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Objective:Heme chloride(Hemin)is an in vitro purified form of natural heme and an important raw material for anti-anemia and antitumor drugs.This study aims to analyze the protective effect of Hemin on tissue damage in low-pressure oxygen chamber simulated plateau hypoxic mice,and explore its role in anti-plateau hypoxia. Methods:Thirty male BALB/c mice were randomly divided into a blank group,a positive drug group(acetazolomide,200 mg/kg),a Hemin low-dose group(15 mg/kg),a Hemin medium-dose group(30 mg/kg),and a Hemin high-dose group(60 mg/kg)with intraperitoneal injection.The anti-hypoxic activity of Hemin was explored by atmospheric closed hypoxia experiment and the optimal dose was screened.Thirty-six male BALB/c mice were randomly divided into a blank group,a hypoxia group,a positive drug group,and a Hemin high-dose group.The plasma inflammatory factor levels and oxidative stress indicators malondialdehyde(MDA),glutataione(GSH),and superoxide dismutase(SOD)levels of myocardium,brain,lung,and liver tissues were measured in different groups with hypoxia for 24 h.The degree of histopathological damage of mice was observed with HE staining.The degree of protection of Hemin against tissue hypoxia injury was detected with the hypoxia probe piperidazole. Results:Compared with the blank group,the survival time of mice in the positive drug group,the Hemin medium-dose group,and high-dose group was significantly extended(all P<0.05),with the highest prolongation rate in the Hemin high-dose group.Compared with the hypoxia group,mice in the Hemin high-dose group showed a significant increase in SOD level and GSH content of brain tissue,and a significant decrease in MDA content of lung tissue(all P<0.05).The results of HE staining and hypoxia probe showed that Hemin had a significant protective effect on the damage of liver,heart,brain and lung tissues of mice with hypoxia,and the most obvious effect on that of the brain tissue. Conclusion:Hemin has an effect of improvement on oxidative stress and inflammatory response caused by hypoxia,and has obvious protective effect on tissue damage caused by hypoxia.
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Objective:Plateau hypoxia exposure causes changes in pharmacokinetic parameters and cerebral-blood distribution of drugs,including many substrates of P-glycoprotein(P-gp).Levetiracetam,a kind of antiepileptic drugs,is a substrate of P-gp.Whether plateau hypoxia exposure changes its pharmacokinetic characteristics and cerebral-blood distribution remains unclear.This study aims to investigate the effects of plateau hypoxia on the pharmacokinetics and cerebra-blood distribution of levetiracetam. Methods:Wistar rats were divided into a low-altitude control group,a high-altitude group,a solvent group,and a P-gp induction group.After 24 h of exposure at altitude of 4 010 m,rats in the high-altitude group were given levetiracetam orally or intravenously.The plasma was respectively collected at 0.083,0.25,0.5,0.83,1.25,2,4,6,8,10,12,and 24 h after oral administration of the drug,while both plasma and brain were respectively collected at 5,45,60,120 and 240 min after intravenous injection.After 3 days administration of dexamethasone,plasma and brain of rats in the P-gp induction group were collected at 120 min after intravenously giving levetiracetam.Plasma and brain concentrations of the drug were determined by high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS).The expression of P-gp in blood-brain barrier was detected by Western blotting. Results:Compared with the low-altitude control group,the area under the curve(AUC)and mean residence time(MRT)of levetiracetam were respectively decreased by 14.69%(P<0.01)and 15.42%(P<0.01),while the clearance(CL)was increased by 16.67%(P<0.01)in the high-altitude group.The ratio of brain/blood plasma drug concentration was decreased by 22.82%(P<0.05),12.42%(P<0.05),17.40%(P<0.01),and 13.22%(P<0.01)at 5,45,120,and 240 min after injection,respectively.The expression of P-gp on the blood-brain barrier was increased by 86.3%(P<0.05).Compared with the solvent control group,the expression of P-gp on the blood-brain barrier in the P-gp induction group was increased by 56.3%(P<0.05),the ratio of brain/blood plasma drug concentration was decreased by 19.3%(P<0.05). Conclusion:After acute plateau hypoxia exposure,the pharmacokinetic of levetiracetam in rats are altered,and the cerebral-blood distribution of the drug in rats is decreased,which may be related to the up-regulation of P-gp expression on the blood-brain barrier.
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Objective:The development of traditional Chinese medicine(TCM)in the plateau area is relatively backward.There is a lack of system to analyze the effects of the special environment of plateau low pressure and hypoxia on human meridians qi and blood,as well as the etiology and pathogenesis of plateau hypoxic diseases.To analyze the composition rules of anti-hypoxia TCM formulation with data mining methods. Methods:The experimental literatures related to high altitude hypoxia were searched in China National Knowledge Infrastructure(CNKI),Wanfang Med Online,VIP,China Biology Medicine disc and other databases,a standardized prescription database was established after screening and standardization of prescription data in the literature.The composition rules of these prescription including drug frequency,drug attributes,drug efficacy,drug combination,and core prescription were analyzed and displayed with visual charts. Results:A total of 135 TCM prescriptions were included,and 229 flavored drugs were included.Among these prescriptions,the TCM with high frequency of use were Astragalus,Danshen,Ginseng,and Angelica,etc.Four natures of the TCM were mostly warm and calm.Five flavours of the TCM were mostly sweet,bitter,and pungent.And channel tropism of the TCM mostly entered the heart,lung,and liver meridians.The frequency combination of TCM was Astragalus-Danshen and Astragalus-Angelica.The core medicines of these prescriptions were Astragalus,Danshen,Angelica,Rhodiola,Goji,and Ginseng.TCM could alleviate symptoms such as chest tightness,chest pain,coughing and wheezing,coughing,vomiting,fatigue,and loss of appetite caused by hypoxia at high altitude. Conclusion:Through data mining,it is concluded that the prevention or treatment of plateau hypoxic diseases mostly utilized products can nourish blood,replenish qi and dispel stasis,and help yang and dispel qi,most of them are compatible with qi tonic drugs and blood circulation and stasis dissolving drugs,and pay attention to the combination of virtual and real,yin and yang.
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Objective @# Based on metabolomics and transcriptomics analysis , to explore the molecular mechanism of spleen inflammation induced by high altitude hypoxia in mice through NOD⁃like receptor signaling pathway . @*Methods @#C57BL/6 mice were raised at an altitude of 400 m and 4 200 m respectively , with five mice in each group , and spleen tissues were collected after 30 days . Differential metabolites and differentially expressed genes in key pathways were screened by metabolomics and transcriptome analysis and correlation KEGG enrichment analysis , and the related network interaction diagram of differential metabolites and differentially expressed genes in key pathways was constructed and verified by RT⁃qPCR . @*Results @#Metabolomics analysis showed that 133 differential metabolites were screened from in the plain spleen control group (PSC group) and the plateau spleen test group (HST group) , 95 of which were up⁃regulated while 38 of which were down⁃regulated . KEGG enrichment analysis showed that they were mainly involved in NOD⁃like receptor signaling pathway , HIF⁃1 signaling pathway , cholesterol metabolism and other metabolic pathways . The results of transcriptome analysis showed that a total of 4213 differentially expressed genes were identified in PSC group and HST group , including 1947 up⁃regulated genes and 2266 down⁃regulated genes . KEGG was enriched in 173 signaling pathways , including NOD⁃like receptor signaling pathway , MAPK signaling pathway , NF⁃κB signaling pathway and other pathways . Comprehensive analysis showed that the differential metabolites and differentially expressed genes were obviously enriched in NOD⁃like receptor signaling pathway . Therefore , the correlation network interaction map was constructed for the differential metabolites ATP and differentially expressed genes in NOD⁃like receptor signaling pathway . RT⁃qPCR results showed that compared with PSC group , the expression levels of DEGs related to NOD1 and NOD2 (CHUK , TAB3 , MAPK8) in the signaling pathway of NOD⁃like receptor and NLRP1 ⁃CASP1 pathway (NLRP1b , CASP1) in HST group were significantly enhanced . The mRNA expression levels of downstream inflammatory factors IL⁃6 , IL⁃1 β , IL⁃18 , INF⁃γ and TNF⁃α were up⁃regulated and differentially expressed . @*Conclusion @# Based on the combined analysis of metabolomics and transcriptomics , it was found that hypoxia stimulation at high altitude may affect the NOD⁃like receptor signaling pathway in vivo , and the differential metabolite ATP is positively correlated with the differential key genes in the pathway . ATP mediates the release of downstream inflammatory factors by activating NOD1 , NOD2 pathways and NLRP1 inflammable⁃CASP1 pathways . Inflammatory response occurred in spleen tissue of mice.
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Objective To investigate the effect of plateau hypoxia on the blood-brain barrier after subarachnoid hemorrhage (SAH) in rats. Methods Adult male SD rats (n = 78) were randomly divided into 4 groups: sham group (sham), SAH model group (SAH), plateau hypoxia sham group (Hp sham) and plateau hypoxia SAH model group (Hp SAH). The rat model of plateau hypoxia was established through low-pressure simulation chamber (altitude 5000 m), and the SAH model was established by endovascular perforation method. At 24 hours after SAH, neurobehavior score and SAH grade were assessed. The morphological changes of neurons and apoptosis of nerve cells in the CA1 region of hippocampal were observed by the staining of Nissl and TUNEL. The expression of phosphorylated PI3K (p-PI3K), PI3K, phosphorylated Akt (p-Akt), Akt, phosphorylated nuclear factor κB (p-NF-κB), NF-κB, matrix metalloproteinase-9 (MMP-9), occludin and claudin-5 in hippocampal were detected by the method of Western blotting. The expression of occludin and claudin-5 proteins in the CA1 region of hippocampal were observed by immunofluorescent staining. Results At 24 hours after SAH, the neurobehavior score decreased significantly and SAH grade increased significantly in the SAH and Hp SAH group (P< 0.05). Neurobehavior score decreased significantly in the Hp SAH group compared with the SAH group (P < 0.05). In the SAH group, neurons in the CA1 region of hippocampus were atrophied and deformed, the arrangement were disordered, the number of neurons decreased significantly, and the apoptosis of nerve cells increased significantly(P< 0.05). Plateau hypoxia could aggravate the morphological damage of neurons and apoptosis of nerve cells. The expression of p-PI3K/PI3K, p-Akt/Akt, occludin and claudin-5 proteins decreased significantly, while the expression of p-NF-κB/NF-κB and MMP-9 proteins increased significantly in the SAH and Hp SAH group (P< 0.05). The expression of p-PI3K/PI3K and MMP-9 proteins increased significantly in Hp SAH group compared with the SAH group. The expression of claudin-5 protein increased significantly in Hp sham group compared with the sham group (P < 0.05). Immunofluorescent staining showed that the expression of occludin and claudin-5 proteins in the CA1 region of hippocampus decreased in the SAH group. Plateau hypoxia could further decreased the expression of occludin and claudin-5 proteins. Conclusion Plateau hypoxia aggravates blood-brain barrier disruption after subarachnoid hemorrhage in rats through inhibiting PI3K/Akt/NF-κB pathway.
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OBJECTIVES@#Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM).@*METHODS@#A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups.@*RESULTS@#The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T1/2), area under the curve (AUC), time to reach maximum concentration (Tmax). Compared with the control group, AUC was increased by 23.5%, Tmax and T1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population.@*CONCLUSIONS@#Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.
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Humans , Diabetes Mellitus, Type 2/drug therapy , Metformin/therapeutic use , Acidosis, Lactic , Tandem Mass Spectrometry , Hypoxia , GlucoseABSTRACT
Metformin is the most common first-line oral hypoglycemic drug ，but there are large individual differences in pharmacokinetic parameters and pharmacodynamics during clinical use. The dosage of some patients should be adjusted to achieve satisfactory therapeutic effect. Pharmacokinetic parameters of metformin are affected by many factors ，including respects of transporter gene polymorphism ，drug interaction ，intestinal flora ，plateau hypoxia and physiological function and so on. In order to guide the clinical individualized use of metformin ，this study reviews the research progress on the influencing factors of metformin pharmacokinetics.
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Plateau environment will affect the metabolism of drugs in the body, which will cause changes in pharmacokinetic parameters, expression and function of drug metabolizing enzymes and transporters. With the rapid development of the pharmaceutical industry, therapeutic drug monitoring (TDM) has been widely paid attention to as a basis for personalized drugs. What impact does the plateau environment on monitoring drugs? In this literature review, we will summarize the types of commonly used therapeutic monitoring drugs, therapeutic windows, and blood samples, analyze the effects of plateau hypoxic environment on the metabolism of commonly used monitoring drugs, provide a reference for the clinical treatment and monitoring drugs of plateau, better ensure the rational use of drugs in the plateau population, and also provide a reference for the later research group to conduct the monitoring of plateau therapeutic drugs and the selection of research drugs.
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Aim To study the protective effects of Mi-toQ against an altitude of 8 000 m plateau hypoxia in-jury on brain tissues of rats. Methods We studied the protective effects of MitoQ against hypoxia by the experiment of closed normobarie hypoxia to choose the best dose firstly. Then, an altitude of 8 000 m plateau hypoxia environment was stimulated using a large scale hypoharic and mionectic chamber, the histopathologi-cal slices were observed, and the level of oxidative stress and mitochondrial function as well as measurement apoptosis related proteins were determined to study the anti-hypobaric hypoxia effects of MitoQ on rats. Results MitoQ reduced the intercellular space, the degree of vacuolization of brain and oxidative stress level, prevented calcium overload, raised mitochondrial membrane potential and increased the activity of mi-tochondrial respiratory chain complexes II, IV. Furthermore, MitoQ decreased the expression level of Cyt C, caspase-3 and Bax, playing a protective role under the condition of hypobaric hypoxia on rats. Conclusions MitoQ prevents the damage and maintains the function of mitochondria of brain to protect rats under the condition of simulated altitude of 8 000 m plateau hypoxia environment.
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A large number of gut flora communities have colonized in the intestine, which is crucial to the metabolism of foreign compounds such as drugs. In recent years, the gut flora has been widely regarded as the "invisible organ" of the body. By reviewing the pertinent literature at home and abroad, classifications and functions of intestinal flora and its influence on the chemical composition and chemical metabolism of Chinese medicine are analyzed in the article. Understanding the impact of intestinal flora on drug metabolism and the process of drug conversion has great significance in guiding clinical rational drug use and individual therapy, evaluating toxicity and promoting drug discovery and development, and providing theoretical guidance for the study of the effects of intestinal flora on drug metabolism in the plateau environment.
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Plateau environment has the characteristic of low ox-ygen and low pressure, which leads to a series of physiological changes and affects the process of drug metabolism in the body. Many factors affect the pharmacokinetic parameters, including gastric emptying, blood rheology, cardiopulmonary function, hepatorenal function, cytochrome P450 enzyme and so on. The present study focuses on drug metabolic enzymes, since drug transporter is the key factor that mediates drugs in their entrance to the body through the cell membrane, producing the curative effect. In order to provide the reference to further research on the effect of plateau hypoxia on pharmacokinetics and guide the rational use of drugs, we review in this paper the classification of the transporter, mediated drug substrates, the influence of hypoxia on expression levels of drug transporter substrates and the regulatory mechanism of drug transporter under the condition of hypoxia.
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Under plateau environment, inadequate oxygen makes people breathe less oxygen, reducing the level of oxygen metabolism and energy supply in the body. Subsequently, the peripheral circulation, the contractile efficiency of myocardial cells, the pump of blood stream, the flow rate of blood in various tissues, and the excretion rate of waste in the body could be greatly reduced, which are key reasons for causing plateau disease. Due to the reason that many metabolic pathways are affected in vivo, the level of endogenous small molecular metabolites can also be changed greatly. Therefore, metabolomics has been gradually applied to the study of plateau diseases, pathogenesis and even pharmacodynamics. This article summarizes the pathogenesis of plateau hypoxia and metabolomics of the associated therapeutic agents based on the preclinical and clinical research reviewed from the altitude sickness-associated metabolic research literature at home and abroad. Previous studies have confirmed that the endogenous metabolites and metabolic pathways altered significantly under plateau hypoxia, and some drugs showed a certain regulatory effect on the pathway metabolism. Moreover, the article summarizes the problems existing in the application of metabolomics in plateau hypoxia disease and the prospect of its future application. It was suggested that metabolomics was a promising tool for the study on the mechanism and the primary assessment of candidate drugs for plateau disease.
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Objective To establish the rat experimental animal model of plateau hypoxia caused stress ulcer.Methods Rats were randomly divided into the normoxia group,plateau hypoxia 2,4,6,8,10 d groups.Except the normoxia group,the rats in other groups were fed in a hypobaric chamber(simulated altitude 5000 m) for 2,4,6,8,10 d srespectively.Then the gastric mucosal ulcer index,gastric juice volume,pepsin activity and PH value of gastric juice were observed in each group.Results Different degrees of point-like and line-like bleeding,erosion and ulcer formation could be seen in rat gastric mucosa in the hypobaric chamber(simulated altitude 5 000 m) on 2,4,6,8,10 d of plateau hypoxia;the ulcer index was significantly increased;the PH value and gastric juice volume were significantly decreased and the pepsin activity was significantly elevated.The changes of various indexes were most obvious on 6 d of plateau hypoxia.Conclusion Rats fed in a hypobaric chamber simulating a altitude of 5 000 m for 2-10 d can eastablish the altitude hypoxia caused stress ulcer animal model,moreover the optimal time is 6 d.
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Objective To establish the rat experimental animal model of plateau hypoxia caused stress ulcer.Methods Rats were randomly divided into the normoxia group,plateau hypoxia 2,4,6,8,10 d groups.Except the normoxia group,the rats in other groups were fed in a hypobaric chamber(simulated altitude 5000 m) for 2,4,6,8,10 d srespectively.Then the gastric mucosal ulcer index,gastric juice volume,pepsin activity and PH value of gastric juice were observed in each group.Results Different degrees of point-like and line-like bleeding,erosion and ulcer formation could be seen in rat gastric mucosa in the hypobaric chamber(simulated altitude 5 000 m) on 2,4,6,8,10 d of plateau hypoxia;the ulcer index was significantly increased;the PH value and gastric juice volume were significantly decreased and the pepsin activity was significantly elevated.The changes of various indexes were most obvious on 6 d of plateau hypoxia.Conclusion Rats fed in a hypobaric chamber simulating a altitude of 5 000 m for 2-10 d can eastablish the altitude hypoxia caused stress ulcer animal model,moreover the optimal time is 6 d.
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Objective To compare the effects of oxygen therapy and local pressurization in alleviating plateau hypoxia at high altitude.Methods Forty-five healthy male soldiers were investigated at an altitude of 3992 meters.The subjects were randomly divided into three groups, ie.an oxygen inhalation group, a single-soldier oxygen increasing respirator (SOIR) group and a BiPAP group.The oxygen inhalation group was treated with oxygen inhalation via nasal catheter at 2 L/min.SOIR was used to assist breath in the SOIR group.The BiPAP group were treated with bi-level positive airway pressure ventilation, with IPAP of 10 cm H20 and EPAP of 4 cm H2O.PaO2、PaCO2、SpO2 and heart rate were measured before and 30 minutes after the treatment.Results There were continuous increase of PaO2 from (53.30±4.88) mm Hg to (58.58±5.05) mm Hg and (54.43±3.01) mm Hg to (91.36±10.99) mm Hg after BiPAP ventilation and oxygen inhalation, respectively (both P < 0.01).However, the PaO2、of the SOIR group was decreased from (56.00±5.75) mm Hg to (50.82±5.40) mm Hg (P < 0.05).In the other hand, the PaCO2、 was increased from (30.41±1.51) mm Hg to (32.5±2.98) mm Hg in the oxygen inhalation group (P< 0.05), declined from (28.74±2.91) mm Hg to (25.82±4.35) mm Hg in the BiPAP group (P < 0.05), and didn't change significantly from (28.65±2.78)mm Hg to (29.75±3.89) nun Hg in the SOIR group (P > 0.05).Conclusions Both BiPAP ventilation and oxygen inhalation can alleviate plateau hypoxia by improving PaO2 at 3992 meter altitude while SOIR has no significant effect.