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Aim To explore the important role of HDAC5 in P-gp expression in rats in high-altitude low oxygen environment and its effect on phenytoin sodium pharmacokinetics. Methods Wistar rats were transported to Batang, Yushu, Qinghai, at an altitude of 4010 m, with 6 rats in each group, divided into 1 d and 3 d groups. Different groups were given phenytoin, phenytoin combined with hypericin, and phenytoin combined with verapamil. Plasma and liver tissues were collected at different time after taking the drug in the plateau area. The concentration of phenytoin sodium in plasma was determined by UFLC-MS method. Changes in protein expression were detected by Western blot. Results The results of UFLC-MS showed that the AUC
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Aim To study the protective effect of catechin on acute altitude injury in rats. Methods Rats were randomly divided into six groups: control group, altitude hypoxia model group, rhodiola capsule group, low -, middle-and high dose of catechin groups. After three days of preventive administration, animals were rushed to 4 010 m altitude. After five days of continuous administration, abdominal aortic blood of rats was collected for blood gas detection. Cardiac, brain and lung tissues were collected for HE staining to observe the pathological changes. MDA content, GSH content, NO content, SOD activity of myocardial, brain and lung tissues were detected, so were IL-6 and TNF-α content in serum. Results Compared with the control group, blood oxygen saturation of rats of altitud hypoxia model group was significantly reduced, while myocardial, brain and lung tissues were damaged to different degrees. MDA and NO content increased, while GSH content and SOD activity decreased. The serum inflammatory factors TNF-α and IL-6 levels were elevated significantly. After catechin treatment, blood oxygen saturation of hypoxia rats significantly increased (P < 0. 05). HE staining results showed that myocardial, brain and lung tissue injury was alleviated to some extent. MDA, NO, IL-6 and TNF-α content were down-regulated, while GSH content and SOD activity were up-regulated respectively. Conclusions Catechin can resist high altitude hypoxia and protect the main organs from hypoxia injury in rats acute exposed to altitude, which is related to alleviating oxidative stress and inflammation caused by acute hypoxia exposure.
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Cerebral hypoxia often brings irreversible damage to the central nervous system, which seriously endangers human health. It is of great significance to further explore the mechanism of hypoxia-associated brain injury. As a programmed cell death, ferroptosis mainly manifests as cell death caused by excessive accumulation of iron-dependent lipid peroxides. It is associated with abnormal glutathione metabolism, lipid peroxidation and iron metabolism, and is involved in the occurrence and development of various diseases. Studies have found that ferroptosis plays an important role in hypoxia-associated brain injury. This review summarizes the mechanism of ferroptosis, and describes its research progress in cerebral ischemia reperfusion injury, neonatal hypoxic-ischemic brain damage, obstructive sleep apnea-induced brain injury and high-altitude hypoxic brain injury.
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Humans , Infant, Newborn , Ferroptosis , Apoptosis , Hypoxia-Ischemia, Brain , Brain Injuries , Iron , Reperfusion InjuryABSTRACT
Hie high altitude hypoxic environment affects the pharmacokinetic process of rlnjgs by changing the body's gastrointestinal emptying rate, organ blood flow, drug plasma protein binding rate, dnjg metabolizing enzymes and transporter expression.Epilepsy is a brain disease that requires long-term medication.Most anti-epileptic drugs have a low therapeutic index and a narrow range of effective blood drug concentrations.'Ilierapeu- tic dnjg monitoring (TDM) is commonly used clinically to find the best individualized medication method for antiepileptic dnjgs.rI1iis article summarizes the commonly used anti-epileptic dnjgs and their treatment windows in clinical practice, and analyzes the influence of the pharmacokinetics of anti-epileptic dnjgs in the high altitude hypoxic environment, so as to provide reference for the clinical use of anti-epileptic drugs at high altitude.
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Aim To investigate the effects of altitude hypoxia on serum sodium valproate eoncentration and eerebral blood distribution.Methods Male mice were divided into control group and plateau group.Each group was given sodium valproate orally and intrave¬nously, respectively.UFLC-MS/MS was used to deter¬mine the concentration of sodium valproate in plasma and brain, and Western blot was used to detect the ex¬pression of P-gp in BBB.Results Compared with the control group, the ratio of brain/blood drug concentra¬tion in plateau group was up-regulated by 44.0% , 57.9% , 176.8% and 184.5% at 10, 30, 60 and 120 min, respectively.The ratio of brain/blood drug con-centration increased by 33.9% , 50.6% and 125.6% at 60 min, 120 min and 240 min in plateau group, re¬spectively.Compared with the control group, the ex¬pression of P-gp protein in BBB of mice in altitude group was significantly down-regulated by 58.46% (P < 0.05 ).Conclusions Compared with the control group, the brain/blood drug concentration ratio of val¬proic acid increases in high altitude hypoxia environ¬ment.Meanwhile, it is found that P-gp expression lev-el decreased in the brain mierovessels of mice under high altitude hypoxia environment, and the cerebral and blood distribution of valproic acid in mic increases in high altitude hypoxia environment.
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In order to clarify the influence of acute hypobaric hypoxia on the bile acids of the rat small intestine, we used ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to identify bile acids in the contents of the small intestine from untreated and acute hypobaric hypoxia-treated rats. Thirty-nine bile acids were detected; PCA and OPLS-DA analysis revealed marked differences in the composition of bile acids between the untreated and the acute hypobaric hypoxia groups. Bile acids were screened with VIP > 1, |log2FC| ≥ 1, P < 0.05, and a total of 7 bile acids with significant differences in content between the two groups were obtained, including 5 conjugated bile acids, 2 unconjugated bile acids; in addition, the content of conjugated bile acids has risen in the treated group. This study demonstrated the influence of high-altitude hypoxic environment on bile acid composition and metabolism in rats. All the animal experiments in this study were approved by the 940th Hospital Ethics Committee (approval No: 2020KYLL012).
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Acute plateau disease refers to a variety of physiological and pathological reactions produced by the body in a short period of time after rapidly advancing into the high-pressure and low-oxygen plateau area with an altitude above 2 500 meters, mainly including acute mountain sickness (AMS), high altitude pulmonary edema (HAPE) and high altitude cerebral edema (H A C E), which seriously affects the health of people in the acute plateau and even threats their lives. The establishment of an animal model of acute plateau disease with good reproducibility and a sound evaluation system are the basis of the research on acute plateau disease. Acute plateau disease is mainly caused by the low oxygen conditions on the plateau, so the animal model of acute plateau disease can be established in plateau environment simulation cabin or plateau field, simple breeding or animal treadmill assisted sports training. The indicators that indicate the success of the model establishment are commonly used blood gas, inflammation factors, organizational water content and pathological section. In this article, the animal models of acute plateau disease established in recent years are reviewed from the aspects of modeling environment, modeling methods and evaluation indicators.
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In this study, the change of intestinal microflora in rat fecal samples after amoxicillin administration was observed. In vitro incubation experiments combined with LC-MS/MS assay were used to test the role of intestinal flora in the metabolism of nifedipine. The effect of changes of intestinal flora was determined after amoxicillin administration on the metabolism of nifedipine. We found that the number and types of intestinal flora decreased after taking amoxicillin. After incubation for 12 h, the results showed that the remaining amounts of nifedipine in the N1 group (nifedipine) and N2 group (amoxicillin + nifedipine) were 0.057 6 and 0.064 8 μmol·L-1, respectively, while the remaining amounts of nifedipine after 24 h of incubation were 0.039 6 and 0.050 4 μmol·L-1, respectively. These results show that the intestinal flora is involved in the metabolism of nifedipine. After administration of amoxicillin, the metabolism of nifedipine was slowed down, the AUC0-t was increased by 39.10%, tmax was advanced by 0.45 h, and the CL was reduced 34.71%. The data suggest that the combination may enhance the therapeutic effect of nifedipine. Therefore, drug-drug interactions mediated by gut microbiota cannot be ignored when combined with antibiotics and nifedipine, one of the important factors affecting drug efficacy.
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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 mRNA and protein were reduced by 50.80% and 71.30% (PP<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.
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<p><b>OBJECTIVE</b>To investigate the effects of cis-combretastatin-A1 phosphate (cis-CA1P) on tumor cell proliferation, and its effects on the blood vessel formations.</p><p><b>METHODS</b>MTT and IC50 values were used to assess the inhibitory effects of cis-CA1P on tumor cell proliferation. Chicken embryo chorioallantoic membrane and thoracic aorta annulations isolated from rats were used to investigate the effects of cis-CAIP on the blood vessel formation.</p><p><b>RESULTS</b>Cis-CA1P concentration-dependently inhibited the proliferations of several cancer cell lines, including human gastric carcinoma cell line MGC-803, human leukemic monocyte lymphoma cell line U937, human melanoma cell line A375, human colon cancer cell line HCT116, human breast carcinoma cell line MDA-MB-231, and human leukemia cell line K562. Cis-CAIP significantly decreased the formation of blood vessels in chicken embryo chorioallantoic membrane and in thoracic aorta annulations.</p><p><b>CONCLUSION</b>Cis-CA1P inhibits cancer cell proliferation and prevents blood vessel formation.</p>