OBJECTIVES: To investigate the targets and mechanisms of 7-hydroxyethyl chrysin (7-HEC) in prevention and treatment of high-altitude cerebral edema (HACE) in rats. METHODS: Fifty-four male Wistar rats were randomly divided into normal control group, HACE model group, and 7-HEC-treated group (18 rats in each group). Except for the normal control group, rats in the two other groups were exposed to a hypobaric hypoxic chamber simulating a 7000 m altitude for 72 h to establish the HACE model. The 7-HEC-treated group was intraperitoneally injected with 7-HEC (150 mg·kg^－¹·d^－¹) for 3 consecutive days before modeling, while the model group received equivalent isotonic sodium chloride solution. Tandem Mass Tag (TMT) proteomics technology was used to detect differentially expressed proteins (DEPs) with screening criteria set at a fold change >1.2 and P<0.05. Western blotting was used to verify the expression levels of target proteins. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed. RESULTS: Compared with the normal control group, 256 DEPs were identified in the HACE model group. Compared with the HACE model group, 87 DEPs were identified in the 7-HEC-treated group. Among them, 19 DEPs that were dysregulated in the HACE model group were restored after 7-HEC intervention, of which seven (HSPA4, Arhgap20, SERT, HACL1, CCDC43, POLR3A, and PCBD1) were confirmed by Western blotting. GO enrichment analysis of the DEPs between the HACE model and 7-HEC-treated groups revealed their involvement in 13 biological processes, five cellular components, and two molecular functions. KEGG pathway analysis indicated associations with the mRNA surveillance pathway, Th17 cell differentiation, serotonergic synapse, RNA polymerase, protein processing in the endoplasmic reticulum, peroxisome, neuroactive ligand-receptor interaction, folate biosynthesis. PPI network analysis demonstrated that HSPA4, POLR3A, and HACL1, which were validated by Western blotting, interacted with multiple signaling pathways and ranked among the top 20 hub proteins by degree value, suggesting their potential role as core regulatory factors. Arhgap20, SERT and PCBD1 also exhibited interactions with several proteins, suggesting their potential as key regulatory proteins, whereas no interactions for CCDC43 were identified. CONCLUSIONS This study applied TMT proteomics to identify seven potential therapeutic targets of 7-HEC for the prevention and treatment of HACE. These targets may be involved in the pathogenesis of HACE through multiple pathways, including maintaining cellular homeostasis, ameliorating oxidative stress, regulating energy metabolism, and reducing vascular permeability.
Animals ; Male ; Proteomics/methods* ; Rats, Wistar ; Flavonoids/therapeutic use* ; Rats ; Brain Edema/etiology* ; Altitude Sickness/metabolism* ; Protein Interaction Maps

OBJECTIVE: High-altitude hypoxia exposure often damages hippocampus-dependent learning and memory. Nogo-A is an important axonal growth inhibitory factor. However, its function in high-altitude hypoxia and its mechanism of action remain unclear. METHODS: In an in vivo study, a low-pressure oxygen chamber was used to simulate high-altitude hypoxia, and genetic or pharmacological intervention was used to block the Nogo-A/NgR1 signaling pathway. Contextual fear conditioning and Morris water maze behavioral tests were used to assess learning and memory in rats, and synaptic damage in the hippocampus and changes in oxidative stress levels were observed. In vitro, SH-SY5Y cells were used to assess oxidative stress and mitochondrial function with or without Nogo-A knockdown in Oxygen Glucose-Deprivation/Reperfusion (OGD/R) models. RESULTS: Exposure to acute high-altitude hypoxia for 3 or 7 days impaired learning and memory in rats, triggered oxidative stress in the hippocampal tissue, and reduced the dendritic spine density of hippocampal neurons. Blocking the Nogo-A/NgR1 pathway ameliorated oxidative stress, synaptic damage, and the learning and memory impairment induced by high-altitude exposure. CONCLUSION: Our results demonstrate the detrimental role of Nogo-A protein in mediating learning and memory impairment under high-altitude hypoxia and suggest the potential of the Nogo-A/NgR1 signaling pathway as a crucial therapeutic target for alleviating learning and memory dysfunction induced by high-altitude exposure. GRAPHICAL ABSTRACT available in www.besjournal.com.
Animals ; Oxidative Stress ; Hippocampus/metabolism* ; Rats ; Nogo Proteins/genetics* ; Male ; Rats, Sprague-Dawley ; Hypoxia/metabolism* ; Altitude ; Synapses ; Humans ; Altitude Sickness/metabolism*

OBJECTIVE: To explore the pathogenesis of erythrocytosis by detecting the key enzymes of glucose metabolism and glucose transporter in bone marrow erythrocytes of chronic mountain sickness (CMS), and analyzing its correlation with hemoglobin. METHODS: Twenty CMS patients hospitalized in Qinghai Provincial People's Hospital from January 2019 to December 2020 were selected as CMS group. Twenty males with leukocyte count > 3.5×10⁹/L who had accepted bone marrow aspiration and had normal result were taken as control group. The mRNA and protein expression of key enzymes and glucose transporter in glucose metabolism in bone marrow CD71⁺ erythrocytes were detected by real time qPCR and Western blot, respectively. Glucose, lactic acid and 2,3-diphosphoglycerate in the bone marrow supernatant and serum were tested by ELISA. The mRNA and protein expression of key enzymes and glucose transporter, glucose, lactic acid and 2,3-diphosphoglycerate of the two groups were compared. Pearson correlation was used to analyze the correlation between key enzymes, glucose transporter in glucose metabolism in bone marrow CD71⁺ erythrocytes and hemoglobin. RESULTS: The expression of HK2, GLUT1 and GLUT2 mRNA in the CMS group were higher than those in the control group (P<0.001), while the expression of HK1, OGDH and COX5B mRNA were not different. The expression of HK2, GLUT1 and GLUT2 protein in the CMS group were higher than those in the control group (P<0.05). The levels of glucose and lactic acid in the bone marrow supernatant and serum in the CMS group were not different from those in the control group, while the level of 2,3-diphosphoglycerate was higher (P<0.001). Both HK2 and GLUT2 proteins were positively correlated with hemoglobin (r=0.511, 0.717). CONCLUSION CMS patients may increase glycolysis by increasing the expression of HK2, and promote the utilization of glucose through high expression of GLUT1 and GLUT2 to meet the need of energy supply.
Male ; Humans ; Altitude Sickness/metabolism* ; Glucose Transporter Type 1 ; 2,3-Diphosphoglycerate ; Hemoglobins ; Chronic Disease ; RNA, Messenger ; Phenotype ; Glucose

Acute mountain sickness (AMS) is a clinical syndrome of multi-system physiological disorder after acute exposure to low pressure and low oxygen at high altitude. Quantitative proteomics can systematically quantify and describe protein composition and dynamic changes. In recent years, quantitative proteomics has been widely used in the prevention, diagnosis, treatment and pathogenesis of many diseases. This review summarizes the progress of quantitative proteomics techniques and its application in the prevention, diagnosis, treatment of AMS and mechanisms of rapidly acclimatizing to plateau, in order to provide a reference for the pathogenesis, early intervention, clinical treatment and proteomic research of AMS.
Humans ; Altitude Sickness/prevention & control* ; Proteomics ; Acute Disease ; Oxygen/metabolism*

OBJECTIVES: The plateau environment is characterized by low oxygen partial pressure, leading to the reduction of oxygen carrying capacity in alveoli and the reduction of available oxygen in tissues, and thus causing tissue damage. Cilostazol is a phosphodiesterase III inhibitor that has been reported to increase the oxygen release of hemoglobin (Hb) in tissues. This study aims to explore the anti-hypoxic activity of cilostazol and its anti-hypoxic effect. METHODS: A total of 40 male BALB/C mice were randomly divided into a low-dose cilostazol (6.5 mg/kg) group, a medium-dose (13 mg/kg) group, a high-dose (26 mg/kg) group, and a control group. The atmospheric airtight hypoxia experiment was used to investigate the anti-hypoxic activity of cilostazol and to screen the optimal dosage. Twenty-four male Wistar rats were randomly divided into a normoxia control group, a hypoxia model group, an acetazolamide (22.33 mg/kg) group, and a cilostazol (9 mg/kg) group. After 3 days of hypoxia in the 4 010 m high altitude, blood from the abdominal aorta was collected to determine blood gas indicators, the levels of IL-6 and TNF-α in plasma were determined by enzyme-linked immunosorbent assay, and the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutataione (GSH) were measured. The degree of pathological damage for rat tissues was observed with HE staining. RESULTS: Compared with the control group, the survival time of mice in the low, medium, and high dose group of cilostazol was significantly prolonged, and the survival time of mice in the medium dose group was the longest, with an extension rate at 29.34%, so the medium dose was the best dose. Compared with the hypoxia model group, the P50 (oxygen partial pressure at Hb oxygen saturation of 50%) value of rats in the cilostazol group was significantly increased by 1.03%; Hb and Hct were significantly reduced by 8.46% and 8.43%, and the levels of IL-6 and TNF-α in plasma were reduced by 50.65% and 30.77%. The MDA contents in heart, brain, lung, liver, and kidney tissues were reduced by 37.12%, 29.55%, 25.00%, 39.34%, and 21.47%, respectively. The SOD activities were increased by 94.93%, 9.14%, 9.42%, 13.29%, and 20.80%, respectively. The GSH contents were increased by 95.24%, 28.62%, 28.57%, 20.80%, and 44.00%, respectively. The results of HE staining showed that compared with the hypoxia model group, cilostazol significantly improved the damage of heart, lung, and kidney tissues in rats after hypoxia. CONCLUSIONS Cilostazol can significantly improve the oxidative stress and inflammatory reaction caused by rapid altitude hypoxia, and it has a significant protective effect on tissue damage caused by hypoxia, suggesting that it has obvious anti-hypoxic activity.
Altitude Sickness ; Animals ; Cilostazol/therapeutic use* ; Hypoxia/drug therapy* ; Interleukin-6/pharmacology* ; Male ; Mice ; Mice, Inbred BALB C ; Oxidative Stress ; Oxygen ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism* ; Tumor Necrosis Factor-alpha/pharmacology*

Adult ; Aged ; Altitude Sickness ; metabolism ; Bone Marrow ; metabolism ; Chronic Disease ; Humans ; Male ; Middle Aged ; Peptide Fragments ; metabolism

OBJECTIVETo assess the relationship of high altitude de-adaptation response (HADAR) with acute high altitude response (AHAR) and cardiac function.

METHODSNinety-six military personnel of rapid entering into high altitude (3 700 to 4 800 m) with strong physical work were analyzed, all subjects were male, aged 18 - 35 years. According to the symptomatic scores of AHAR were divided into 3 groups: sever AHAR (group A, 24), mild to moderate AHAR (group B, 47) and non-AHAR (group C, 25) at high altitude. According to the symptomatic scores of HADAR were divided into 3 groups: severe HADAR (group E, 19), mild to moderate HADAR (group F, 40) and non-HADAR (group G, 37) after return to lower altitude (1 500 m). Mean pulmonary arterial pressure (mPAP), right ventricular internal dimension (RVID), outflow tract of right ventricle (RVOT), left ventricular internal dimension (LVID), left ventricular ejection fraction (LVEF), cardiac muscle work index (Tei index), creatine kinase isoenzymes-MB (CK-MB), lactic dehydrogenase isoenzyme-1 (LDH-1) were measured at high altitude stayed 50 days and after return to lower altitude 12 h, 15 d, and 30 d. Fifty healthy volunteers (group D) at 1 500 m altitude served as control.

RESULTSLevel of mPAP, RVID, RVOT, RVID/LVID ratio, Tei index, CK-MB,and LDH-1 were higher, and LVEF was lower in group A than those in group B, C and D, there were significant differences between group B and C, C and D (all P < 0.01). AHAR scores were positively correlated with HADAR scores (r = 0.863, P < 0.01). Twelve hours after return to lower altitude, level of mPAP, RVID, RVOT, RVI/LVID ratio, Tei index, CK-MB, and LDH-1 were higher, and LVEF was lower in group E than those in group F, G and D, there were significant differences between group F and G, G and D (all P < 0.01). Fifteen days after return to lower altitude, level of mPAP, RVID, RVOT, RVID/LVID ratio were higher in group E than those in group F, G, and D, there were significant differences between group F and G, and D (P < 0.01 or P < 0.05), there were no significant differences between group G and D (all P > 0.05), LVEF, Tei index, CK-MB, LDH-1 showed no significant differences among groups (all P > 0.05). Thirty days after return to lower altitude, these parameters in group E, F, and G showed no significantly differences compared with those of group D (all P > 0.05).

CONCLUSIONThe severity of HADAR is associated with severity of AHAR and cardiac injury, the more serious of AHAR and cardiac injury at high altitude, the more serious of HADAR and cardiac injury after return to lower altitude, the more long of restore of right cardiac morphologic injury.

Adaptation, Physiological ; Adolescent ; Adult ; Altitude ; Altitude Sickness ; metabolism ; physiopathology ; Case-Control Studies ; Heart ; physiopathology ; Heart Function Tests ; Humans ; Male ; Myocardium ; enzymology ; Young Adult

Adult ; Altitude Sickness ; metabolism ; pathology ; Apoptosis ; BH3 Interacting Domain Death Agonist Protein ; metabolism ; Erythroblasts ; cytology ; pathology ; Humans ; Male ; Middle Aged ; RNA, Messenger ; genetics ; bcl-2-Associated X Protein ; metabolism ; bcl-X Protein ; metabolism

OBJECTIVEHigh-altitude cerebral edema (HACE) is one of the most serious acute mountain sickness and its underlying mechanism is still unknown clearly. The aim of this study was to determine the changes of plasma proteins in high altitude cerebral edema patients for discovering essential biomarkers used for the routine prophylaxis, diagnosis and treatment.

METHODSPlasma protein profiling two dimensional gel electrophoresis followed by mass spectrometry was used to explore protein alterations in one patient with high-altitude cerebral edema (HACE). Striking differences in two-dimensional gel proteomes of plasma were observed between high-altitude cerebral edema (HACE) and high-altitude pulmonary edema (HAPE) and between high-altitude cerebral edema (HACE) and mild acute mountain sickness (mAMS). Furthermore, apolipoprotein E altered in high-altitude cerebral edema was validated by ELISA.

RESULTSDifferent six spots were found in this study from the comparison between HACE and HAPE, and there were different six spots which were detected from the plasma of HACE patient in comparison to mAMS. Apolipoprotein E was identified in the two groups of comparative maps and results of ELISA consisted with the results of 2-DE.

CONCLUSIONIn this study, we used proteomic approach to explore HACE firstly and found different proteins that were probably associated with HACE. This would offer a clue to a better understanding of HACE for precaution, diagnosis and treatment.

Adult ; Altitude ; Altitude Sickness ; complications ; Apolipoproteins E ; blood ; Blood Proteins ; metabolism ; Brain Edema ; blood ; etiology ; Female ; Humans ; Proteomics ; methods

The aim of this study was to investigate the effect of integripetal rhodiola herb on pulmonary arterial remodeling and expression of vascular endothelial growth factor (VEGF) in high altitude pulmonary hypertension in rats. Fifty healthy male Wistar rats were divided into five groups randomly: Plain control group (LC group), 10-day plateau group (H(10) group), 30-day plateau group (H(30) group), 10-day rhodiola-treated plateau group (R(10) group), and 30-day rhodiola-treated plateau group (R(30) group). Each group included 10 rats. The rats in LC group were kept in Chengdu (500 meters above sea level), and rats in H and R groups were kept in Lhasa (3 700 meters above sea level). The rats in R group were daily treated with integripetal rhodiola herb extract (24%, 10 mL/kg) intragastrically for 10 d or 30 d, while rats in LC and H groups were treated with the same volume of saline. Mean pulmonary arterial pressure (mPAP) was detected via a catheter in the pulmonary artery by pressure waveform monitoring. The ratio value of right ventricle weight to left ventricle plus septum weight [RV/(LV + S)] was measured. The microstructure of pulmonary arterioles was examined by electron microscopy. The expression of VEGF in the lung was investigated using immunohistochemistry. The results showed that mPAP and [RV/(LV + S)] in H(10) group and H(30) group were higher than those in LC group (P < 0.05); but there was no significant difference between H(10) group and R(10) group (P < 0.05); and mPAP and [RV/(LV + S)] in H(30) group were lower than those in H(30) group (P < 0.05). Electron microscopy showed that compared to LC group, arteriolar endothelial cells were arranged in a columnar or palisading form, protruding into the lumen, accompanied with luminal stenosis, irregular internal elastic membrane, and proliferation of vascular smooth muscle cells in H groups, which was more obvious in H(30) group than in H(10) group; while these pathological changes were attenuated in the R groups compared to H groups. The levels of VEGF protein in H groups were also higher than those in LC group (P < 0.05); while the expression of VEGF in R(30) group was lower than that in H(30) group. In summary, the results show that the integripetal rhodiola herb can attenuate high altitude-induced pulmonary arterial remodeling in rats, and the inhibition of VEGF protein expression by rhodiola may be one of the mechanisms.
Altitude ; Altitude Sickness ; prevention & control ; Animals ; Arterioles ; metabolism ; pathology ; Drugs, Chinese Herbal ; pharmacology ; Hypertension, Pulmonary ; metabolism ; pathology ; physiopathology ; Male ; Pulmonary Artery ; metabolism ; pathology ; RNA, Messenger ; metabolism ; Rats ; Rats, Wistar ; Rhodiola ; Vascular Endothelial Growth Factor A ; metabolism