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1.
Article En | MEDLINE | ID: mdl-35839967

The glucocorticoid receptor (GR) forms a protein complex with FKBP51 that is increased in post-traumatic stress disorder (PTSD) and by fear conditioned learning. Disrupting the GR-FKBP51 complex with a synthetic peptide can block the storage or retrieval of fear conditioned memories, which could be a novel approach to the alleviate fear associated memory in PTSD. However, a potential unacceptable side effect could be the impairment of other types of memory. Thus, we investigated the effect of disrupting the GR-FKBP51 complex on recognition memory using the novel object and displaced object recognition tasks, spatial memory in the Morris water maze, and on social interaction in Crawley's three-chamber social interaction test. We did not observe adverse effects on these other types of memory and conclude that the GR-FKBP51 interaction remains a promising target for treating psychiatric disorders characterized by unwanted aversive memories such as in PTSD.


Receptors, Glucocorticoid , Recognition, Psychology , Stress Disorders, Post-Traumatic , Tacrolimus Binding Proteins , Fear , Humans , Receptors, Glucocorticoid/metabolism , Stress Disorders, Post-Traumatic/drug therapy , Stress Disorders, Post-Traumatic/metabolism , Tacrolimus Binding Proteins/metabolism
2.
Int J Cardiol ; 281: 90-98, 2019 Apr 15.
Article En | MEDLINE | ID: mdl-30728103

BACKGROUND: Diabetes is associated with an increased risk of heart failure, cardiac arrhythmias and sudden cardiac death. We previously showed that ROCK2 expression is elevated in diabetic rat hearts, and that ROCK inhibition acutely improves their contractile function. In the present study we investigated whether inhibition of ROCK or partial deletion of ROCK2 improves impaired Ca2+ handling in the diabetic heart. METHODS: Contractile properties and Ca2+ transients were measured before and after treatment with the ROCK inhibitor Y-27632 (1 µM) in fluo-4-loaded cardiomyocytes isolated from streptozotocin (STZ)-diabetic or non-diabetic rats. Cardiac function was determined in vivo, and contractile properties and Ca2+ transients also measured in cardiomyocytes from non-diabetic and STZ-diabetic wild-type (WT) and ROCK2+/- mice. RESULTS: ROCK inhibition improved some parameters of contractile function and Ca2+ handling in cardiomyocytes from diabetic rat hearts. In addition, ROCK inhibition attenuated the diabetes-induced delayed aftercontractions (DACs) and associated irregular Ca2+ transients induced by increased [Ca2+]o. Although no overt cardiac dysfunction was detected in diabetic WT mice, cardiomyocytes from these mice also developed arrhythmic Ca2+ transients in response to increased [Ca2+]. These were attenuated in cardiomyocytes from diabetic ROCK2+/- mice, in association with decreased diastolic Ca2+ leak and with reduction of the diabetes-induced increased phosphorylation of both CaMKII and the ryanodine receptor (RyR). CONCLUSIONS: These data suggest that ROCK2 contributes to diabetes-induced impaired cardiac Ca2+ homeostasis, at least in part by promoting CaMKII-mediated phosphorylation of RyR. This may have important clinical implications for the treatment of the increased incidence of dysrhythmias in diabetes.


Arrhythmias, Cardiac/metabolism , Calcium/metabolism , Diabetes Mellitus, Experimental/metabolism , Myocytes, Cardiac/metabolism , rho-Associated Kinases/metabolism , Amides/pharmacology , Animals , Arrhythmias, Cardiac/genetics , Cells, Cultured , Diabetes Mellitus, Experimental/genetics , Male , Mice , Mice, Transgenic , Myocytes, Cardiac/drug effects , Phosphorylation/physiology , Pyridines/pharmacology , Rats , Rats, Wistar , rho-Associated Kinases/genetics
3.
Free Radic Biol Med ; 130: 436-445, 2019 01.
Article En | MEDLINE | ID: mdl-30395972

Heavy ion radiotherapy has shown great promise for cancer therapy. Understanding the cellular response mechanism to heavy ion radiation is required to explore measures of overcoming devastating side effects. Here, we performed a quantitative proteomic analysis to investigate the mechanism of carbon ion irradiation on human AHH-1 lymphoblastoid cells. We identified 4602 proteins and quantified 4569 proteins showing high coverage in the mitochondria. Data are available via ProteomeXchange with identifier PXD008351. After stringent filtering, 290 proteins were found to be significantly up-regulated and 16 proteins were down-regulated. Functional analysis revealed that these up-regulated proteins were enriched in the process of DNA damage repair, mitochondrial ribosome, and particularly mitochondrial respiratory chain, accounting for approximately 50% of the accumulated proteins. Bioinformatics and functional analysis demonstrated that these up-regulated mitochondrial respiratory chain proteins enhanced ATP production and simultaneously reactive oxygen species release. More importantly, increased reactive oxygen species led to secondary organelle injury and lagged DNA double-strand breaks. Consistently, the expression of antioxidant enzymes was up-regulated for free radical scavenging. The mechanism of lagged secondary injury originated from disturbances in the mitochondrial respiratory chain. Our results provided a novel target for cell self-repair against heavy ion radiation-induced cellular damage.


Electron Transport/radiation effects , Mitochondria/radiation effects , Neoplasms/radiotherapy , Proteomics , Antioxidants/pharmacology , Cell Line, Tumor , DNA Damage/genetics , DNA Damage/radiation effects , DNA Repair/genetics , DNA Repair/radiation effects , Heavy Ion Radiotherapy/adverse effects , Humans , Mitochondria/metabolism , Neoplasms/genetics , Neoplasms/metabolism , Reactive Oxygen Species/metabolism
4.
PLoS One ; 12(10): e0186645, 2017.
Article En | MEDLINE | ID: mdl-29053735

Pyridoxine dependent epilepsy (PDE) is caused by likely pathogenic variants in ALDH7A1 (PDE-ALDH7A1) and inherited autosomal recessively. Neurotoxic alpha-amino adipic semialdehyde (alpha-AASA), piperideine 6-carboxylate and pipecolic acid accumulate in body fluids. Neonatal or infantile onset seizures refractory to anti-epileptic medications are clinical features. Treatment with pyridoxine, arginine and lysine-restricted diet does not normalize neurodevelopmental outcome or accumulation of neurotoxic metabolites. There is no animal model for high throughput drug screening. For this reason, we developed and characterized the first knock-out aldh7a1 zebrafish model using CRISPR-Cas9 technology. Zebrafish aldh7a1 mutants were generated by using a vector free method of CRISPR-Cas9 mutagenesis. Genotype analysis of aldh7a1 knock-out zebrafish was performed by high resolution melt analysis, direct sequencing and QIAxcel system. Electroencephalogram was performed. Alpha-AASA, piperideine 6-carboxylate and pipecolic acid, were measured by liquid chromatography-tandem mass spectrometry. Our knock-out aldh7a1 zebrafish has homozygous 5 base pair (bp) mutation in ALDH7A1. Knock-out aldh7a1 embryos have spontaneous rapid increase in locomotion and a rapid circling swim behavior earliest 8-day post fertilization (dpf). Electroencephalogram revealed large amplitude spike discharges compared to wild type. Knock-out aldh7a1 embryos have elevated alpha-AASA, piperideine 6-carboxylate and pipecolic acid compared to wild type embryos at 3 dpf. Knock-out aldh7a1 embryos showed no aldh7a1 protein by western blot compared to wild type. Our knock-out aldh7a1 zebrafish is a well characterized model for large-scale drug screening using behavioral and biochemical features and accurately recapitulates the human PDE-ALDH7A1 disease.


Aldehyde Dehydrogenase/genetics , Clustered Regularly Interspaced Short Palindromic Repeats , Epilepsy/chemically induced , Pyridoxine/toxicity , Zebrafish/genetics , Action Potentials , Animals , Behavior, Animal , Electroencephalography , Epilepsy/genetics , Epilepsy/physiopathology , Gene Knockdown Techniques , Zebrafish/embryology
5.
Nan Fang Yi Ke Da Xue Xue Bao ; 36(9): 1169-1172, 2016 Aug 20.
Article Zh | MEDLINE | ID: mdl-27687645

OBJECTIVE: To study the changes in the physiological parameters and gene expression of two drug efflux transporters MDR1 and MRP2 in the small intestine, liver and kidney of rats exposed to acute hypoxia. METHODS: Eighteen Wistar rats were randomly divided into control group, hypoxia for 24 h group and hypoxia for 72 h group. Blood samples were obtained from the abdominal aorta of the rats after the exposure for analyzing the physiological indexes. The mRNA expressions of MDR1 and MRP2 were determined using Real-Time PCR, and their protein expressions were detected with enzyme-linked immunosorbent assay (ELISA). RESULTS: The physiological parameters of the rats in hypoxia group were significantly changed compared with those in the control group. The expressions of MDR1 and MRP2 mRNA and proteins in the small intestine, liver and kidney were significantly increased in rats with hypoxic exposure than in the control rats (P<0.05 or 0.01). As the hypoxic exposure prolonged, the two transporters showed different patterns of variation in different tissues. CONCLUSION: Acute hypoxia affects the physiological parameters and expression levels of MDR1 and MRP2, thus causing changes in the metabolism of the substrates of the transporters. These changes may play an important role in the pharmacokinetics of drugs at a high altitude.


ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP-Binding Cassette Transporters/metabolism , Hypoxia , Animals , Intestine, Small/metabolism , Kidney/metabolism , Liver/metabolism , RNA, Messenger/metabolism , Rats , Rats, Wistar
6.
J Ethnopharmacol ; 187: 232-8, 2016 Jul 01.
Article En | MEDLINE | ID: mdl-27085939

BACKGROUND: Fibrinolysis prevents blood clots from growing and becoming problematic. Antifibrinolytics are used as inhibitors of fibrinolysis. Aprotinin was doubted after identification of major side effects, especially on kidney. Lysine analogues has their own defects and whether they are adequate substitutes for aprotinin is still under doubt. Lamiophlomis rotata (Benth.) Kudo. was previous found to have hemostatic activity. But the active compound in L. rotata and its hemostatic mechanism were unknown. OBJECTIVES: To find the major hemostatic compound in L. rotata and identify its haemostasis mechanism. METHODS: Traumatic hemorrhage model and coagulant activity assays were monitored in mice and platelets in drug treatment group and control group. Hyperfibrinolysis model was established by intravenous administration of urokinase in mice. Capillary blood clotting time (CBCT), activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen and euglobulin clot lysis time (ECLT) were measured. RESULTS: The anti-fibrinolytic activity come from 8-O-Acetyl shanzhiside methylester (ASM) one of the highest iridoid glycosides contents in TIG extracted from L. rotata. ASM significantly (P<0.05) shorten CBCT and reduced blood loss volume in vivo, but did not influence mice APTT, PT or TT. In particular, it significantly prolonged ECLT in hyperfibrinolysis mice. It indicated that ASM could inhibit fibrinolysis. ASM was also effective in CBCT, traumatic bleeding volume and ECLT in hyperfibrinolysis mice model. CONCLUSIONS: ASM was the major hemostatic compound in L. rotata. The haemostasis mechanism of ASM was achieved by anti-fibrinolytic activity. ASM was a new fibrinolysis inhibitor as iridoid glycoside compound.


Antifibrinolytic Agents/therapeutic use , Glucosides/therapeutic use , Hemorrhage/drug therapy , Lamiaceae , Pyrans/therapeutic use , Animals , Antifibrinolytic Agents/pharmacology , Blood Coagulation/drug effects , Blood Coagulation Tests , Fibrinolysis/drug effects , Glucosides/pharmacology , Male , Mice, Inbred BALB C , Partial Thromboplastin Time , Prothrombin Time , Pyrans/pharmacology
8.
Yao Xue Xue Bao ; 51(9): 1412-6, 2016 09.
Article Zh | MEDLINE | ID: mdl-29924524

The drug transporter play a key role in the absorption of drugs. Investigation of the changes of drug transporters in response to hypoxia will provide insight into the mechanism of drug absorption. In this study we investigated the mRNA and protein expression of the transporter P-gp after acute hypoxia, and evaluated the effects of P-gp changes on absorption of levofloxacin in the intestine. The relative expression of m RNA and protein were reduced by 50.80% and 71.30%(P < 0.05). In the single-pass intestinal perfusion model, the intestinal wall permeability was increased by 56.16%, 226.00%, 77.74% and 141.00% in the time intervals at 30-60 min, 60-90 min, 90-120 min and 120-150 min although P-gp expression was decreased(P < 0.05). These results suggest that hypoxia may decrease the expression of P-gp in the intestine to reduce the excretion of levofloxacin and increase the absorption.


ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Hypoxia/metabolism , Intestine, Small/metabolism , Levofloxacin/metabolism , Animals , Biological Transport , Intestinal Absorption , Perfusion , Permeability , Rats
9.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 44(5): 571-7, 2015 09.
Article Zh | MEDLINE | ID: mdl-26713534

OBJECTIVE: To detect the expression of the plateau adaptablity gene(EPAS1, EGLN1 and PPARα) and proteins(HIF-2, PHD2 and PPARα) in rats blood, heart, liver, lung and kidney tissue after the rats exposed to high altitude. METHODS: The Wistar rats were randomly divided into plain group(Shanghai, 55 m), acute exposure to high altitude 3400 m group, acute exposure to high altitude 4300 m group. Blood and organs of rats were collected in 1, 3, 5 days after arrival. Real time PCR and ELISA were used to compare the expression of plateau adaptablity gene and related protein between plain group and high altitude exposure groups. RESULTS: The count of red blood cells, hemoglobin and HCT in high altitude 4300 m were higher than those in plain group. Compared with plain group, the expression of EPAS1 gene in blood, heart, liver and kidney tissue of rats at high altitude increased obviously(all P<0.05); the expression of EGLN1 in the heart, liver, brain and kidney increased, and PPARα gene in the heart, liver and kidney increased(all P<0.05). Compared with plain group, the expression of HIF-2 protein increased significantly at high altitudes in the liver, brain and kidney tissues. PHD2 and PPARα increased in the heart, liver and kidney. CONCLUSION: Plateau adaptive genes(EPAS1, EGLN1 and PPARα) and protein(HIF-2, PHD2 and PPARα) differed in different altitude and different organizations. They might be used as target markers of plateau hypoxia.


Adaptation, Physiological , Altitude , Basic Helix-Loop-Helix Transcription Factors/metabolism , Animals , Brain , China , Heart , Hypoxia , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Kidney , Liver , Lung , PPAR alpha/metabolism , Procollagen-Proline Dioxygenase/metabolism , Rats , Rats, Wistar
10.
Zhong Yao Cai ; 38(4): 790-3, 2015 Apr.
Article Zh | MEDLINE | ID: mdl-26672349

OBJECTIVE: To study the protective effect of Saussurea involucrata alcohol extract on liver mitochondria in mice under hypoxia condition. METHODS: The hypoxia mice model was established, the BALB/c mice were randomly divided into four groups:normal group ,hypoxia model group, positive control group and Saussurea involucrata alcohol extract group. Mice were put into low pressure oxygen chamber and decompressed, adapted to hypobaric hypoxia environment of simulated altitude of 8,000 m for 12 h, and then recovered to normal altitude. The mice were sacrificed and the liver mitochondria was isolated, the mitochondrial membrane potential and the activity of malate dehydrogenase, aconitase, α-ketoglutarate dehydrogenase, pyruvate dehydrogenase and mitochondrial complex I, II and V were measured. RESULTS: Compared with hypoxia model group, Saussurea involucrata alcohol extract protected mitochondrial membrane potential, sustained the activities of aconitase, α-ketoglutarate dehydrogenase, pyruvate dehydrogenase, and mitochondrial complex I, II and V under hypoxia condition. CONCLUSION: Saussurea involucrata alcohol extract can protect the liver mitochondrial function in mice under hypoxia condtion.


Hypoxia/drug therapy , Mitochondria, Liver/drug effects , Plant Extracts/pharmacology , Saussurea/chemistry , Altitude , Animals , Decompression , Disease Models, Animal , Ethanol , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred BALB C
11.
Sci Rep ; 5: 15578, 2015 Oct 23.
Article En | MEDLINE | ID: mdl-26493375

Light is recently recognized as a modulator able to activate the hippocampus and modulate memory processing, but little is known about the molecular mechanisms. Here, we report that in mice, a short pulse of white light before learning dramatically improves consolidation of contextual fear memory during the night. The light exposure increases hippocampal active p21-activated kinase 1 (PAK1) and CA1 long-term potentiation (LTP). These light effects are abolished in PAK1 knockout and dominant-negative transgenic mice, but preserved by expression of constitutively active PAK1 in the hippocampus. Our results indicate that light can act as a switch of PAK1 activity that modulate CA1 LTP and thereby memory consolidation without affecting learning and short-term memory.


Light , Memory , Animals , Hippocampus/enzymology , Hippocampus/physiology , Hippocampus/radiation effects , Long-Term Potentiation , Mice , Mice, Inbred C57BL , Mice, Transgenic , p21-Activated Kinases/genetics , p21-Activated Kinases/metabolism
12.
Biol Pharm Bull ; 38(9): 1280-9, 2015.
Article En | MEDLINE | ID: mdl-26328483

Nitric oxide (NO) may act as either a pro-oxidant or an antioxidant in biological systems. Previous work has found inhalation of NO improved survival in a high altitude rat model. NO donor isosorbide mononitrate derivants might have a protective effect against hypoxia. We synthesized a series of isosorbide mononitrate derivant compounds to test their anti-hypoxia activities. Normobaric hypoxia and hypobaric hypoxia models were used to study the protective role of NO donor in mice. The results showed isosorbide mononitrate derivants had protective effects in hypoxia mice. Among those compounds, acetyl ferulic isosorbide mononitrate (AFIM) was the most effective. It prolonged the survival time during the normobaric hypoxia test. It decreased malondialdehyde (MDA) and H2O2 in hypobaric hypoxia mice. The antioxidase activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) remained in normal ranges in the AFIM group. As a sign of mitochondrial dysfunction, the activities of ATPase were down regulated in mice under hypobaric hypoxia conditions. AFIM also protected ATPase activities. The protective effects of AFIM might come from a sustained NO supply and the release of acetyl ferulic acid with anti-oxidant activity.


Altitude Sickness/drug therapy , Hypoxia/drug therapy , Isosorbide Dinitrate/analogs & derivatives , Nitric Oxide Donors/therapeutic use , Adenosine Triphosphate/metabolism , Altitude Sickness/metabolism , Animals , Blood Pressure/drug effects , Catalase/metabolism , Cerebrum/drug effects , Cerebrum/metabolism , Glutathione Peroxidase/metabolism , Heart Rate/drug effects , Hydrogen Peroxide/metabolism , Hypoxia/metabolism , Isosorbide Dinitrate/pharmacology , Isosorbide Dinitrate/therapeutic use , L-Lactate Dehydrogenase/metabolism , Lactic Acid/blood , Malondialdehyde/metabolism , Mice, Inbred BALB C , Myocardium/metabolism , Nitric Oxide Donors/pharmacology , Rats , Superoxide Dismutase/metabolism
13.
Zhong Yao Cai ; 38(1): 89-92, 2015 Jan.
Article Zh | MEDLINE | ID: mdl-26214875

OBJECTIVE: To investigate the chemical constituents with anti-hypoxia activity from Saussurea involucrata. METHODS: The chemical constituents, isolated and purified by column chromatography from Saussurea involucrata, were identified by several spectroscopic methods. The anti-hypoxic activities of these compounds were examined using the normobaric hypoxic model of mice. RESULTS: Twelve compounds were isolated from petroleum ether extract of Saussurea involucrata and identified as n-octacosane (1), 1-undecanol (2), heptadecan-l-ol(3), heptacosan-1-ol(4), myristicin (5), apiol(6), ß-sitosterol(7), lupeol(8), moslosooflavone (9), mosloflavone (10), negletein(11), and 5, 6-dihydroxy-7, 8-dimethoxyflavone(12). CONCLUSION: All compounds except 7 and 8 are isolated from this plant for the first time. Compound 1, 5 and 8 - 12 can significantly prolong the survival time of hypoxic mice.


Hypoxia/drug therapy , Phytochemicals/pharmacology , Plant Extracts/pharmacology , Saussurea/chemistry , Alkanes , Animals , Flavonoids , Mice , Phytochemicals/isolation & purification , Plant Extracts/chemistry , Sitosterols , Solvents
14.
Nat Prod Commun ; 10(3): 387-8, 2015 Mar.
Article En | MEDLINE | ID: mdl-25924511

A convergent synthesis route of moslooflavone, isowogonin and norwogoninis reported,starting from chrysin, an easily available flavone, by methylation, bromination, methoxylation and demethylation procedures. This synthetic route is convenient and can give the three rare flavones in good yield.


Flavones/chemical synthesis , Flavonoids/chemistry , Flavonoids/chemical synthesis , Computational Biology
15.
Acta Physiol (Oxf) ; 2015 Mar 09.
Article En | MEDLINE | ID: mdl-25753758

Despite decades of research, the exact pathogenic mechanisms underlying acute mountain sickness (AMS) are still poorly understood. This fact frustrates the search for novel pharmacological prophylaxis for AMS. The prevailing view is that AMS results from an insufficient physiological response to hypoxia and that prophylaxis should aim at stimulating the response. Starting off from the opposite hypothesis that AMS may be caused by an initial excessive response to hypoxia we suggest that directly or indirectly blunting specific parts of the response might provide promising research alternatives. This reasoning is based on the observations that 1) humans, once acclimatized, can climb Mt Everest experiencing arterial partial oxygen pressures (PaO2 ) as low as 25 mmHg without AMS symptoms, 2) paradoxically AMS usually develops at much higher PaO2 levels, and 3) several biomarkers, suggesting initial activation of specific pathways at such PaO2 , are correlated with AMS. Apart from looking for substances that stimulate certain hypoxia triggered effects, such as the ventilatory response to hypoxia, we suggest to also investigate pharmacological means aiming at blunting certain other specific hypoxia activated pathways, or stimulating their agonists, in the quest for better pharmacological prophylaxis for AMS. This article is protected by copyright. All rights reserved.

16.
Zhong Yao Cai ; 38(9): 1919-24, 2015 Sep.
Article Zh | MEDLINE | ID: mdl-26930987

OBJECTIVE: To study the effects and potential mechanism of Kaixin-San and Danggui-Shaoyao-San on glucose and lipid metabolism in chronic stress rats fed with high-fat diet. METHODS: 50 male Wistar rats were randomly divided into normal control group (distilled water), high-fat diet with chronic stress group (distilled water), melatonin group(20 mg/kg), Kaixin-San group (445 mg/kg) and Danggui-Shaoyao-San group (3360 mg/kg). All drugs were orally administered. In addition to the normal control group, each group of rats were fed with high-fat, diet. Simultaneously, stress were carried out after drugs administration 1 h daily. The duration was lasted for six weeks. The rat body weight daily was recorded, and the 24 h period urine was collected to detect the level of urine corticosterone (CORT) after three weeks. The level of plasma intraperitoneal glucose tolerance (IVGTT) was detected after six weeks. Finally, rats were executed, and serum fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), insulin (INS), adrenocorticotropic hormone releasing hormone (CRH), adrenocorticotropic hormone (ACTH), CORT and melatonin ( MLT) were determined. The weight of adrenal gland, liver glycogen and muscle glycogen levels were detected. The adrenal gland index, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and insulin sensitivity index( ISI) were calculated. RESULTS: Compared with normal group, model rats body weight, IVGTT (120 min), plasm CORT were decreased significantly. Serum TG, TC, LDL-C and urine CORT after three weeks were increased significantly. Kaixin-San and Danggui- Shaoyao-San could regulate the above indexes. CONCLUSION: Kaixin-San and Danggui-Shaoyao-San may regulate the activity of HPA axis, and improve glucose and lipid metabolism disorder in model rats by increasing melatonin secretion.


Drugs, Chinese Herbal/pharmacology , Glucose/metabolism , Hypothalamo-Hypophyseal System , Lipid Metabolism , Pituitary-Adrenal System , Animals , Diet, High-Fat , Male , Melatonin/metabolism , Rats , Rats, Wistar , Stress, Physiological
17.
Cardiovasc Toxicol ; 15(3): 241-9, 2015 Jul.
Article En | MEDLINE | ID: mdl-25377428

Apigenin (Api), a mainly bioactive component of Apium graveolens L. var. dulce DC. (a traditional Chinese medicinal herb), possesses a wide range of biological activities, including antioxidant effects. It also has been shown to associate with lower prevalence of cardiovascular diseases, but its mechanisms of action remain unclear. The aim of the present study is to investigate the role of Api in isolated rat heart model of ischemia/reperfusion (I/R). Langendorff-perfused isolated rat hearts were used in our study. Api was added to the perfusate before ischemia and during reperfusion in the isolated pulsed rat heart exposed to 30-min ischemia followed by 50-min reperfusion. The treatment with Api conferred a cardioprotective effect, and the treated hearts demonstrated an improved ischemic cardiac functional recovery, a decreased myocardial infarct size, a reduced activities of creatine kinase isoenzyme and lactate dehydrogenase in the coronary flow, a reduced number of apoptotic cardiomyocytes, a reduced activity of caspase-3, up-regulation of the anti-apoptotic protein Bcl-2 and down-regulation of the pro-apoptotic protein Bax. In addition, Api inhibited the phosphorylation of p38 MAPKS during I/R. In conclusion, these observations provide preliminary evidence that Api can protect cardiomyocytes from I-/R-induced injury, at least partially, through the inhibition of p38 MAPKS signaling pathway.


Apigenin/therapeutic use , Cardiotonic Agents/therapeutic use , Heart/drug effects , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/prevention & control , Animals , Apigenin/pharmacology , Apoptosis/drug effects , Apoptosis/physiology , Cardiotonic Agents/pharmacology , Caspase 3/metabolism , Male , Myocardial Reperfusion Injury/pathology , Organ Culture Techniques , Rats , Rats, Sprague-Dawley , bcl-2-Associated X Protein/antagonists & inhibitors , bcl-2-Associated X Protein/metabolism , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolism
18.
Nan Fang Yi Ke Da Xue Xue Bao ; 34(10): 1431-5, 2014 Oct.
Article Zh | MEDLINE | ID: mdl-25345937

OBJECTIVE: To establish a method based on restricted access media-high performance liquid chromatography for direct online sample injection and detection of plasma and urine furosemide in rats. METHODS: The column of restricted access media was used as the pre-treatment column and a C18 column as the analytical column. The mobile phase of the pre- treatment column was water-methanol (95:5, V/V) with a volume percentage of formic acid of 0.1%. The mobile phase of the analytical column was methanol-water (65:35, V/V) for plasma and methanol-water (55:45, V/V) for urine samples, all containing a volume percentage of formic acid of 0.1% with a flow rate of 1 ml/min. The detection wavelength was 274 nm and the column temperature was maintained at 25 degrees celsius. RESULTS: The calibration curve showed an excellent linear relationship in rat plasma furosemide concentration range of 0.1-3.2 µg/ml (r=0.9995) and in urine concentration range of 0.5-32 µg/ml (r=0.9991). The average recoveries of furosemide at 3 spiked levels ranged from 101.82% to 113.36% for plasma and from 98.75% to 112.27% for urine samples. The detection showed good intra- and inter-day assay precisions and accuracies with the relative standard deviations all below 5%. The pharmacokinetic parameters AUC(0→24) was 6.265 g/(ml·h) with a t(1/2) of 2.447 h and a C(Max) of 1.414 g/ml. The mean cumulative excretory rate of furosemide in the urine of rats over 24 h was 32.50%-39.08%. CONCLUSION: Detection of furosemide in plasma and urine samples using restricted access media-high performance liquid chromatography is simple and efficient and allows direct online injection of the samples.


Chromatography, High Pressure Liquid/methods , Furosemide/blood , Furosemide/urine , Animals , Calibration , Rats , Reproducibility of Results
19.
Zhongguo Zhong Yao Za Zhi ; 39(14): 2710-5, 2014 Jul.
Article Zh | MEDLINE | ID: mdl-25272501

OBJECTIVE: To investigate the protective effect and action mechanism of petroleum ether extracts from Saussurea involucrate on brain tissues of hypoxia rats under constant pressure and closed conditions. METHOD: The PESI dosage-dependent experiment for hypoxia rats was conducted under constant pressure and closed conditions by intraperitoneally injecting 125, 250, 500 mg x kg(-1) to finalize that the optimum dosage is the high dose of PESI. Afterwards, 90 Wistar rats were randomly divided into the hypoxic model group, the acetazolamide 250 mg x kg(-1) group and the PESI high dose group. Each group was further divided into three subgroups according to different hypoxia times, with 10 rats in each subgroup. Under the same hypoxia and administration conditions, the rats were sacrificed after 0, 3, 6 h respectively. Their brain samples were collected for common pathological observation and immunohistochemical staining of HIF-1alpha. Real-time RT-PCR was used to detect HIF-1alpha, EPO, HO-1 and Caspase-3 gene expressions. And the Western blot assay was adopted to detect HIF-1alpha protein expression. RESULT: The brain tissues of the hypoxia model group were severely damaged with the increase in the hypoxia time. The acetazolamide group and the PESI high does group were damaged in a much lower degree. According to the gene expression and the Western blot assay, high dose of PESI could inhibit HIF-1alpha expression. According to the pure gene expression test, high dose of PESI could increase EPO and HO-1 mRNA expressions, but inhibit Caspase-3 mRNA expression. CONCLUSION: PESI's protective mechanism for brain tissues of hypoxia rats under constant pressure and closed conditions may be related to its effects in inhibiting HIF-1alpha expression, increasing EPO expression and resisting cell apoptosis.


Alkanes/chemistry , Brain/cytology , Brain/drug effects , Cytoprotection/drug effects , Drugs, Chinese Herbal/pharmacology , Saussurea/chemistry , Animals , Brain/metabolism , Caspase 3/genetics , Cell Hypoxia/drug effects , Dose-Response Relationship, Drug , Erythropoietin/genetics , Gene Expression Regulation, Enzymologic/drug effects , Heme Oxygenase-1/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Male , Rats , Rats, Wistar
20.
Iran J Pharm Res ; 13(2): 441-7, 2014.
Article En | MEDLINE | ID: mdl-25237339

A quantitative analysis method for fudosteine in human serum by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI/MS/MS) was established, which shows high sensitivity and selectivity. The mobile phase composition was 75% 20 mM acetic acid and 25% acetonitril, which was pumped at a flow rate of 0.40 mL/min. The overall chromatographic run time was approximately 7 min. The autosampler was set with an injection volume of 10 µL. The calibration curve was linear in the concentration range of 0.1~15.0 µg/mL. The coefficient of determination (r) was greater than 0.9998. This method has been fully validated and shown to be specific, accurate and precise. The method was simple, rapid and the sample preparation was minimal. It was successfully applied to the analysis of healthy volunteer.

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