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High-altitude polycythemia (HAPC) is a common chronic altitude disease caused by living in low-pressure and low-oxygen environment. At present, there is still no effective cure for HAPC. HIF-2α may play an important role in the development of HAPC in regulating the increased red blood cell excessively induced by HIF-EPO and the blood vessel formation induced by VEGF-VEGFR. Here, we established a rat HAPC model and treated it with the HIF-2α inhibitor PT2385. We mainly evaluated the therapeutic effect of PT2385 on HAPC rats by observing the changes in rat phenotype, tissue and organ damage, red blood cell and hemoglobin content, angiogenesis, lipid peroxidation reaction, and inflammatory factors. The results showed that PT2385 treatment improved the congestion phenotype characteristics, inhibited increased erythrocytes and hemoglobin, reduced blood vessel formation, lipid peroxidation, and inflammation, and reduced tissue and organ damage in HAPC rats. This study preliminarly explains the physiological, pathological, and immunological effects of PT2385 treatment for HAPC. It provides a new idea, a reliable experimental basis, and theoretical support for the clinical prevention and treatment of HAPC., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Exposure to a hypobaric hypoxic environment at high altitudes can lead to lung injury. In this study, we aimed to determine whether curcumin (Cur) could improve lung barrier function and protect against high-altitude-associated acute lung injury., Methods: Two hundred healthy rats were randomly divided into standard control, high-altitude control (HC), salidroside (40 mg/kg, positive control), and Cur (200 mg/kg) groups. Each group was further divided into five subgroups. Basic vital signs, lung injury histopathology, routine blood parameters, plasma lactate level, and arterial blood gas indicators were evaluated. Protein and inflammatory factor (tumor necrosis factor α (TNF-α), interleukin [IL]-1β, IL-6, and IL-10) concentrations in bronchoalveolar lavage fluid (BALF) were determined using the bicinchoninic acid method and enzyme-linked immunosorbent assay, respectively. Inflammation-related and lung barrier function-related proteins were analyzed using immunoblotting., Results: Cur improved blood routine indicators such as hemoglobin and hematocrit and reduced the BALF protein content and TNF-α, IL-1β, and IL-6 levels compared with those in the HC group. It increased IL-10 levels and reduced pulmonary capillary congestion, alveolar hemorrhage, and the degree of pulmonary interstitial edema. It increased oxygen partial pressure, oxygen saturation, carbonic acid hydrogen radical, and base excess levels, and the expression of zonula occludens 1, occludin, claudin-4, and reduced carbon dioxide partial pressure, plasma lactic acid, and the expression of phospho-nuclear factor kappa., Conclusions: Exposure to a high-altitude environment for 48 h resulted in severe lung injury in rats. Cur improved lung barrier function and alleviated acute lung injury in rats at high altitudes., (© 2024. The Author(s).)

Prophylactic use of acetazolamide (ACZ) to prevent acute mountain sickness (AMS) is a common practice among high altitude travelers and mountaineers. With its use comes a possible risk of acute kidney injury (AKI). We present a case in which a 56-year-old male hiker in Grand Canyon National Park developed acute exertional rhabdomyolysis and subsequent AKI while taking prophylactic ACZ to prevent AMS. This medication was prescribed despite the hiker encountering only moderate altitude at Grand Canyon with a planned descent within <24 h. The resulting AKI was determined to be the combined result of acute exertional rhabdomyolysis and dehydration/hypovolemia, with the ACZ, a diuretic, as a contributing factor. Medical providers need to recognize the risks/benefits with ACZ use for AMS prophylaxis and avoid prescribing it to individuals whose altitude exposure and activity fall outside the clinical practice guidelines recommended for use.

Background/purpose: Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba (R. crenulate), a famous and characteristic Tibetan medicine, has been demonstrated to exert an outstanding brain protection role in the treatment of high-altitude hypoxia disease. However, the metabolic effects of R. crenulate on high-altitude hypoxic brain injury (HHBI) are still incompletely understood. Herein, the anti-hypoxic effect and associated mechanisms of R. crenulate were explored through both in vivo and in vitro experiments., Study Design/methods: The mice model of HHBI was established using an animal hypobaric and hypoxic chamber. R. crenulate extract (RCE, 0.5, 1.0 and 2.0 g/kg) and salidroside (Sal, 25, 50 and 100 mg/kg) was given by gavage for 7 days. Pathological changes and neuronal apoptosis of mice hippocampus and cortex were evaluated using H&E and TUNEL staining, respectively. The effects of RCE and Sal on the permeability of blood brain barrier (BBB) were detected by Evans blue staining and NIR-II fluorescence imaging. Meanwhile, the ultrastructural BBB and cerebrovascular damages were observed using a transmission electron microscope (TEM). The levels of tight junction proteins Claudin-1, ZO-1 and occludin were detected by immunofluorescence. Additionally, the metabolites in mice serum and brain were determined using UHPLC-MS and MALDI-MSI analysis. The cell viability of Sal on hypoxic HT22 cells induced by CoCl 2 was investigated by cell counting kit-8. The contents of LDH, MDA, SOD, GSH-PX and SDH were detected by using commercial biochemical kits. Meanwhile, intracellular ROS, Ca 2+ and mitochondrial membrane potential were determined by corresponding specific labeled probes. The intracellular metabolites of HT22 cells were performed by the targeted metabolomics analysis of the Q300 kit. The cell apoptosis and necrosis were examined by YO-PRO-1/PI, Annexin V/PI and TUNEL staining. In addition, mitochondrial morphology was tested by Mito-tracker red with confocal microscopy and TEM. Real-time ATP production, oxygen consumption rate, and proton efflux rate were measured using a Seahorse analyzer. Subsequently, MCU, OPA1, p-Drp1ser616, p-AMPKα, p-AMPKβ and Sirt1 were determined by immunofluorescent and western blot analyses., Results: The results demonstrated that R. crenulate and Sal exert anti-hypoxic brain protection from inhibiting neuronal apoptosis, maintaining BBB integrity, increasing tight junction protein Claudin-1, ZO-1 and occludin and improving mitochondrial morphology and function. Mechanistically, R. crenulate and Sal alleviated HHBI by enhancing the tricarboxylic acid cycle to meet the demand of energy of brain. Additionally, experiments in vitro confirmed that Sal could ameliorate the apoptosis of HT22 cells, improve mitochondrial morphology and energy metabolism by enhancing mitochondrial respiration and glycolysis. Meanwhile, Sal-mediated MCU inhibited the activation of Drp1 and enhanced the expression of OPA1 to maintain mitochondrial homeostasis, as well as activation of AMPK and Sirt1 to enhance ATP production., Conclusion: Collectively, the findings suggested that RCE and Sal may afford a protective intervention in HHBI through maintaining BBB integrity and improving energy metabolism via balancing MCU-mediated mitochondrial homeostasis by activating the AMPK/Sirt1 signaling pathway., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to the research, author- ship, and publication of this article., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

High-altitude myocardial injury (HAMI) represents a critical form of altitude illness for which effective drug therapies are generally lacking. Notoginsenoside R1, a prominent constituent derived from Panax notoginseng, has demonstrated various cardioprotective properties in models of myocardial ischemia/reperfusion injury, sepsis-induced cardiomyopathy, cardiac fibrosis, and myocardial injury. The potential utility of notoginsenoside R1 in the management of HAMI warrants prompt investigation. Following the successful construction of a HAMI model, a series of experimental analyses were conducted to assess the effects of notoginsenoside R1 at dosages of 50 mg/Kg and 100 mg/Kg. The results indicated that notoginsenoside R1 exhibited protective effects against hypoxic injury by reducing levels of CK, CK-MB, LDH, and BNP, leading to improved cardiac function and decreased incidence of arrhythmias. Furthermore, notoginsenoside R1 was found to enhance Nrf2 nuclear translocation, subsequently regulating the SLC7A11/GPX4/HO-1 pathway and iron metabolism to mitigate ferroptosis, thereby mitigating cardiac inflammation and oxidative stress induced by high-altitude conditions. In addition, the application of ML385 has confirmed the involvement of Nrf2 nuclear translocation in the therapeutic approach to HAMI. Collectively, the advantageous impacts of notoginsenoside R1 on HAMI have been linked to the suppression of ferroptosis via Nrf2 nuclear translocation signaling., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: High-altitude pulmonary edema (HAPE) is a severe and potentially fatal condition with limited treatment options. Although ceramide kinase (CERK)-derived ceramide-1-phosphate (C1P) has been demonstrated to offer protection against various pulmonary diseases, its effects on HAPE remain unclear., Objectives: Our study aimed to investigate the potential role of CERK-derived C1P in the development of HAPE and to reveal the molecular mechanisms underlying its protective effects. We hypothesized that CERK-derived C1P could protect against HAPE by stabilizing circadian rhythms and maintaining mitochondrial dynamics., Methods: To test our hypothesis, we used CERK-knockout mice and established HAPE mouse models using a FLYDWC50-1C hypobaric hypoxic cabin. We utilized a range of methods, including lipidomics, transcriptomics, immunofluorescence, Western blotting, and transmission electron microscopy, to identify the mechanisms of regulation., Results: Our findings demonstrated that CERK-derived C1P played a protective role against HAPE. Inhibition of CERK exacerbated HAPE induced by the hypobaric hypoxic environment. Specifically, we identified a novel mechanism in which CERK inhibition induced aryl hydrocarbon receptor nuclear translocator-like (ARNTL) autophagic degradation, inducing the circadian rhythm and triggering mitochondrial damage by controlling the expression of proteins required for mitochondrial fission and fusion. The decreased ARNTL caused by CERK inhibition impaired mitochondrial dynamics, induced oxidative stress damage, and resulted in defects in mitophagy, particularly under hypoxia. Exogenous C1P prevented ARNTL degradation, alleviated mitochondrial damage, neutralized oxidative stress induced by CERK inhibition, and ultimately relieved HAPE., Conclusions: This study provides evidence for the protective effect of C1P against HAPE, specifically, through stabilizing circadian rhythms and maintaining mitochondrial dynamics. Exogenous C1P therapy may be a promising strategy for treating HAPE. Our findings also highlight the importance of the circadian rhythm and mitochondrial dynamics in the pathogenesis of HAPE, suggesting that targeting these pathways may be a potential therapeutic approach for this condition., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Background: Bawei Chenxiang Wan (BCW) is among the most effective and widely used therapies for coronary heart disease and angina pectoris in Tibet. However, whether it confers protection through a right-ventricle (RV) myocardial metabolic mechanism is unknown., Methods: Male Sprague-Dawley rats were orally administrated with BCW, which was injected concurrently with a bolus of Sugen5416, and subjected to hypoxia exposure (SuHx; 5000 m altitude) for 4 weeks. Right ventricular hypertrophy (RVH) in high-altitude heart disease (HAHD) was assessed using Fulton's index (FI; ratio of RV to left ventricle + septum weights) and heart-weight-to-body-weight ratio (HW/BW). The effect of therapeutic administration of BCW on the RVH hemodynamics was assessed through catheterization (mean right ventricular pressure and mean pulmonary artery pressure (mRVP and mPAP, respectively)). Tissue samples were used to perform histological staining, and confirmatory analyses of mRNA and protein levels were conducted to detect alterations in the mechanisms of RVH in HAHD. The protective mechanism of BCW was further verified via cell culture., Results: BCW considerably reduced SuHx-associated RVH, as indicated by macro morphology, HW/BW ratio, FI, mPAP, mRVP, hypertrophy markers, heart function, pathological structure, and myocardial enzymes. Moreover, BCW can alleviate the disorder of glucose and fatty acid metabolism through upregulation of carnitine palmitoyltransferase1ɑ, citrate synthase, and acetyl-CoA and downregulation of glucose transport-4, phosphofructokinase, and pyruvate, which resulted in the reduced levels of free fatty acid and lactic acid and increased aerobic oxidation. This process may be mediated via the regulation of sirtuin 3 (SIRT3)-hypoxia-inducible factor 1α (HIF1α)-pyruvate dehydrogenase kinase (PDK)/pyruvate dehydrogenase (PDH) signaling pathway. Subsequently, the inhibition of SIRT3 expression by 3-TYP (a selective inhibitor of SIRT3) can reverse substantially the anti-RVH effect of BCW in HAHD, as indicated by hypertrophy marker and serum myocardial enzyme levels., Conclusions: BCW prevented SuHx-induced RVH in HAHD via the SIRT3-HIF1ɑ-PDK/PDH signaling pathway to alleviate the disturbance in fatty acid and glucose metabolism. Therefore, BCW can be used as an alternative drug for the treatment of RVH in HAHD., (© 2024. The Author(s).)

Nitric oxide was first identified as a novel and effective treatment for persistent pulmonary hypertension of the newborn (PPHN), and has since been found to be efficacious in treating acute respiratory distress syndrome (ARDS) and pulmonary hypertension. Physicians and researchers have also found it shows promise in resource-constrained settings, both within and outside of the hospital, such as in high altitude pulmonary edema (HAPE) and COVID-19. The treatment has been well tolerated in these settings, and is both efficacious and versatile when studied across a variety of clinical environments. Advancements in inhaled nitric oxide continue, and the gas is worthy of investigation as physicians contend with new respiratory and cardiovascular illnesses, as well as unforeseen logistical challenges., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Liu, Bo, Minlan Yuan, Mei Yang, Hongru Zhu, and Wei Zhang. The effect of high-altitude hypoxia on neuropsychiatric functions. High Alt Med Biol . 25:26-41, 2024. Background: In recent years, there has been a growing popularity in engaging in activities at high altitudes, such as hiking and work. However, these high-altitude environments pose risks of hypoxia, which can lead to various acute or chronic cerebral diseases. These conditions include common neurological diseases such as acute mountain sickness (AMS), high-altitude cerebral edema, and altitude-related cerebrovascular diseases, as well as psychiatric disorders such as anxiety, depression, and psychosis. However, reviews of altitude-related neuropsychiatric conditions and their potential mechanisms are rare. Methods: We conducted searches on PubMed and Google Scholar, exploring existing literature encompassing preclinical and clinical studies. Our aim was to summarize the prevalent neuropsychiatric diseases induced by altitude hypoxia, the potential pathophysiological mechanisms, as well as the available pharmacological and nonpharmacological strategies for prevention and intervention. Results: The development of altitude-related cerebral diseases may arise from various pathogenic processes, including neurovascular alterations associated with hypoxia, cytotoxic responses, activation of reactive oxygen species, and dysregulation of the expression of hypoxia inducible factor-1 and nuclear factor erythroid 2-related factor 2. Furthermore, the interplay between hypoxia-induced neurological and psychiatric changes is believed to play a role in the progression of brain damage. Conclusions: While there is some evidence pointing to pathophysiological changes in hypoxia-induced brain damage, the precise mechanisms responsible for neuropsychiatric alterations remain elusive. Currently, the range of prevention and intervention strategies available is primarily focused on addressing AMS, with a preference for prevention rather than treatment.

Poudel, Sangeeta, Sandesh Gautam, Purushottam Adhikari, and Ken Zafren. Physiological effects of sildenafil versus placebo at high altitude: a systematic review. High Alt Med Biol . 25:16-25, 2024. Introduction: High altitude pulmonary edema (HAPE), a life-threatening condition that affects individuals ascending to high altitude, requires the development of pulmonary hypertension. Sildenafil can be used to prevent and treat HAPE, presumably by decreasing pulmonary artery pressure (PaP). We compared the physiological effects of sildenafil versus placebo at high altitude (above 2,500 m), including the effects on PaP. Methods: We performed a systematic search of PubMed, EMBASE, and Cochrane CENTRAL for randomized controlled studies of the physiological effects of sildenafil in hypoxia in healthy individuals. We conducted a systematic review of all studies meeting our criteria. Results: Of the 14 studies that met the inclusion criteria, 8 were hypobaric hypoxia studies. Six studies reported data at rest at altitudes from 3,650 to 5,245 m. Two were simulations reporting exercise data at equivalent altitudes of 2,750-5,000 m. Nine studies used normobaric hypoxia corresponding to altitudes between 2,500 and 6,400 m. One reported only rest data, two reported rest and exercise data, and the others reported only exercise data. Sildenafil significantly reduced PaP at rest and exercise in hypobaric or normobaric hypoxia. There were no significant differences between arterial oxygen saturation (SpO 2 ) with sildenafil in hypobaric or normobaric hypoxia at rest or exercise. There were no significant differences in heart rate or mean arterial pressure (MAP) at rest or exercise and cardiac output during exercise in hypobaric or normobaric hypoxia. Conclusions: Sildenafil significantly reduces PaP at rest and exercise in normobaric or hypobaric hypoxia. Sildenafil has no significant effects on SpO 2 , heart rate, cardiac output (during exercise), or MAP at rest or exercise in hypobaric or normobaric hypoxia.

Various strategies can be employed to prevent and manage altitude illnesses, including habituation, oxygenation, nutritional support, and medication. Nevertheless, the utilization of drugs for the prevention and treatment of hypoxia is accompanied by certain adverse effects. Consequently, the quest for medications that exhibit minimal side effects while demonstrating high efficacy remains a prominent area of research. In this context, it is noteworthy that free radical scavengers exhibit remarkable anti-hypoxia activity. These scavengers effectively eliminate excessive free radicals and mitigate the production of reactive oxygen species (ROS), thereby safeguarding the body against oxidative damage induced by plateau hypoxia. In this review, we aim to elucidate the pathogenesis of plateau diseases that are triggered by hypoxia-induced oxidative stress at high altitudes. Additionally, we present a range of free radical scavengers as potential therapeutic and preventive approaches to mitigate the occurrence of common diseases associated with hypoxia at high altitudes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

High-altitude hypoxic environments have critical implications on cardiovascular system function as well as blood pressure regulation. Such environments place patients with hypertension at risk by activating the sympathetic nervous system, which leads to an increase in blood pressure. In addition, the high-altitude hypoxic environment alters the in vivo metabolism and antihypertensive effects of antihypertensive drugs, which changes the activity and expression of drug-metabolizing enzymes and drug transporters. The present study reviewed the pharmacodynamics and pharmacokinetics of antihypertensive drugs and its effects on patients with hypertension in a high-altitude hypoxic environment. It also proposes a new strategy for the rational use of antihypertensive drugs in clinical practice in high-altitude hypoxic environments. The increase in blood pressure on exposure to a high-altitude hypoxic environment was mainly dependent on increased sympathetic nervous system activity. Blood pressure also increased proportionally to altitude, whilst ambulatory blood pressure increased more than conventional blood pressure, especially at night. High-altitude hypoxia can reduce the activities and expression of drug-metabolizing enzymes, such as CYP1A1, CYP1A2, CYP3A1, and CYP2E1, while increasing those of CYP2D1, CYP2D6, and CYP3A6. Drug transporter changes were related to tissue type, hypoxic degree, and hypoxic exposure time. Furthermore, the effects of high-altitude hypoxia on drug-metabolism enzymes and transporters altered drug pharmacokinetics, causing changes in pharmacodynamic responses. These findings suggest that high-altitude hypoxic environments affect the blood pressure, pharmacokinetics, and pharmacodynamics of antihypertensive drugs. The optimal hypertension treatment plan and safe and effective medication strategy should be formulated considering high-altitude hypoxic environments.

We sought to determine the effects of three treatments on hemoglobin (Hb) levels in patients with chronic mountain sickness (CMS): 1 ) descent to lower altitude, 2 ) nocturnal O 2 supply, 3 ) administration of acetazolamide. Nineteen patients with CMS living at an altitude of 3,940 ± 130 m participated in the study, which consisted of a 3-wk intervention phase and a 4-wk postintervention phase. Six patients spent 3 wk at an altitude of 1,050 m (low altitude group, LAG), six received supplemental oxygen for 12 h overnight (oxygen group, OXG), and seven received 250 mg of acetazolamide daily (acetazolamide group, ACZG). Hemoglobin mass (Hbmass) was determined using an adapted carbon monoxide (CO) rebreathing method before, weekly during, and 4 wk postintervention. Hbmass decreased by 245 ± 116 g ( P < 0.01) in the LAG and by 100 ± 38 g in OXG, and 99 ± 64 g in ACZG ( P < 0.05, each), respectively. In LAG, hemoglobin concentration ([Hb]) decreased by 2.1 ± 0.8 g/dL and hematocrit by 7.4 ± 2.9% (both P < 0.01), whereas OXG and ACZG only trended toward lower values. Erythropoietin concentration ([EPO]) decreased between 81 ± 12% and 73 ± 21% in LAG at low altitude ( P < 0.01) and increased by 161 ± 118% 5 days after return ( P < 0.01). In OXG and ACZG, the [EPO] decrease was ∼75% and ∼50%, respectively, during the intervention ( P < 0.01). Descent to low altitude (from 3,940 m to 1,050 m) is a fast-acting measure for the treatment of excessive erythrocytosis in patients with CMS, reducing Hbmass by 16% within 3 wk. Nighttime oxygen supplementation and daily acetazolamide administration are also effective, but reduce Hbmass by only 6%. NEW & NOTEWORTHY To our knowledge, this is the first study examining the effect of three different treatments [descending to lower altitude (from 3,900 m to 1,050 m), nocturnal oxygen supply, and administration of acetazolamide] on changes in hemoglobin mass in patients experiencing chronic mountain sickness (CMS). We report that descent to low altitude is a fast-acting measure for the treatment of excessive erythrocytosis in patients with CMS, reducing Hbmass by 16% within 3 wk. Nighttime oxygen supplementation and daily acetazolamide administration are also effective, but reduce Hbmass by only 6%. In all three treatments, the underlying mechanism is a reduction in plasma erythropoietin concentration due to higher oxygen availability.

More and more people travel to high altitudes, some develop mountain sickness, a possible life-threatening condition. The most common and benign case of mountain sickness is acute mountain sicknes, this condition is easily treatable by descending or low dose aceatazolamide. Treatment is important to avoid development to the more severe cases of mountain sickness high-altitude cerebral oedema and high-altitude pulmonary oedema. These conditions require early recognition and treatment. This review gives an overview of available treatment of these conditions and how to avoid them in the first place.

Doherty, Connor J., Jou-Chung Chang, Benjamin P. Thompson, Erik R. Swenson, Glen E. Foster, and Paolo B. Dominelli. The impact of acetazolamide and methazolamide on exercise performance in normoxia and hypoxia. High Alt Med Biol . 24:7-18, 2023.-Carbonic anhydrase (CA) inhibitors are commonly prescribed for acute mountain sickness (AMS). In this review, we sought to examine how two CA inhibitors, acetazolamide (AZ) and methazolamide (MZ), affect exercise performance in normoxia and hypoxia. First, we briefly describe the role of CA inhibition in facilitating the increase in ventilation and arterial oxygenation in preventing and treating AMS. Next, we detail how AZ affects exercise performance in normoxia and hypoxia and this is followed by a discussion on MZ. We emphasize that the overarching focus of the review is how the two drugs potentially affect exercise performance, rather than their ability to prevent/treat AMS per se , their interrelationship will be discussed. Overall, we suggest that AZ hinders exercise performance in normoxia, but may be beneficial in hypoxia. Based upon head-to-head studies of AZ and MZ in humans on diaphragmatic and locomotor strength in normoxia, MZ may be a better CA inhibitor when exercise performance is crucial at high altitude.

Background: The amount of metabolites converted into active metabolites is correspondingly reduced since only more than 50% of clopidogrel is absorbed., Objective: Exploring the effect of gut microbiota altered by altitude hypoxia on the pre-absorption metabolism of clopidogrel., Methods: In vitro and in vivo experiments were conducted to analyze the metabolism of clopidogrel through LCMS/ MS, while 16S rRNA analysis was used to investigate the changes in the gut microbiota of high-altitude animals., Results: We demonstrated that the intestinal flora is involved in the metabolism of clopidogrel through in vivo and in vitro experiments. In addition, the plateau environment caused changes in the number and composition of intestinal microbes. Intriguingly, alterations in the microbial population could lead to an increase in the pre-absorption metabolism of clopidogrel after rapid entry into the plateau, the amount of absorbed blood is thus reduced, which may affect the bioavailability and therapeutic effect of clopidogrel., Conclusion: Our results not only as a first clinical reference for dose adjustment of clopidogrel in high-altitude environments but also would be helpful to provide a statement on the broader significance within the field of pharmacokinetics or personalized medicine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The special environment of high-altitude hypoxia not only changes the physiological state of the body but also affects the metabolic process of many drugs, which may affect the safety and efficacy of these drugs. The number of drugs is huge, so it is not wise to blindly repeat the pharmacokinetic studies of all of them on the plateau. Mastering the law of drug metabolism on the plateau is conducive to the comprehensive development of rational drug use on the plateau. Therefore, it is very important to determine the impacts and elucidate the mechanism of drug metabolism in hypobaric hypoxia conditions., Methods: In this review, we searched published studies on changes in drug metabolism in hypoxia conditions to summarize and analyze the mechanisms by which hypoxia alters drug metabolism., Results: Although the reported effects of high-altitude hypoxia on drug metabolism are sometimes controversial, metabolism kinetics for most of the tested drugs are found to be affected. Mechanism studies showed that the major reasons causing metabolism changes are: regulated drug-metabolizing enzymes expression and activity mediated by HIF-1, nuclear receptors and inflammatory cytokines, and change in direct or indirect effects of intestinal microflora on drug metabolism by itself or the host mediated by microflora-derived drug-metabolizing enzymes, metabolites, and immunoregulation., Conclusion: Altered enzyme expression and activity in the liver and altered intestinal microflora are the two major reasons to cause altered drug metabolism in hypoxia conditions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Competing Interests: Conflict of interest: D.P. received speaker’s fees from Daiichi Sankyo, outside the submitted work. M.V. reports personal fees for speaker bureau and/or consulting in Advisory Boards from Amgen, Astra Zeneca, Daiichi Sankyo, Menarini Int, MSD, Novartis Pharma, and Novo Nordisk, outside the submitted work.

Hypoxic exposure makes plateau migrators susceptible to high altitude polycythemia (HAPC). Astragalus membranaceus (AM) is an edible and medicinal plant with remarkable immunomodulatory activities. The purpose of this study was to discover if AM could be a candidate for the prevention of HAPC and its mechanism. Here, network pharmacology was applied to screen active compounds, key targets, and enriched pathways of AM in the treatment of HAPC. Molecular docking evaluated the affinity between compounds and core targets. Subsequently, the mechanisms of AM were further verified using the hypoxia exposure-induced mice model of HAPC. The network pharmacology analysis and molecular docking results identified 14 core targets of AM on HAPC, which were predominantly mainly enriched in the HIF-1 pathway. In the HAPC animal models, we found that AM inhibited the differentiation of hematopoietic stem cells into the erythroid lineage. It also suppressed the production of erythrocytes and hemoglobin in peripheral blood by reducing the expression of HIF-1α, EPO, VEGFA, and Gata-1 mRNA. Furthermore, AM downregulated the expression of IL-6, TNF-α, and IFN-γ mRNA, thereby alleviating organ inflammation. In conclusion, AM supplementation alleviates hypoxia-induced HAPC in mice, and TNF-α, AKT1, HIF-1α, VEGFA, IL-6, and IL-1B may be the key targets.

Vizcarra-Vizcarra, Cristhian A., Eduardo Chávez-Velázquez, Carmen Asato-Higa, and Abdías Hurtado-Aréstegui. Treatment of focal and segmental glomerulosclerosis secondary to high altitude polycythemia with acetazolamide. High Alt Med Biol . 23:286-290, 2022.-Focal segmental glomerulosclerosis (FSGS) is a morphological pattern, caused by glomerular injury and is the leading cause of nephrotic syndrome in adults. We present the case of a 59-year-old female patient, resident of a high-altitude city (3,824 m), who had polycythemia and nephrotic syndrome. A renal biopsy was performed, and the findings were compatible with FSGS. The patient received phlebotomy 500 ml three times, which reduced, partially, the hemoglobin concentration. However, she had refractory proteinuria, despite the use of enalapril and spironolactone. We observed that proteinuria worsened with the increase in hemoglobin levels. So, she was treated with acetazolamide 250 mg bid for 4 months, which reduced proteinuria and hemoglobin. During the coronavirus disease 2019 (COVID-19) pandemic, the patient did not take acetazolamide and again, she had an increase in hemoglobin and proteinuria levels. We conclude that acetazolamide may be an effective treatment in FSGS due to high altitude polycythemia.

High-altitude cerebral edema (HACE) is the severe type of acute mountain sickness, which is still lack of effective therapy. This study investigated for the first time the protective effect of mitochondrial division inhibitor-1 (mdivi-1) against cerebral edema induced by simulated high-altitude exposure in mice. It was found that mdivi-1 effectively inhibited phosphorylation of dynamin-related protein-1 (Drp1), reduced expression of AQP4, decreased secretion of IL-6 and TNF-α, and alleviated cerebral edema in mice. In primary cultured astrocytes or microglia, mdivi-1 significantly decreased the hypoxia-induced Drp1 phosphorylation and mitochondrial fragmentation, inhibited the activation of the NF-κB signaling pathway, reduced the secretion of IL-6 and TNF-α. In addition, mdivi-1 inhibited mitochondrial reactive oxygen species (ROS) generation induced by hypoxia in both astrocytes and microglia. When astrocytes were treated with the conditioned medium of microglia exposed to hypoxia (H-MCM), the protein levels of p-Drp1, p-p65, and AQP4 as well as the mRNA levels of IL-6, TNF-α, and IL-1β in astrocytes were increased. When the mitochondrial components in H-MCM were removed, the influence of microglia on astrocytes under hypoxia was significantly alleviated. Treated with mdivi-1, the integrity of mitochondria released from microglia induced by hypoxia were significantly improved. In conclusion, pharmacological inhibition of mitochondrial division by mdivi-1 alleviated cerebral edema induced by simulated high-altitude exposure in mice. Inhibition of ROS/NF-κB signaling pathway may contribute to the protective effect of mdivi-1. Under hypoxic conditions, mdivi-1 may attenuate the activation of astrocytes by reducing the release of damaged mitochondria from microglia., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Rhodiola crenulata (Hook.f. & Thomson) H.Ohba has a long history of clinical application for the prevention and treatment of acute mountain sickness (AMS) in traditional Chinese medicine. However, gaps in knowledge still exist in understanding the underlying mechanisms of Rhodiola crenulata against AMS., Aims: To address this problem, a comprehensive method was established by combining UHPLC-Q-TOF-MS/MS analysis and network pharmacology., Materials and Methods: The ingredients of Rhodiola crenulata were comprehensively analyzed using UHPLC-Q-TOF-MS/MS method. On this basis, a network pharmacology method incorporated target prediction, protein-protein interaction network, gene enrichment analysis and components-targets-pathways network was performed. Finally, the possible mechanisms were verified through molecular docking, in vitro and in vivo experiments., Results: A total of 106 constituents of Rhodiola crenulata were charactered via UHPLC-Q-TOF-MS/MS. The 98 potentially active compounds out of 106 were screened and corresponded to 53 anti-AMS targets. Gene enrichment analysis revealed that hypoxia and inflammation related genes may be the central factors for Rhodiola crenulata to modulate AMS. Molecular docking revealed that TNF, VEGFA and HIF-1α had high affinities to Rhodiola crenulata compounds. Subsequently, Rhodiola crenulata extract was indicated to inhibit the protein expression level of TNF in hypoxia induced H9c2 cells. Lastly, Rhodiola crenulata extract was further verified to ameliorate heart injury and decreased the heart levels of TNF, VEGFA and HIF-1α in acute hypoxia-induced rats., Conclusions: This study used UHPLC-Q-TOF-MS/MS analysis and a network pharmacology to provide an important reference for revealing the potential mechanism of Rhodiola crenulata in the prevention and treatment of AMS., (Copyright © 2022 Elsevier B.V. All rights reserved.)

High altitude cerebral edema (HACE) is a potentially life-threatening disease encountered at high altitudes. However, effective methods for HACE prophylaxis are limited. Convincing evidence confirms that oxidative stress induced by hypobaric hypoxia (HH) is one of the main factors that account for the development of HACE. 5,6,7,8-Tetrahydroxyflavone (THF), a flavone with four consecutive OH groups in ring A, exhibited excellent antioxidant activity in vitro and could attenuate HH induced injury in vivo. The aim of this study was to investigate the protective effect of THF against HACE and its underlying mechanisms. THF administration significantly suppressed HH induced oxidative stress by reducing the formation of hydrogen peroxide and malondialdehyde, by increasing the levels of glutathione and superoxide dismutase in brain tissue. Simultaneously, THF administration inhibited inflammatory responses by decreasing the levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in serum and brain tissue. In addition, THF administration mitigated the energy metabolism disorder induced by HACE as evidenced by decreased levels of lactic acid, lactate dehydrogenase and pyruvate kinase as well as increased ATP levels and ATPase activities. Furthermore, THF administration decreased the expression of matrix metalloproteinase-9, aquaporin 4, hypoxia-inducible factor-1α and vascular endothelial growth factor, which attenuated blood-brain barrier (BBB) disruption and brain edema. Additionally, THF administration improved HACE induced cognitive dysfunction. These results show that THF is a promising agent in the prevention and treatment of HACE., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Acetazolamide prevents acute mountain sickness (AMS) by inhibition of carbonic anhydrase. Since it also reduces acute hypoxic pulmonary vasoconstriction (HPV), it may also prevent high-altitude pulmonary edema (HAPE) by lowering pulmonary artery pressure. We tested this hypothesis in a randomized, placebo-controlled, double-blind study. Thirteen healthy, nonacclimatized lowlanders with a history of HAPE ascended (<22 h) from 1,130 to 4,559 m with one overnight stay at 3,611 m. Medications were started 48 h before ascent (acetazolamide: n = 7, 250 mg 3 times/day; placebo: n = 6, 3 times/day). HAPE was diagnosed by chest radiography and pulmonary artery pressure by measurement of right ventricular to atrial pressure gradient (RVPG) by transthoracic echocardiography. AMS was evaluated with the Lake Louise Score (LLS) and AMS-C score. The incidence of HAPE was 43% versus 67% (acetazolamide vs. placebo, P = 0.39). Ascent to altitude increased RVPG from 20 ± 5 to 43 ± 10 mmHg ( P < 0.001) without a group difference ( P = 0.68). Arterial Po 2 fell to 36 ± 9 mmHg ( P < 0.001) and was 8.5 mmHg higher with acetazolamide at high altitude ( P = 0.025). At high altitude, the LLS and AMS-C score remained lower in those taking acetazolamide (both P < 0.05). Although acetazolamide reduced HAPE incidence by 35%, this effect was not statistically significant, and was considerably less than reductions of about 70%-100% with prophylactic dexamethasone, tadalafil, and nifedipine performed with the same ascent profile at the same location. We could not demonstrate a reduction in RVPG compared with placebo treatment despite reductions in AMS severity and better arterial oxygenation. Limited by small sample size, our data do not support recommending acetazolamide for the prevention of HAPE in mountaineers ascending rapidly to over 4,500 m. NEW & NOTEWORTHY This randomized, placebo-controlled, double-blind study is the first to investigate whether acetazolamide, which reduces acute mountain sickness (AMS), inhibits short-term hypoxic pulmonary vasoconstriction, and also prevents high-altitude pulmonary edema (HAPE) in a fast-climbing ascent to 4,559 m. We found no statistically significant reduction in HAPE incidence or differences in hypoxic pulmonary artery pressures compared with placebo despite reductions in AMS and greater ventilation-induced arterial oxygenation. Our data do not support recommending acetazolamide for HAPE prevention.

A fit and healthy 44-year-old woman took a single dose of oral acetazolamide (125 mg) in preparation for a hiking trip to Everest base camp. She awoke the next morning with profoundly blurred distance vision. She presented to eye casualty later that morning, approximately 18 hours postingestion: examination demonstrated myopia and bilateral choroidal effusions. Acetazolamide is used to minimise symptoms of altitude sickness. Rarely, its use can be linked with ophthalmic side effects, such as myopia. A handful of case reports also describe choroidal effusions secondary to its use as part of ophthalmic treatment (eg, postoperatively). This is the first reported case in which choroidal effusions have been demonstrated as a side effect of its prophylactic use against altitude sickness., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

BACKGROUND: We evaluated the efficacy of acetazolamide in preventing adverse altitude effects in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and in healthy lowlanders 40 years of age or older. METHODS: Trial 1 was a randomized, double-blind, parallel-design trial in which 176 patients with COPD were treated with acetazolamide capsules (375 mg/day) or placebo, starting 24 hours before staying for 2 days at 3100 m. The mean (±SD) age of participants was 57±9 years, and 34% were women. At 760 m, COPD patients had oxygen saturation measured by pulse oximetry of 92% or greater, arterial partial pressure of carbon dioxide less than 45 mm Hg, and mean forced expiratory volume in 1 second of 63±11% of predicted. The primary outcome in trial 1 was the incidence of the composite end point of altitude-related adverse health effects (ARAHE) at 3100 m. Criteria for ARAHE included acute mountain sickness (AMS) and symptoms or findings relevant to well-being and safety, such as severe hypoxemia, requiring intervention. Trial 2 comprised 345 healthy lowlanders. Their mean age was 53±7 years, and 69% were women. The participants in trial 2 underwent the same protocol as did the patients with COPD in trial 1. The primary outcome in trial 2 was the incidence of AMS assessed at 3100 m by the Lake Louise questionnaire score (the scale of self-assessed symptoms ranges from 0 to 15 points, indicating absent to severe, with 3 or more points including headache, indicating AMS). RESULTS: In trial 1 of patients with COPD, 68 of 90 (76%) receiving placebo and 42 of 86 (49%) receiving acetazolamide experienced ARAHE (hazard ratio, 0.54; 95% confidence interval [CI], 0.37 to 0.79; P<0.001). The number needed to treat (NNT) to prevent one case of ARAHE was 4 (95% CI, 3 to 8). In trial 2 of healthy individuals, 54 of 170 (32%) receiving placebo and 38 of 175 (22%) receiving acetazolamide experienced AMS (hazard ratio, 0.48; 95% CI, 0.29 to 0.80; chi-square statistic P=0.035). The NNT to prevent one case of AMS was 10 (95% CI, 5 to 141). No serious adverse events occurred in these trials. CONCLUSIONS: Preventive treatment with acetazolamide reduced the incidence of adverse altitude effects requiring an intervention in patients with COPD and the incidence of AMS in healthy lowlanders 40 years of age or older during a high-altitude sojourn. (Funded by the Swiss National Science Foundation [Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung], Lunge Zürich, and the Swiss Lung Foundation; ClinicalTrials.gov numbers, NCT03156231 and NCT03561675.)

Context: Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba (Crassulaceae) is used to prevent and treat acute mountain sickness. However, the mechanisms underlying its effects on the central nervous system remain unclear., Objective: To investigate the effect of Rhodiola crenulata on cellular metabolism in the central nervous system., Materials and Methods: The viability and Hif-1α levels of microglia and neurons at 5% O 2 for 1, 3, 5 and 24 h were examined. We performed the binding of salidroside (Sal), rhodiosin, tyrosol and p -hydroxybenzyl alcohol to Hif-1α, Hif-1α, lactate, oxidative phosphorylation and glycolysis assays. Forty male C57BL/6J mice were divided into control and Sal (25, 50 and 100 mg/kg) groups to measure the levels of Hif-1α and lactate., Results: Microglia sensed low oxygen levels earlier than neurons, accompanied by elevated expression of Hif-1α protein. Salidroside, rhodiosin, tyrosol, and p -hydroxybenzyl alcohol decreased BV-2 (IC 50 =1.93 ± 0.34 mM, 959.74 ± 10.24 μM, 7.47 ± 1.03 and 8.42 ± 1.63 mM) and PC-12 (IC 50 =6.89 ± 0.57 mM, 159.28 ± 8.89 μM, 8.65 ± 1.20 and 8.64 ± 1.42 mM) viability. They (10 μM) reduced Hif-1α degradation in BV-2 (3.7-, 2.5-, 2.9- and 2.5-fold) and PC-12 cells (2.8-, 2.8-, 2.3- and 2.0-fold) under normoxia. Salidroside increased glycolytic capacity but attenuated oxidative phosphorylation. Salidroside (50 and 100 mg/kg) treatment increased the protein expression of Hif-1α and the release of lactate in the brain tissue of mice., Conclusions: These results suggest that Sal induces metabolic reprogramming by regulating the Hif-1α signalling pathway to activate compensatory responses, which may be the core mechanism underlying the effect of Rhodiola crenulata on the central nervous system.

The ongoing Covid-19 is a contagious disease, and it is characterised by different symptoms such as fever, cough, and shortness of breath. Rising concerns about Covid-19 have severely affected the healthcare system in all countries as the Covid-19 outbreak has developed at a rapid rate all around the globe. Intriguing, a clinically used drug, acetazolamide (a specific inhibitor of carbonic anhydrase, CA, EC 4.2.1.1), is used to treat high-altitude pulmonary oedema (HAPE), showing a high degree of clinical similarities with the pulmonary disease caused by Covid-19. In this context, this preliminary study aims to provide insights into some factors affecting the Covid-19 patients, such as hypoxaemia, hypoxia as well as the blood CA activity. We hypothesise that patients with Covid-19 problems could show a dysregulated acid-base status influenced by CA activity. These preliminary results suggest that the use of CA inhibitors as a pharmacological treatment for Covid-19 may be beneficial.

Context: Previous studies indicate that compound Danshen Dripping Pill (CDDP) improves the adaptation to high-altitude exposure. However, its mechanism of action is not clear., Objective: To explore the protective effect of CDDP on hypobaric hypoxia (HH) and its possible mechanism., Materials and Methods: A meta-analysis of 1051 human volunteers was performed to evaluate the effectiveness of CDDP at high altitudes. Male Sprague-Dawley rats were randomized into 5 groups ( n  = 6): control at normal pressure, model, CDDP-170 mg/kg, CDDP-340 mg/kg and acetazolamide groups. HH was simulated at an altitude of 5500 m for 24 h. Animal blood was collected for arterial blood-gas analysis and cytokines detection and their organs were harvested for pathological examination. Expression levels of AQP1, NF-κB and Nrf2 were determined by immunohistochemical staining., Results: The meta-analysis data indicated that the ratio between the combined RR of the total effective rate and the 95% CI was 0.23 (0.06, 0.91), the SMD and 95% CI of SO 2 was 0.37 (0.12, 0.62). Pre-treatment of CDDP protected rats from HH-induced pulmonary edoema and heart injury, left-shifted oxygen-dissociation curve and decreased P50 (30.25 ± 3.72 vs. 37.23 ± 4.30). Mechanistically, CDDP alleviated HH-reinforced ROS by improving SOD and GPX1 while inhibiting pro-inflammatory cytokines and NF-κB expression. CDDP also decreased HH-evoked D-dimer, erythrocyte aggregation and blood hemorheology, promoting AQP1 and Nrf2 expression., Discussion and Conclusions: Pre-treatment with CDDP could prevent HH-induced tissue damage, oxidative stress and inflammatory response. Suppressed NF-κB and up-regulated Nrf2 might play significant roles in the mechanism of CDDP.

Introduction: Sleep disturbance is common at high altitude and likely driven by an exaggerated peripheral chemoreceptor response which leads to apnoeic episodes and arousal. We hypothesised that this heightened response is in part mediated through angiotensin II receptors in the carotid body. To examine this link, we studied the effect of angiotensin II receptor blocker on sleep disturbance., Methods: Twenty participants paired by age, gender and ACE phenotype ascended to the Whymper Hut (5000 m) on Chimborazo in the Ecuadorean Andes as part of a double-blinded randomised placebo-controlled study of physiological mechanisms. Subjects were randomised to either losartan 100 mg daily or placebo. The primary outcome of sleep efficiency was measured using wrist-mounted actigraphs. One pair was excluded from analysis after descending before the end of the study due to acute mountain sickness., Results: There was a significantly different response to altitude between the two groups (F=3.274, p=0.029), as a decline in sleep efficiency in the placebo group (F=10.259, p<0.001) was not replicated in the angiotensin II receptor blocker group (F=0.459, p=0.713)., Conclusion: The absence of any significant sleep disturbance in the intervention group suggests that peripheral chemoreceptor hypersensitivity is largely mediated by angiotensin II receptor activation. However, further research is needed to confirm our findings and to study the potential mechanisms of action., Competing Interests: Competing interests: KP has acted as a consultant for Nektar Therapeutics. The work for Nektar has no bearing on the contents of this manuscript. KP is named as a co-inventor on a provisional UK patent application titled “Use of cerebral nitric oxide donors in the assessment of the extent of brain dysfunction following injury”., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To compare and predict the preventive effects of acetazolamide and other drugs on acute mountain sickness(AMS). Methods: Following the retrieval strategy of PRISMA statement of systematic review and meta-analysis, we searched the databases of PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, etc. from January 1, 1980 to November 30, 2020, and randomized controlled trials (RCT) consistent with drug prevention of AMS were conducted. Using R and other statistical software, Markov chain-Monte Carlo method was carried out for network meta-analysis under Bayesian framework, and node separation method was performed to check the consistency of closed-loop research. Results: Twenty-three literatures (25 studies) were included to compare the preventive effects of 4 drugs on AMS. Bayesian network meta-analysis showed that the incidence of AMS in acetazolamide group (ACE), dexamethasone group (DEX), ginkgo biloba extract group (GBE) and rhodiola group (RHO) was lower than that in placebo group (PLA). In the comparison of drug groups, the incidence of AMS in ACE, DEX and RHO was lower than that in GBE. There was no statistically significant difference in the incidence of AMS among ACE, DEX and RHO groups. Eight of these studies reported the effects of two drugs on pulse oxygen saturation (SpO 2 ) in people entering the target altitude. Bayesian network meta-analysis showed that SpO 2 in RHO was higher than that in ACE and PLA, but there was no statistically significant difference in SpO2 between ACE and PLA. The probability ranking of prevention AMS effect grade showed that the rank 5th probability of AMS in ACE, DEX, GBE, RHO and PLA was 45.72%, 48.80%, 0, 5.48% and 0, respectively. The probability ranking of improving the SpO 2 level of the target altitude population showed that the probability of the ACE, RHO and PLA ranking 1st in improving the SpO 2 effect at the target altitude was 2.27%, 97.66% and 0.07%, respectively; the results of direct comparison were in good agreement with those of Bayesian prediction model indirectly, and there was no statistical difference. Conclusions: Acetazolamide and dexamethasone can effectively prevent AMS, and should be the first choice for related supplementary research in the future. Rhodiola not only improves the SpO 2 of people entering high altitude, but also reduces the incidence of AMS, which needs more attention. Ginkgo biloba extract is not as effective as the above three drugs in preventing AMS and should be used depending on clinical situations.

The highlands evoke both fascination and awe. Regardless of the reason to live in the highlands, symptoms related to altitude sickness are unbearable because of low atmospheric pressure, low oxygen concentration, strong ultraviolet radiation, cold, and psychological factors. Food and herbal medicines and/or health-care foods have protected highland dwellers owing to their multisystem regulation. These versatile products combine health-care properties with medical values by enhancing immunity, relieving physical fatigue, improving sleep, and augmenting hypoxia tolerance, with rare side effects. We therefore aimed to provide a more comprehensive analysis of these nutraceuticals, which can be used to prevent and treat symptoms of altitude hypoxia in the Chinese market. Finally, we dissect a new perspective for their promotion and development from molecular aspects., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Chronic mountain sickness (CMS) is a significant pathology in most high-altitude regions globally, affecting the cardiopulmonary system and its mechanism is largely unknown. A metabonomic approach using 1 H nuclear magnetic resonance spectroscopy allows for detecting differential metabolites, which provides a global view and mechanisms during CMS development. In this study, we simulated a high-altitude environment to establish a rat model of CMS. Irbesartan was administered to CMS rats at three doses (6.75, 13.5, and 27 mg/kg) once a day for 15 days. HE staining and transmission electron microscopy were used to evaluate the effect of changes on the lung. Based on 1 H NMR spectra obtained from serum samples, partial least squares-discriminant analysis (PLS-DA) and its variant orthogonal PLS-DA (OPLS-DA) models were applied to distinguish the different groups. Histopathological sections showed that the alveolar structure was abnormal, inflammatory infiltration occurred in CMS rats, and CMS induced notable metabolic disorder according to the 1 H NMR result. However, irbesartan reversed the imbalanced metabolites via energy metabolism, amino acid metabolism, and taurine metabolism pathways, and its effect was also confirmed by the general signs and morphology of the lung. The results revealed that irbesartan as an effective therapeutic agent to improve CMS is warranted., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To study the effects of irbesartan on pulmonary artery lesions in a rat model with chronic mountain sickness (CMS) and identify the biomarkers involved., Methods: In this study, we used a rat model of CMS to evaluate the therapeutic effect of irbesartan by measuring pulmonary artery pressure and evaluating the histopathology of the pulmonary artery. We also used proteomics technology to identify differentially expressed proteins (DEPs) in the serum and performed bioinformatics analysis. Results were then verified by enzyme linked immunosorbent assay (ELISA) and immunohistochemistry (IHC)., Results: Irbesartan treatment induced a significant decrease (P < 0.05) in the pulmonary artery pressure of CMS rats. Histopathological and electron microscope further confirmed that high altitude hypoxia induced changes in the structure of the pulmonary artery tissue and caused ultrastructural lesions. Proteomics analysis identified 40 DEPs; bioinformatics analysis further revealed that the cholesterol metabolism pathway plays a crucial role in the occurrence of CMS. ELISA and IHC verified that several DEPs (Apo-A1, Apo-C1, Apo-E, IGF-1, Profilin1, and Col1a1) represent critical biological markers in pulmonary artery disease caused by CMS., Conclusions: Irbesartan significantly improved pulmonary artery damage in a rat model of CMS possibly by impacting on the cholesterol metabolism pathway and by reducing damage to vascular endothelial cells. Irbesartan also inhibited the expression levels of IGF-1, Profilin1 and Col1a1 to relieve pulmonary artery pressure and improve lung function by inhibiting vascular remodeling. Several proteins were identified as potential biomarkers of CMS, including Apo-A1, Apo-C1, Apo-E, IGF-1, Profilin1, and Col1a1., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

To use isobaric tags for relative and absolute quantification (iTRAQ) technology to study the pathogenesis of chronic mountain sickness (CMS), identify biomarkers for CMS, and investigate the effect of total flavones of Dracocephalum moldavica L. (TFDM) on a rat model of CMS. We simulated high altitude hypobaric hypoxia conditions and generated a rat model of CMS. Following the administration of TFDM, we measured the pulmonary artery pressure and serum levels of hemoglobin (Hb), the hematocrit (Hct), and observed the structure of the pulmonary artery in experimental rats. Furthermore, we applied iTRAQ-labeled quantitative proteomics technology to identify differentially expressed proteins (DEPs) in the serum, performed bioinformatics analysis, and verified the DEPs by immunohistochemistry. Analysis showed that the pulmonary artery pressure, serum levels of Hb, and the Hct, were significantly increased in a rat model of CMS (P < 0.05). Pathological analysis of lung tissue and pulmonary artery tissue showed that the alveolar compartment had obvious hyperplasia and the pulmonary artery degree of muscularization was enhanced. Both pulmonary artery pressure and tissue morphology were improved following the administration of TFDM. We identified 532 DEPs by quantitative proteomics; gene ontology (GO)and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis further revealed that metabolic pathways associated with coagulation and complement play crucial roles in the occurrence of CMS. Immunohistochemistry verified that several DEPs (α-1-acid glycoprotein, collagen, fibulin, haptoglobin, PLTP, and TAGLN2) are important biological markers for CMS. Our analyses demonstrated that TFDM can improve CMS and exert action by influencing the metabolic pathways associated with coagulation and complement. This process relieves pulmonary artery pressure and improves lung function. We also identified that α-1-acid glycoprotein, collagen, fibulin, haptoglobin, PLTP, and TAGLN2 may represent potential biomarkers for CMS., (© 2021. The Author(s).)

The alkaloid ephedrine derived from Ephedra vulgaris is at the origin of psychostimulant-drugs as amphetamine. These drugs have been principally utilized for medical treatments in the past, while their utilization has been largely reduced from the 1970s when the high risk of addiction and abuse has been recognized. The first reported treatments were as anti-asthmatics and to contrast narcolepsy until their recreational stimulant and anorexic effects were reported. Benzedrine and Pervitin use were of great importance during the Second World War due to their abundant utilization among military troops. Nowadays the use of selective amphetamine-like drugs is limited to ADHD treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To evaluate the protective effect of Shouzhangshen (Rhizoma Gymnadeniae Crassinervidis) extract against acute high altitude hypoxia-induced brain injury in mice., Methods: Sixty C57BL/6J mice were selected and assigned to six groups (n = 10): normal control group, low-pressure hypoxia group, positive control group (dexamethasone 500 mg/kg), and three groups treated with Shouzhangshen extract (250, 500, and 750 mg/kg, respectively). The Morris water maze test was performed to evaluate alterations in spatial learning and memory deficits. Nissl staining was performed to detect Nissl bodies and neuron damage. Hypoxia-inducible factor (HIF)-1α, interleukin (IL)-1β, tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), and malondialdehyde (MDA) expression in brain tissue and serum, as well as superoxide dismutase (SOD) and glutathione (GSH) activity in brain tissues were measured by enzyme-linked immunosorbent assays, quantitative real-time-polymerase chain reaction and western blots., Results: The Morris water maze test results showed that Shouzhangshen extract can significantly reduce the latency and swimming distance to escape onto a visible platform, increase neuron density and hierarchy and the number of pyramidal neurons, and decrease the expression of HIF-1α, IL-1β, TNF-α, and VEGF mRNAs and proteins in both brain tissue and serum (P < 0.05). Furthermore, significantly lower MDA expression and higher GSH activity were detected in the three groups treated with Shouzhangshen compared with the low-pressure hypoxia group (P < 0.05). However, no significant alteration was observed for SOD activity (P > 0.05)., Conclusion: Our findings suggest that Shouzhangshen extract may have a significant effect on acute high altitude hypoxia-induced brain injury in mice.

High-altitude pulmonary edema (HAPE) is a life-threatening disease occurs in hypobaric hypoxia (HH) environment, which could be treated by Dexamethasone, but might cause side-effects. Potentilla anserina L polysaccharide (PAP) holds promising physiological and pharmacological properties which could be beneficial for HAPE treatment. In our study, the anti-hypoxia effect of PAP was firstly investigated through anti-normobaric hypoxia test and anti-acute hypoxia test. Then we established a model of HAPE and measured the lung water content, pathological changes and MDA, NO, SOD, GSH concentrations in lung tissues. We also evaluated the protein and mRNA levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, VEGF, NF-κB and HIF-1α) by ELISA kits, RT-PCR and Western blotting. As expected, PAP could dramatically reduce the lung water content, alleviate lung tissue injury, and inhibit MDA and NO production, it also promote SOD activity and GSH expression. In addition, it has been found that PAP blocked the NF-κB and HIF-1α signaling pathway activation, inhibited the generation of downstream pro-inflammatory cytokines. Therefore, PAP provides great potential in HAPE treatment mainly through suppression of oxidative stress and inflammatory suppression., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: High-altitude pulmonary hypertension (HAPH) is one of the diseases with higher occurrence among people living in plateau areas. The possible mechanism of angiotensin II receptor 1 inhibitor irbesartan in improving HAPH was explored from the perspective of intestinal bacterial flora in this study., Materials and Methods: A HAPH rat model was established under simulated high-altitude hypobaric hypoxia. The levels of oxidative stress and vasoactive substances were detected after irbesartan intervention, and intestinal flora genomics analysis was performed., Results: High-altitude hypobaric hypoxia-induced the increase in pulmonary artery pressure and left ventricular systolic dysfunction in HAPH model rats, but its effects were alleviated by irbesartan. Changes in the levels of oxidative damage in intestinal tissues, such as the increase in superoxide dismutase and glutathione peroxidase in intestinal tissues and the decrease in malondialdehyde content, were also reversed by irbesartan. The serum levels of angiotensin II, endothelin 1, interleukin-6, and C-reactive protein increased substantially whereas the level of nitric oxide decreased in HAPH model rats. The levels of these vasoconstriction and inflammatory indicators were also reversed after irbesartan intervention. The distribution of intestinal florae in rats was changed by the simulated high-altitude hypoxia environment as manifested by the increased Firmicutes-to-Bacteroidetes ratio (F/B), the increased abundance of Lactobacillaceae and Lachnospiraceae, and the decreased abundance of Prevotellaceae and Desulfovibrionaceae at the family level. However, the changes in F/B ratio and the abundance of these florae were reversed by irbesartan., Conclusions: Irbesartan can alleviate pulmonary artery pressure and left ventricular relaxation in HAPH model rats, reduce the oxidative damage caused by high-altitude hypoxia, and lower the release of vasoconstrictor factors and inflammatory mediators. These effects might be caused by the increased abundance of Lactobacillaceae and Lachnospiraceae and the decreased abundance of Prevotellaceae and Desulfovibrionaceae in the intestines.

Objective: To investigate the protective effects of betelnut polyphenols on the vital organs against high-altitude hypoxia in rats., Objective: We compared low-, medium-, and high- dose betelnut polyphenols (400, 800, and 1600 mg/kg, respectively) and rhodiola the effects of against high-altitude hypoxia in Wistar rats. The rats were kept in normal condition and given the drugs daily for 3 days before transfer to a facility at the altitude of 4010 m, where the rats were kept for 5 consecutive days for hypoxic exposure. The rats were then euthanized for measuring arterial blood gas and assessing liver, lung, brain and cardiac pathologies with HE staining. SOD activity, MDA content and GSH content in the organs were measured, and serum levels of inflammatory factors were detected using a protein microarray., Objective: Acute exposure to hypoxia significantly reduced blood oxygen saturation of the rats ( P < 0.05), caused damages in the liver, lung, brain and myocardium, lowered SOD activity and GSH content and increased MDA content in the vital organs, and increased serum levels of TIMP-1, MCP-1, ICAM-1, and L-selectin ( P < 0.05). Treatment with betelnut polyphenols significantly improved blood oxygen saturation, alleviated organ damages, decreased MDA content and increased SOD activity and GSH content in the tissues, and significantly lowered serum levels of inflammatory cytokines in rats with acute exposure to high-altitude hypoxia ( P < 0.05)., Objective: Betelnut polyphenols provides protection of the vital organs against acute high-altitude hypoxia in rats by enhancing the antioxidant capacity and reducing inflammatory response.

Aims: Memantine is a non-competitive antagonist of glutamatergic NMDA receptor that is mainly used in the treatment of Alzheimer's disease. The excitatory toxicity mediated by glutamate via glutamatergic receptor signals is considered to be one of the mechanisms mediating neuronal injury and cognitive impairment after exposure to a hypoxic environment at a high altitude. Therefore, in this study, we hypothesized that inhibiting glutamate signaling using memantine could alleviate neuronal injury and cognitive impairment in rats exposed to chronic hypoxia., Main Methods: we made animal models in the natural environment of the Qinghai-Tibet Plateau at an altitude of 4300 m, and used animal behavior, morphology, molecular biology and other methods to evaluate the impact of chronic hypoxia exposure on cognitive function and the neuroprotective effect of Memantine., Key Findings: Our results showed that the expression of NMDA receptors increased, while the expression of AMPA receptors decreased, after 4 weeks of chronic hypoxia exposure. Concomitantly, apoptotic neuronal cell death in the hippocampus and frontal cortex was significantly increased, along with levels of oxidative stress, whereas innate ability to inhibit free radicals decreased. Moreover, after 8 weeks of hypoxia exposure, learning, memory, and space exploration abilities were significantly decreased. Notably, after treatment with memantine, apoptotic neuronal cell death, oxidative stress, and free radical levels decreased, and the cognitive function of the animals improved., Significance: Present study shows that chronic hypoxia can produce the excitatory toxicity leading to neural injury and cognitive impairment that can be suppressed with memantine treatment by inhibiting excitatory toxicity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

After loosening of travel restrictions due to the COVID-19 pandemic, tourism to high-altitude destinations over 2500 metres is expected to increase again.In line with this trend, it can be expected that patients after recovery from COVID-19 infection will seek advice from specialists on altitude or travel medicine before travelling to high altitudes.Here, the physician on altitude medicine is faced with major challenges, as such a question has not been raised so far.In addition to the basics of altitude sickness and high altitude pulmonary edema, this article deals with the current studies on pulmonological pathologies and disease course of COVID-19 infections and, in accordance with the current state of knowledge, provides recommendations for advice in altitude medicine for patients after COVID-19 infection., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Delamere, John P., Susie B. Bradwell, Christopher T. Lewis, Alex Clarke, and Arthur R. Bradwell. Losartan has no effect on high altitude diuresis or acute mountain sickness in well-acclimatizing individuals. High Alt Med Biol . 22:96-101, 2021. Introduction: The diuretic response that occurs on ascent to altitude is associated with suppression of aldosterone. We speculated that losartan, an angiotensin II receptor blocker, might further reduce aldosterone activity thereby enhancing the diuresis. Materials and Methods: Twenty subjects (paired for angiotensin converting enzyme genotypes [ II:ID:DD ] gender and age) were randomized, on a double-blind basis, to either daily losartan, 100 mg, or placebo. During 7 days of motorized ascent from 2,850 to 5,035 m, collections of 24-hour urine output were measured daily with samples taken for sodium (Na + ) and potassium (K + ) concentrations. In addition, measurements were made of blood gases and aldosterone concentrations. Results: During the main ascent, there were similar progressive increases in 24-hour urine volumes in placebo and losartan groups with no change in Na + or K + excretion. There were negative correlations between mean 24-hour urine volumes and PaO 2 ( r  = -0.97, p  < 0.03), and the diuretic response and acute mountain sickness scores at 5,053 m ( r  = -0.51, p  < 0.03). There were no significant changes in aldosterone concentrations measured at baseline and at our high point on day 6 within or between the losartan and placebo groups. Conclusion: The high altitude diuretic response was not increased by losartan indicating aldosterone activity was suppressed in individuals on placebo who were acclimatizing well to altitude.