High altitude medicine & biology最新文献

Zhang, Wenxin, Yuting Yang, Jing Guo, Fei Hu, Yuan Ma, and Qing Ouyang. Phenothiazine confers neuroprotection via Dpp2/7 in high altitude traumatic brain injury mouse model. High Alt Med Biol. 26:256-264, 2025. Background: Traumatic brain injury (TBI) in high altitude areas can lead to more severe cerebral edema, higher disability, and mortality than in low altitude areas. This study was designed to evaluate the neuroprotective effects and underlying mechanisms of phenothiazine on TBI at high altitudes. Methods: Mice were kept in a hypobaric chamber for 7 days under simulated conditions of 5,000 m above sea level. A controlled cortical impact (CCI) model was established and followed by phenothiazine (chlorpromazine and promethazine) and Dpp2/7 inhibitor UAMC00039 treatment. Hematoxylin-eosin (HE) staining, immunohistochemistry (IHC), western blot, label-free quantitative proteomics, and real-time quantitative polymerase chain reaction (RT-qPCR) assays were performed to assess the effects of phenothiazine and UAMC00039 on TBI. Results: HE staining confirmed that phenothiazine treatment could ameliorate CCI-induced brain injury. IHC, western blot, and RT-qPCR showed that cell apoptosis was alleviated by phenothiazine after high altitude TBI, as proved by the reduction of cleaved-Caspase-3 and increased Bcl-2 expression. Label-free quantitative proteomics, IHC, and western blot showed that phenothiazine significantly upregulated Dpp2/7 after high altitude TBI. Western blot and IHC showed that UAMC00039 treatment significantly reversed phenothiazine-mediated Bcl-2 upregulation and cleaved-Caspase-3 downregulation after high altitude TBI. Conclusions: The results indicated that phenothiazine offers neuroprotective effects via antiapoptosis after high altitude TBI, and this protective mechanism is associated with Dpp2/7-mediated Bcl-2 expression and Caspase-3 cleaving.

Tian, Lu, Guiqin Liu, Qin Zhao, Junjun Han, Yue Lin, Qian Wang, Qiangqiang Jia, Delong Duo, Duan Yabin, Zhu Junbo, and Li Xiangyang. Pharmacokinetics of midazolam in plasma and brain tissue of rats after exposure to acute and chronic high altitude hypoxia. High Alt Med Biol. 26:273-282, 2025. Background: Midazolam effectively improves sleep quality under high altitude hypoxia by reducing central nervous system excitability. Methods: Field modeling and sample collection were performed at an altitude of 4,300 m in a high altitude hypoxic environment with a pressure of inspired oxygen of 107 mmHg. Pharmacokinetic alterations of midazolam in high altitude hypoxic rats are determined by high performance liquid chromatography-mass spectrometry. Quantitative real-time polymerase chain reaction and Western blot were used to confirm the connection with drug metabolism and alterations in hypoxia CYP3A4 and P-glycoprotein (P-gp) expression. Results: This study demonstrated that high altitude hypoxia increased blood-brain barrier permeability in rats, caused brain tissue damage, and altered the expression of inflammatory cytokines in the brain. In the acute high altitude group and the chronic high altitude group, the area under the curve and T_max of plasma midazolam revealed substantial increases of 88.6% and 283% and 28.6% and 85.3%, respectively. The clearance rate reduced by 47.3% and 90.0%, while the brain-blood drug concentration ratio (C_brain/C_plasma) diminished by 11.4% and 82.1%, respectively. The relative expression of CYP3A1 mRNA in the brain tissue of high altitude rats decreased by 42.4% and 66.8%, respectively, and the protein expression was downregulated, while the relative expression of P-gp mRNA increased by 61.3% and 91.2%, respectively (p < 0.05 for all parameters), and the protein expression was upregulated. High altitude hypoxia altered CYP3A1 and P-gp expression and activity, causing alterations in midazolam metabolism. Conclusions: This research provided a new reference for the rational use of midazolam in highland areas.

Epçaçan, Serdar, Emrah Şişli, Yasemin Nuran Dönmez, and Şeyma Memur. The course of ductus arteriosus from the neonatal period to childhood in a moderate altitude region. High Alt Med Biol. 26:283-290, 2025. Aim: The aim of the study is to evaluate the course of patent ductus arteriosus (PDA) in a moderate altitude region. Study Design: This is a retrospectively designed cross-sectional study analyzing the neonates diagnosed with PDA. Methods: Demographic and clinical data and echocardiographic, interventional, and surgical files of the subjects and follow-up findings were analyzed. Results: Overall, the mean gestational age and weight at delivery for all 711 patients were 35.7 ± 3.1 weeks (24-44 weeks) and 2712 ± 762 g (570-4,900 g). In total, 330 patients were premature. Medical closure was applied in 95/597 patients and was successful in 40 of 95 patients. The spontaneous closure rate within 2.3  ±  2.8 months (4 days-2.1 years) was 616/711 (86.6%). Overall, only 8 patients necessitated surgical PDA closure and 38 patients for transcatheter closure. Gestational age and delivery weight had a considerable influence on spontaneous closure. The duration of spontaneous PDA closure was negatively correlated with the gestational age and gestational weight. The duration of spontaneous PDA closure was higher in patients with prematurity and hypothyroidism. Conclusions: The spontaneous closure of the duct may be prolonged in moderate and high-altitude areas. Transcatheter or surgical interventions are rarely needed in the early neonatal period.

Ge, Ri-Li. Medical problems of chronic hypoxia in highlanders living on the tibetan plateau. High Alt Med Biol. 26:308-317, 2025.-Health issues at high altitudes arise due to the lower atmospheric pressure and subsequent reduction in the partial pressure of oxygen in ambient air. While much research has been published on health problems of lowlanders who move to high altitudes, less is known about the medical challenges faced by long-term and permanent high-altitude residents, especially in the Qinghai-Tibetan plateau. In this review, we briefly summarized the chronic hypoxia-related health issues in highlanders, focusing on the specific population of the Qinghai-Tibetan plateau. It deals with important health problems for highlanders, including the main disease categories, from chronic mountain sicknesses and pulmonary hypertension (PH) to kidney, neurocognitive impairments, perinatal problems, and congenital heart defect. However, the most hallmark of disorders is excessive erythrocytosis associated with specific symptoms and signs, and high-altitude heart disease is characterized by excessive PH, right ventricular hypertrophy, and right heart failure. We also provide information on potential treatment strategies, including some traditional Tibetan medical practices and also a combination of Western medicine and traditional Chinese medicine to prevent and treat these conditions effectively. This mini-review is heavily based on a couple of decades of research carried out by Chinese high-altitude medical research groups at the Qinghai-Tibetan Plateau. We believe that this review will provide valuable perspective to researchers whose study interest and base lie in high altitude.

Guo, Yan, Chao Yu, Zhongsheng Lu, Menglan Zhang, Qiang Zhang, and Xiao Liu. Zinc homeostasis plays important roles in hypoxia tolerance: a study conducted clinically and in vitro. High Alt Med Biol. 26:242-255, 2025. Objective: High-altitude environments pose significant challenges to human physiology due to reduced oxygen availability, often resulting in altitude-related illnesses such as high-altitude cerebral edema (HACE). This study focuses on understanding the role of zinc homeostasis in enhancing hypoxia tolerance, which may be pivotal in mitigating the adverse effects of such illnesses. Methods: The study involved healthy individuals from high-altitude (4,500-5,000 m) and low-altitude areas (0-200 m), as well as patients with HACE. Blood samples were collected and analyzed. Additionally, a hypoxic model was developed using human brain microvascular endothelial cells (HBMECs), and zinc intervention was implemented. Results: In the blood samples of patients with HACE and those of healthy individuals, there were over 4,000 differentially expressed genes (DEGs), with more than 300 of them linked to zinc. Among these zinc-associated genes, only carbonic anhydrase I (CA1) exhibited a substantial upregulation in expression, while the expression of others was notably downregulated. Compared with the high-altitude group, hemoglobin (Hb) (14.7 vs. 19.5 g/dl) and plasma zinc (37.0 vs. 94.0 mmol/dl) were lower in HACE, while CA1 (55.4 vs. 8.6 g/l) was elevated (p < 0.01). In vitro studies confirmed that exposure to hypoxia (O₂ 8%-8.5%, 24 hours) inhibited HBMECs proliferation and migration, increased apoptosis and necrosis, and led to abnormal expression of CA1 and various zinc transport proteins. However, zinc intervention (6 μM, 24 hours) significantly mitigated these adverse effects and improved the cell's ability to tolerate hypoxia. Conclusion: Zinc homeostasis was crucial for hypoxia tolerance. Proper zinc supplementation could potentially alleviate symptoms associated with hypoxia intolerance, such as altitude sickness, but further confirmation was needed.

Yin, Jiaojiao, Yuhang Wang, Bing Li, Xiaoyan Hu, Yao Ma, Chong Zhang, Xiaoqin Ha, Linyan Wang, and Yaozhu Pan. Hypobaric hypoxia increased autophagy and apoptosis in PC12 rat pheochromocytoma cells more than normobaric hypoxia. High Alt Med Biol. 26:301-307, 2025. Purpose: Currently, in vitro studies have focused on hypoxia injury in acute mountain sickness (AMS), but little effort has been made to assess the effects of hypobaric hypoxia. AMS is a neurological disorder, and rat pheochromocytoma (PC12) cells are a model to study neuronal survival and apoptosis. Here, we developed a novel cell culture method that mimics hypobaric hypoxia at high attitude and compared the effects of hypobaric hypoxia and normobaric hypoxia on autophagy and apoptosis of PC12 cells. Methods: PC12 cells were cultured under normal conditions, normobaric hypoxia, and hypobaric hypoxia. Autophagy was observed by transmission electron microscopy and immunofluorescence microscopy. The hypoxia-inducible factor1-α (HIF1-α), LC3, caspase-3, and cleaved caspase-3 expression levels were determined by Western blot. Results: The cell culture chamber mimicking hypobaric hypoxia at high attitude perfectly maintained the air pressure at 41.1 kPa and the oxygen density at 1% (PO₂ around 3.08 mmHg). Hypobaric hypoxic treatment of PC12 cells at 0, 4, 8, 16, 24, and 48 hours resulted in an increase in HIF1-α and LC3Ⅱ protein levels, and the ratio of HIF1-α/actin and LC3Ⅱ/actin both peaked at 16 hours (p < 0. 01) when the cell viability was 88.02%. There was a 1.5-fold increase in LC3Ⅱ expression, a 2-fold increase in LC3B-positive spots, and an increase in autophagosome accumulation at hypobaric hypoxia compared to PC12 cells at normobaric hypoxia for 16 hours (p < 0.001). Interestingly, the promotion of autophagy (coculture with rapamycin or 3-MA) in PC12 cells under normobaric hypoxia reduced cleaved caspase-3 expression (the ratio of cleaved caspase-3/caspase-3 decreased, p < 0.01). However, under hypobaric hypoxia, the promotion of autophagy inversely increased cleaved caspase-3 (the ratio of cleaved caspase-3/caspase-3 increased, p < 0.01), and the inhibition of autophagy (hydroxychloroquine [HCQ] coculture) decreased cleaved caspase-3 (the ratio of cleaved caspase-3/caspase-3 decreased, p < 0.01). Conclusions: Compared with normobaric hypoxia cells, hypobaric hypoxia cells cultured in vitro exhibited increased autophagy and apoptosis.

Adams, Edmund and Tamlyn Peel. Chronic mountain sickness: A comprehensive review of current management and proposals for novel therapies. High Alt Med Biol. 26:318-327, 2025.-Chronic mountain sickness (CMS) is an acquired condition affecting 5%-10% of high-altitude residents. Lifelong exposure to chronic hypoxia triggers excessive erythrocytosis, resulting in an expanded hematocrit. Patients present with symptoms such as dyspnea, fatigue, and palpitations. Complications such as pulmonary hypertension and heart failure are often fatal. Relocation to sea level remains the only definitive management of CMS but poses an unacceptable personal burden. Long-term oxygen therapy provides symptomatic relief, but dependency issues remain a concern. Phlebotomy reduces hematocrit and offers short-term symptom relief. However, side effects and cultural conflicts continue to pose challenges. Acetazolamide, enalapril, and medroxyprogesterone have lowered hematocrit and alleviated symptoms in human trials. Further research into systemic side effects, application in women, and long-term use is required. Methylxanthines, adrenergic blockers, almitrine, and dopamine antagonists showed promise in murine and/or short-term human trials, highlighting the need for further long-term human trials. Inhibition of hypoxia-inducible factor and Janus Kinase-signal transducer and activator of transcription pathways is currently used to suppress hematocrit in polycythemia vera, demonstrating potential application in CMS. Topiramate may stimulate ventilation via acid-base modulation, thus providing therapeutic value. Similarly, the effect of aspirin and caffeine on ventilation may provide a low-cost, accessible intervention.

McLaughlin, Kyle, Steve Roy, Marika Falla, Giacomo Strapazzon, Andrew M. Luks, Ken Zafren, Hermann Brugger, Martin Musi, Iztok Tomazin, John Ellerton, Ghan Bahadur Thapa, and Peter Paal. Pharmacological prophylaxis and supplemental oxygen for unacclimatized rescuers at very high altitude: scoping review and 2025 joint recommendations of the International Commission for Mountain Emergency Medicine and the International Society for Mountain Medicine. High Alt Med Biol. 00:00-00, 2025. Background: Mountain rescuers and pilots rapidly ascending to altitudes above 3,500 m are exposed to the detrimental effects of hypobaric hypoxia, including cognitive and physical impairment, as well as high-altitude illness (HAI). We conducted a scoping review of oxygen supplementation and pharmacologic measures to improve cognitive and physical performance and prevent HAI in unacclimatized rescuers rapidly ascending above 3,500 m during rescue missions. Methods: Following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, 723 articles were screened, 133 reviewed and a total of 50 articles were included for data extraction, based on the intervention: 6 on oxygen, 29 on acetazolamide (AZ), 17 on dexamethasone (DEX), 3 on nifedipine, and 5 on phosphodiesterase-5 inhibitors. Discussion: Supplemental oxygen improves physical and cognitive performance at high altitude and is recommended for rapid ascent rescues >30 minutes between 3,500 and 4,000 m, and for rescues of any duration above 4,000 m. If oxygen is administered, pharmacological prophylaxis is not required. If oxygen is unavailable, AZ or DEX can be used for rapid ascent rescues above 3,500 m for longer than 3 hours to reduce the incidence and severity of acute mountain sickness. At altitudes above 5,000 m or for rescues requiring prolonged physical work, the use of both AZ and DEX is recommended. Conclusions: To enhance the safety and effectiveness of high-altitude rescues, we provide recommendations for the use of supplemental oxygen and pharmacologic prophylaxis to reduce the risk of HAI and improve cognitive and physical performance during rapid ascents to altitudes >3,500 m.