Research progress of long chain non-coding RNA H19 in anoxic environment mechanism / 中南大学学报(医学版)

LncRNA H19 encoded by the H19 imprinting gene plays an important regulatory role in the cell. Recently study has found that in hypoxic cells, the expression of H19 gene changes, and the transcription factors and protein involved in the expression change accordingly. Through the involvement of specific protein 1 (SP1), hypoxia-inducible factor-1α (HIF-1α) binds directly to the H19 promoter and induces the up-regulation of H19 expression under hypoxic conditions. The tumor suppressor protein p53 may also mediate the expression of the H19 gene, in part by interfering with HIF-la activity under hypoxia stress. The miR675-5p encoded by exon 1 of H19 promotes hypoxia response by driving the nuclear accumulation of HIF-1α and reducing the expression of VHL gene, which is a physiological HIF-1α inhibitor. In addition, under the condition of hypoxia, the expression of transporter on cell membrane changes, and the transition of the intracellular glucose metabolism pathway from aerobic oxidation to anaerobic glycolysis is also involved in the involvement of H19. Therefore, H19 may be a key gene that maintains intracellular balance under hypoxic conditions and drives adaptive cell survival under conditions of hypoxia stress.

Effect of acute exposure to high altitude on pharmacokinetics of propranolol and metoprolol in rats / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the pharmacokinetics of propranolol and metoprolol in rats after acute exposure to high altitude.</p><p><b>METHODS</b>Wistar rats were randomly assigned into 4 groups for treatment with intragastric administration of propranolol or metoprolol after acute exposure to high altitude (4010 m) or normal altitude (50 m). Venous blood samples were collected from the rats at different time points after drug administration to determine the drug concentrations in the plasma and plasma ultrafiltrate using liquid chromatography-mass spectrometry (LC-MS/MS).</p><p><b>RESULTS</b>The protein binding rate of propranolol was significantly increased but that of metoprolol remained unchanged after acute exposure to high altitude. Compared with the rats exposed to normal altitude, the rats with acute exposure to high altitude showed significant alterations in the pharmacokinetic parameters of the drugs, shown by increased Cmax and AUC, prolonged t1/2 and MRT, and lowered Clz/F of propranolol, and by increased Tmax and prolonged t1/2 and MRT of metoprolol without obvious changes of the parameters of the compartmental model.</p><p><b>CONCLUSION</b>Significant changes in the pharmacokinetics of propranolol and metoprolol occur in rats after acute exposure to high altitude possibly in relation to, apart from the changes in plasma protein binding ratio and blood gas, alterations in metabolic enzyme activities, increased blood viscosity, and species and general conditions of the animals.</p>

Myocardial injury in rats following a sudden increase of altitudes / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the influence of a sudden increase of altitudes (within 2500 m) in winter on cardiomyocyte functions in rats.</p><p><b>METHODS</b>Thirty male Wistar rats were randomly divided into groups A (55 m), B (1520 m), and C (2260 m) and subjected to simulated conditions at the indicated altitudes in winter for 3 days. Blood gas analysis, venous blood biochemistry, and measurements of SOD activity and myocardial concentrations of MDA and NO were performed. Histopathological changes in the left ventricle were observed with HE staining and electron microscopy.</p><p><b>RESULTS</b>Blood pH and PCO2 did not differ significantly between the 3 groups, but PO2 and BE in groups B and C decreased significantly compared with those in group A (P<0.01). Compared with group A, the rats in group C showed obviously increased myocardial enzymes, MYB, Tn-I, and MDA contents (P<0.01) with significantly decreased SOD activity (P<0.05); both groups B and C showed significantly decreased NO content in the myocardium (P<0.01). Histopathologically, the myocardial fiber in group C showed irregular alignment, disruption, and mitochondrial expansion.</p><p><b>CONCLUSION</b>A sudden increase of altitude to 2260 m in winter can potentially cause hypoxic cardiomyocyte damage as a result of oxidative and environmental stresses.</p>

Effects of acute exposure to high altitude on hepatic function and CYP1A2 and CYP3A4 activities in rats / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the changes in hepatic functions and activities of CYP1A2 and CYP3A4 in rats after acute exposure to high altitude.</p><p><b>METHODS</b>Twelve healthy male Wistar rats were randomly divided into control group and exposure group for acute exposure to normal and high altitude (4010 m) environment. Blood samples were collected from the vena orbitalis posterior for detection of the hepatic function. Hepatic pathologies of the rats were examined microscopically with HE staining. Liver microsomes were extracted by differential centrifugation to assess the activities of CYP1A2 and 3A4 using P450-GloTM kit.</p><p><b>RESULTS</b>In rats with acute exposure to high altitude, AST, ALT, and ALP all increased significantly by 48.50%, 47.90%, and 103.02%, respectively, and TP decreased significantly by 17.80% as compared with those in rats maintained in normal altitude environment (P<0.05). Pathological examination of the liver revealed edema of the central vein of the liver and hepatocyte karyopyknosis in rats after acute exposure to high altitude, which also resulted in significantly lowered activities of CYP1A2 and 3A4 in the liver (by 96.56% and 43.53%, respectively).</p><p><b>CONCLUSION</b>Acute exposure to high altitude can cause obvious liver injuries and lowered activities of CYP1A2 and 3A4 in rats to severely affect drug metabolism in the liver and result in increased concentration, prolonged half-life and reduced clearance of drugs.</p>

Effect of acute exposure to high altitude on the pharmacokinetics of propranolol / 中南大学学报(医学版)

Objective:To study the pharmacokinetics of propranolol in Wistar rats after acute exposure to high altitude. Methods:Fourteen male Wistar rats (200±20) g were selected. After administration of propranolol tablets (0.05 g/kg, i.g.), blood samples (3 mL) were collected at 0, 20, 40 min,1, 1.5, 2, 4, 6, 8, 12 and 24 h, respectively. The pharmacokinetic parameters were determined by LC-MS/MS and DAS 2.0 software. Results:The main pharmacokinetic area under concentration-time curve (AUC), mean retention time (MRT), half-life (t1/2) and peak plasma concentration (Cmax) of propranolol were increased by 442.61%, 47.45%, 73.13%and 352.97%, respectively, whereas Tmax and clearance (CL) were decreased by 80.87%and 68.94%, respectively. Conclusion:This study displays significant changes in the pharmacokinetics of propranolol under high altitude, which may provide evidence for clinical rational application of propranolol at high altitude.

Effects on the pharmacokinetics of furosemide after acute exposure to high altitude at 4010 meters in rats / 药学学报

The paper is to report the pharmacokinetics of furosemide in rats living at plain area and high altitude. After intragastric administration of furosemide (2.87 mg x kg(-1)), serial blood samples (0.5 mL) were collected by retro-orbital puncture at 0, 20 min, 40 min, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 h, samples were determined by LC-MS/MS, and plasma concentration-time data were analyzed by DAS 2.0 software to get the related pharmacokinetic parameters. The main pharmacokinetic parameters: area under curve (AUC), mean residence time (MRT), the biological half-life (t1/2) and the peak concentration (C(max)) of furosemide, were significantly increased at high altitude, the time to reach peak concentration (t(max)) and clearance (CL) was significantly decreased. This study found significant changes on the pharmacokinetics of furosemide under the special environment of high altitude. This finding may provide some references for clinical rational application of furosemide at high altitude.

Effects of methotrexate enantiomers on ECV304 cell inhibition and its mechanisms / 中国药理学通报

Aim To investigate the effect of MTX(included(±)MTX,(+)MTX and(-)MTX)on the proliferation of ECV304 cells and to explore its mechanisms.Methods ECV304 cells were cultured.The cell proliferation was determined by MTT.The morphological changes were inspected by inverted microscope.Cell cycle phases were assayed by propidium iodide staining flow cytometry.Results ECV304 cells were treated with(+)MTX,(-)MTX and(±)MTX at 1～150 μmol·L~(-1) for 24,48,72 h.The results showed that the proliferation of ECV304 cells was significantly inhibited under different conditions.The order of the inhibited efficacy was(+)MTX>(±)MTX>(-)MTX.The morphology of ECV304 cells were changed by(+)MTX,(-)MTX and(±)MTX treatment,which included the cell shrinkage,chromatin condensation.After administration of 10 μmol·L~(-1) of(+)MTX,(-)MTX and(±)MTX for 48 h,the cell cycle phases were assayed by propidium iodide staining flow cytometry.The result showed DNA replication was interfered by(+)MTX,(-)MTX and(±)MTX treatment.Conclusions The proliferation of ECV304 cells has the chiral selective effects by(+)MTX and(-)MTX treatment,and the inhibition on ECV304 cells proliferation of(+)MTX is significantly stronger than that of (-)MTX.