) was observed within10 s. Stimulation of protein kinase C by short-term pretreatment(15 mm) of glom erular epithelial cells with phorbol 12-mynstate13-acetate caused a dose-dependent inhibition of the histamine-inducedinositol phosphate accumulation. The baseline of [Ca2+]i inthe cells was 115 ±2.7 nmol/l (n=103). Histamine (ED50:approx. 2x107mol/l) caused a rapid and transient increasein [Ca2+]i, as detected by fura-2 microfluorimetry studies.In a calcium-free extracellular solution the rapid increaseof [Ca2+]i was still present. The H1 receptor antagonist mepyramine(IC50: approx. 8 x 109 mol/l) inhibited the histamine(106 mol/l) response on [Ca2+]i Cimetidine, a potentH2 receptor antagonist, showed no effect. This data indicates that H1 receptor activation causes hydrolysisof phosphatidylinositol 4, 5-bisphosphate by phospholipase Cactivation, and consecutive mobil ization of intracellular calcium.Since histamine is a mediator of inflammation, antigen responseand cellular injury, these findings could be of importance forthe understanding of glomerular epithelial cell pathology. 相似文献