A conjoint analysis of renal structure and omics characteristics reveal new insight to yak high-altitude hypoxia adaptation.

BACKGROUND: Yaks have unique adaptive mechanisms to the hypoxic environment, in which the kidney plays an important role. The aim of this study was to explore the histological changes of yak kidney at different altitudes and the metabolites and genes associated with adaptation to the hypoxic environment. METHODS: We analyzed the tissue structure and transcriptomic metabolomic data of yak kidney tissue at two altitudes, 2600 and 4400 m. We compared and identified the morphological adaptations of the kidney and the metabolites and genes associated with hypoxia adaptation in yaks. Changes in renal morphological adaptations, differential metabolites and genes were compared and identified, combining the two in a joint analysis. RESULTS: High-altitude yak kidneys showed significant adaptive changes: increased mitochondria, increased glomerular thylakoid area, and decreased localized ribosomes. Transcriptomics and metabolomics identified 69 DAMs (Differential metabolites) and 594 DEGs (differential genes). Functional enrichment analysis showed that the DAMs were associated with protein digestion and absorption, ABC transporter, and MTOR signaling pathway; the DEGs were significantly enriched in Cholesterol metabolism and P53 signaling pathway. The joint analysis indicated that metabolites such as lysine and arginine, as well as key genes such as ABCB5 and COL1A2, were particularly affected under hypoxic conditions, whereas changes in mitochondria in the tissue structure may be related to the expression of MFN1 and OPA1, and changes in glomerular thylakoid membranes are related to VEGFA and TGFB3. CONCLUSION: The kidney regulates metabolites and gene expression related to hormone synthesis, protein metabolism, and angiogenesis by adjusting the mitochondrial and glomerular thylakoid membrane structure to support the survival of yaks in high-altitude environments.

Role of neutrophil myeloperoxidase in the development and progression of high-altitude pulmonary edema.

BACKGROUND: Neutrophil infiltration and hypoxic pulmonary vasoconstriction induced by hypobaric hypoxic stress are vital in high-altitude pulmonary edema (HAPE). Myeloperoxidase (MPO), an important enzyme in neutrophils, is associated with inflammation and oxidative stress and is also involved in the regulation of nitric oxide synthase (NOS), an enzyme that catalyzes the production of the vasodilatory factor nitric oxide (NO). However, the role of neutrophil MPO in HAPE's progression is still uncertain. Therefore, we hypothesize that MPO is involved in the development of HAPE via NOS. METHODS: In Xining, China (altitude: 2260 m), C57BL/6 N wild-type and mpo-/- mice served as normoxic controls, while a hypobaric chamber simulated 7000 m altitude for hypoxia. L-NAME, a nitric oxide synthase (NOS) inhibitor to inhibit NO production, was the experimental drug, and D-NAME, without NOS inhibitory effects, was the control. After measuring pulmonary artery pressure (PAP), samples were collected and analyzed for blood neutrophils, oxidative stress, inflammation, vasoactive substances, pulmonary alveolar-capillary barrier permeability, and lung tissue morphology. RESULTS: Wild-type mice's lung injury scores, permeability, and neutrophil counts rose at 24 and 48 h of hypoxia exposure. Under hypoxia, PAP increased from 12.89 ± 1.51 mmHg under normoxia to 20.62 ± 3.33 mmHg significantly in wild-type mice and from 13.24 ± 0.79 mmHg to 16.50 ± 2.07 mmHg in mpo-/- mice. Consistent with PAP, inducible NOS activity, lung permeability, lung injury scores, oxidative stress response, and inflammation showed more significant increases in wild-type mice than in mpo-/- mice. Additionally, endothelial NOS activity and NO levels decreased more pronouncedly in wild-type mice than in mpo-/- mice. NOS inhibition during hypoxia led to more significant increases in PAP, permeability, and lung injury scores compared to the drug control group, especially in wild-type mice. CONCLUSION: MPO knockout reduces oxidative stress and inflammation to preserve alveolar-capillary barrier permeability and limits the decline in endothelial NOS activity to reduce PAP elevation during hypoxia. MPO inhibition emerges as a prospective therapeutic strategy for HAPE, offering avenues for precise interventions.

Protective effect of heme chloride on hypoxia-induced tissue injury in mice. / æ°¯åŒ–è¡€çº¢ç´ å¯¹ç¼ºæ°§å¯¼è‡´å°é¼ ç»„ç»‡æŸä¼¤çš„ä¿æŠ¤ä½œç”¨.

OBJECTIVES: Heme chloride (Hemin) is an in vitro purified form of natural heme and an important raw material for anti-anemia and antitumor drugs. This study aims to analyze the protective effect of Hemin on tissue damage in low-pressure oxygen chamber simulated plateau hypoxic mice, and explore its role in anti-plateau hypoxia. METHODS: Thirty male BALB/c mice were randomly divided into a blank group, a positive drug group (acetazolomide, 200 mg/kg), a Hemin low-dose group (15 mg/kg), a Hemin medium-dose group (30 mg/kg), and a Hemin high-dose group (60 mg/kg) with intraperitoneal injection. The anti-hypoxic activity of Hemin was explored by atmospheric closed hypoxia experiment and the optimal dose was screened. Thirty-six male BALB/c mice were randomly divided into a blank group, a hypoxia group, a positive drug group, and a Hemin high-dose group. The plasma inflammatory factor levels and oxidative stress indicators malondialdehyde (MDA), glutataione (GSH), and superoxide dismutase (SOD) levels of myocardium, brain, lung, and liver tissues were measured in different groups with hypoxia for 24 h. The degree of histopathological damage of mice was observed with HE staining. The degree of protection of Hemin against tissue hypoxia injury was detected with the hypoxia probe piperidazole. RESULTS: Compared with the blank group, the survival time of mice in the positive drug group, the Hemin medium-dose group, and high-dose group was significantly extended (all P<0.05), with the highest prolongation rate in the Hemin high-dose group. Compared with the hypoxia group, mice in the Hemin high-dose group showed a significant increase in SOD level and GSH content of brain tissue, and a significant decrease in MDA content of lung tissue (all P<0.05). The results of HE staining and hypoxia probe showed that Hemin had a significant protective effect on the damage of liver, heart, brain and lung tissues of mice with hypoxia, and the most obvious effect on that of the brain tissue. CONCLUSIONS: Hemin has an effect of improvement on oxidative stress and inflammatory response caused by hypoxia, and has obvious protective effect on tissue damage caused by hypoxia.

Effects of plateau hypoxia on pharmacokinetic parameters and cerebral-blood distribution of levetiracetam in rats. / é«˜åŽŸä½Žæ°§å¯¹å¤§é¼ å·¦ä¹™æ‹‰è¥¿å¦è¯ä»£åŠ¨åŠ›å­¦ç‰¹å¾åŠè„‘è¡€åˆ†å¸ƒçš„å½±å“.

OBJECTIVES: Plateau hypoxia exposure causes changes in pharmacokinetic parameters and cerebral-blood distribution of drugs, including many substrates of P-glycoprotein (P-gp). Levetiracetam, a kind of antiepileptic drugs, is a substrate of P-gp. Whether plateau hypoxia exposure changes its pharmacokinetic characteristics and cerebral-blood distribution remains unclear. This study aims to investigate the effects of plateau hypoxia on the pharmacokinetics and cerebra-blood distribution of levetiracetam. METHODS: Wistar rats were divided into a low-altitude control group, a high-altitude group, a solvent group, and a P-gp induction group. After 24 h of exposure at altitude of 4 010 m, rats in the high-altitude group were given levetiracetam orally or intravenously. The plasma was respectively collected at 0.083, 0.25, 0.5, 0.83, 1.25, 2, 4, 6, 8, 10, 12, and 24 h after oral administration of the drug, while both plasma and brain were respectively collected at 5, 45, 60,120 and 240 min after intravenous injection. After 3 days administration of dexamethasone, plasma and brain of rats in the P-gp induction group were collected at 120 min after intravenously giving levetiracetam. Plasma and brain concentrations of the drug were determined by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The expression of P-gp in blood-brain barrier was detected by Western blotting. RESULTS: Compared with the low-altitude control group, the area under the curve (AUC) and mean residence time (MRT) of levetiracetam were respectively decreased by 14.69% (P<0.01) and 15.42% (P<0.01), while the clearance (CL) was increased by 16.67% (P<0.01) in the high-altitude group. The ratio of brain/blood plasma drug concentration was decreased by 22.82% (P<0.05), 12.42% (P<0.05), 17.40% (P<0.01), and 13.22% (P<0.01) at 5, 45, 120, and 240 min after injection, respectively. The expression of P-gp on the blood-brain barrier was increased by 86.3% (P<0.05). Compared with the solvent control group, the expression of P-gp on the blood-brain barrier in the P-gp induction group was increased by 56.3% (P<0.05), the ratio of brain/blood plasma drug concentration was decreased by 19.3% (P<0.05). CONCLUSIONS: After acute plateau hypoxia exposure, the pharmacokinetic of levetiracetam in rats are altered, and the cerebral-blood distribution of the drug in rats is decreased, which may be related to the up-regulation of P-gp expression on the blood-brain barrier.

Medication rule of traditional Chinese medicine in the treatment of plateau hypoxia based on data mining. / 基于数据挖掘中药治疗高原性缺氧的组方规律.

OBJECTIVES: The development of traditional Chinese medicine (TCM) in the plateau area is relatively backward. There is a lack of system to analyze the effects of the special environment of plateau low pressure and hypoxia on human meridians qi and blood, as well as the etiology and pathogenesis of plateau hypoxic diseases. To analyze the composition rules of anti-hypoxia TCM formulation with data mining methods. METHODS: The experimental literatures related to high altitude hypoxia were searched in China National Knowledge Infrastructure (CNKI), Wanfang Med Online, VIP, China Biology Medicine disc and other databases, a standardized prescription database was established after screening and standardization of prescription data in the literature. The composition rules of these prescription including drug frequency, drug attributes, drug efficacy, drug combination, and core prescription were analyzed and displayed with visual charts. RESULTS: A total of 135 TCM prescriptions were included, and 229 flavored drugs were included. Among these prescriptions, the TCM with high frequency of use were Astragalus, Danshen, Ginseng, and Angelica, etc. Four natures of the TCM were mostly warm and calm. Five flavours of the TCM were mostly sweet, bitter, and pungent. And channel tropism of the TCM mostly entered the heart, lung, and liver meridians. The frequency combination of TCM was Astragalus-Danshen and Astragalus-Angelica. The core medicines of these prescriptions were Astragalus, Danshen, Angelica, Rhodiola, Goji, and Ginseng. TCM could alleviate symptoms such as chest tightness, chest pain, coughing and wheezing, coughing, vomiting, fatigue, and loss of appetite caused by hypoxia at high altitude. CONCLUSIONS: Through data mining, it is concluded that the prevention or treatment of plateau hypoxic diseases mostly utilized products can nourish blood, replenish qi and dispel stasis, and help yang and dispel qi, most of them are compatible with qi tonic drugs and blood circulation and stasis dissolving drugs, and pay attention to the combination of virtual and real, yin and yang.

Effects of plateau hypoxia on population pharmacokinetics and pharmacodynamics of metformin in patients with Type 2 diabetes. / 高原低氧对2åž‹ç³–å°¿ç— æ‚£è€ äºŒç”²åŒèƒç¾¤ä½“è¯åŠ¨å­¦å’Œè¯æ•ˆå­¦çš„å½±å“ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM). METHODS: A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups. RESULTS: The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T1/2), area under the curve (AUC), time to reach maximum concentration (Tmax). Compared with the control group, AUC was increased by 23.5%, Tmax and T1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population. CONCLUSIONS: Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.

A Multimodal MR Imaging Study of the Effect of Hippocampal Damage on Affective and Cognitive Functions in a Rat Model of Chronic Exposure to a Plateau Environment.

Prolonged exposure to high altitudes above 2500 m above sea level (a.s.l.) can cause cognitive and behavioral dysfunctions. Herein, we sought to investigate the effects of chronic exposure to plateau hypoxia on the hippocampus in a rat model by using voxel-based morphometry, creatine chemical exchange saturation transfer (CrCEST) and dynamic contrast-enhanced MR imaging techniques. 58 healthy 4-week-old male rats were randomized into plateau hypoxia rats (H group) as the experimental group and plain rats (P group) as the control group. H group rats were transported from Chengdu (500 m a.s.l.), a city in a plateau located in southwestern China, to the Qinghai-Tibet Plateau (4250 m a.s.l.), Yushu, China, and then fed for 8 months there, while P group rats were fed in Chengdu (500 m a.s.l.), China. After 8 months of exposure to plateau hypoxia, open-field and elevated plus maze tests revealed that the anxiety-like behavior of the H group rats was more serious than that of the P group rats, and the Morris water maze test revealed impaired spatial memory function in the H group rats. Multimodal MR imaging analysis revealed a decreased volume of the regional gray matter, lower CrCEST contrast and higher transport coefficient Ktrans in the hippocampus compared with the P group rats. Further correlation analysis found associations of quantitative MRI parameters of the hippocampus with the behavioral performance of H group rats. In this study, we validated the viability of using noninvasive multimodal MR imaging techniques to evaluate the effects of chronic exposure to a plateau hypoxic environment on the hippocampus.

Aldehyde dehydrogenase 2 serves as a key cardiometabolic adaptation regulator in response to plateau hypoxia in mice.

High-altitude heart disease (HAHD) is a complex pathophysiological condition related to systemic hypobaric hypoxia in response to transitioning to high altitude. Hypoxia can cause myocardial metabolic dysregulation, leading to an increased risk of heart failure and sudden cardiac death. Aldehyde dehydrogenase 2 (ALDH2) could regulate myocardial energy metabolism and plays a protective role in various cardiovascular diseases. This study aims to determine the effects of plateau hypoxia (PH) on cardiac metabolism and function, investigate the associated role of ALDH2, and explore potential therapeutic targets. We discovered that PH significantly reduced survival rate and cardiac function. These effects were exacerbated by ALDH2 deficiency. PH also caused a shift in the myocardial fuel source from fatty acids to glucose; ALDH2 deficiency impaired this adaptive metabolic shift. Untargeted/targeted metabolomics and transmission electron microscopy revealed that ALDH2 deficiency promoted myocardial fatty-acid deposition, leading to enhanced fatty-acid transport, lipotoxicity and mitochondrial dysfunction. Furthermore, results showed that ALDH2 attenuated PH-induced impairment of adaptive metabolic programs through 4-HNE/CPT1 signaling, and the CPT1 inhibitor etomoxir significantly ameliorated ALDH2 deficiency-induced cardiac impairment and improved survival in PH mice. Together, our data reveal ALDH2 acts as a key cardiometabolic adaptation regulator in response to PH. CPT1 inhibitor, etomoxir, may attenuate ALDH2 deficiency-induced effects and improved cardiac function in response to PH.

[Effects of three Polyphenolic compounds on the intestinal flora of mice exposed simulated intermittent plateau hypoxia].

OBJECTIVE: To investigate the protective effects of three Polyphenolic compounds on intestinal microbial communities in mice exposed intermittent plateau hypoxia. METHODS: In this study, 60 healthy male Balb/c mice were randomly divided into plain control group, plateau control group, primary anthocyanin intervention group, quercetin intervention group and resveratrol intervention group, 12 mice in each group. Primary anthocyanin, quercetin and resveratrol were administrated by gavage at the doses of 50, 100 and 20 mg/kg in pharmacological intervention group, respectively. After exposure of the mice to simulation plateau-condition for 30 days, the serum samples were collected for DAO testing, sterile feces were collected in mice, and the diversity and genus level of the mouse gut bacteria were detected by using 16S rRNA technology. Ileum tissue was fixed and stained with HE. RESULTS: HE staining showed that the plateau control group had significant damage to the intestinal tissue structure compared to the plain control group, and the serum DAO concentration was increased (P＜0.05), but there was no statistical difference in the abundance and diversity of intestinal flora species. Contrast to simulated intermittent plateau hypoxia group, the structure of the intestine tissue and the level of DAO in the quercetin intervention group and resveratrol intervention group were improved(P＜0.05), the abundance and α diversity of the intestinal flora were decreased, the relative abundance of Bacteroidetes was reduced(P＜0.05), and the Firmicutes was increased. Concomitantly, significant decreases in relative abundance were observed for Corynebacterium glutamicum and Lactobacillus reuteri(P＜ 0.05). CONCLUSION: Quercetin and resveratrol showed some degree of protection to mice intestinal microbial communities, and increased the diversity and the abundance of the dominant flora and inhibited the growth of conditional pathogenic bacteria.

Research progress on the mechanism of cerebral blood flow regulation in hypoxia environment at plateau.

The plateau is a special environment with low air pressure and low oxygen content. The average altitude of Qinghai-Tibet is 3,500 m, and the atmospheric oxygen partial pressure in most areas is lower than 60% of that at sea level. In order to adapt to the plateau low-oxygen environment, the human body has developed corresponding physiological structure and functions adjust. In the present review, the regulation mechanism of cerebral blood flow (CBF) under high-altitude environments was elaborated in eight aspects: the arterial blood gas, endogenous substances in the nerve and blood, the cerebral neovascularization, the hematocrit, cerebral auto-regulation mechanism, cerebrovascular reactivity, pulmonary vasoconstriction, and sympathetic automatic regulation, aiming to further explore the characteristics of changes in brain tissue and cerebral blood flow in a hypoxic environment.

Same total normal forms sperm counts of males from Lhasa and Shanghai, China.

Male infertility may be caused by genetic and/or environmental factors that impair spermatogenesis and sperm maturation. High-altitude (HA) hypoxic environments represent one of the most serious challenges faced by humans that reside in these areas. To assess the influence of the plateau environment on semen parameters, 2,798 males, including 1,111 native Tibetans and 1,687 Han Chinese individuals living in the plains (HCILP) who underwent pre-pregnancy checkups, were enrolled in this study. The semen samples of males were evaluated to determine conventional sperm parameters, sperm morphology, and sperm movement. Reproductive endocrine hormones (REHs) were detected in 474 males, including 221 Tibetans and 253 HCILP. Due to recurrent abortions in partners, the DNA fragmentation index (DFI) of 133 native Tibetans and 393 HCILP individuals was further compared. Luteinizing hormone (LH) (4.94 ± 2.12 vs. 3.29 ± 1.43 U/L), prolactin (11.34 ± 3.87 vs. 8.97 ± 3.48 nmol/L), E2/T (0.22 ± 0.11 vs 0.11 ± 0.05), median total sperm motility (61.20% vs. 51.56%), and DFI (23.11% vs. 7.22%) were higher in males from plateau areas while median progressive motility (PR) (35.60% vs. 41.12%), total number of PR sperms (51.61 vs. 59.63 mil/ejaculate), percentage of normal form sperms (3.70% vs. 6.00%), curvilinear velocity (36.10 vs. 48.97 µm/s), straight-line (rectilinear) velocity (14.70 vs. 31.52 µm/s), estradiol (103.82 ± 45.92 vs. 146.01 ± 39.73 pmol/L), progesterone (0.29 ± 0.27 vs. 2.22 ± 0.84 nmol/L), testosterone (4.90 ± 1.96 vs. 14.36 ± 5.24 nmol/L), and testosterone secretion index (ratio of testosterone to LH) (33.45 ± 22.86 vs 145.78 ± 73.41) were lower than those in males from the plains. There was no difference in median total sperm number (157.76 vs. 151.65 mil/mL), sperm concentration (52.40 vs. 51.79 mil/mL), volume (3.10 vs. 3.10 mL), total normal form sperms (5.91 vs. 6.58 mil/ejaculate, p50), and follicle-stimulating hormone (FSH) levels (4.13 ± 2.55 U/L vs 3.82 ± 2.35 U/L) between the two groups of males. The REH and sperm parameters of males from HA hypoxic environments were adaptively altered. Although the total number of PR sperm decreased and DFI increased, the Tibetan population that lives at HAs has been found to grown continuously and rapidly. These results supplement prior findings regarding the impact of HA on male reproductive function.

Modulation of thalamic network connectivity using transcranial direct current stimulation based on resting-state functional magnetic resonance imaging to improve hypoxia-induced cognitive impairments.

Hypoxic conditions at high altitudes severely affect cognitive functions such as vigilance, attention, and memory and reduce cognitive ability. Hence, there is a critical need to investigate methods and associated mechanisms for improving the cognitive ability of workers at high altitudes. This study aimed to use transcranial direct current stimulation (tDCS) to modulate thalamic network functional connectivity to enhance cognitive ability. We recruited 20 healthy participants that underwent hypoxia exposure in a hypoxic chamber at atmospheric pressure to simulate a hypoxic environment at 4,000 m. Participants received both sham and real stimulation. tDCS significantly improved the participants' emotional status, including depression, fatigue, and energy level. These effects were sustained for more than 6 h (P < 0.05 at the second to fifth measurements). In addition, tDCS enhanced vigilance, but this was only effective within 2 h (P < 0.05 at the second and third measurements). Central fatigue was significantly ameliorated, and cerebral blood oxygen saturation was increased within 4 h (P < 0.05 at the second, third, and fourth measurements). Furthermore, functional connectivity results using the thalamus as a seed revealed enhanced connectivity between the thalamus and hippocampus, cingulate gyrus, and amygdala after tDCS. These results indicated that tDCS increased local cerebral blood oxygen saturation and enhanced thalamic network connectivity in a hypoxic environment, thereby improving vigilance, depression, fatigue, and energy levels. These findings suggest that tDCS may partially rescue the cognitive decline caused by hypoxia within a short period. This approach affords a safe and effective cognitive enhancement method for all types of high-altitude workers with a large mental load.

Gene Expression Profile Reveals Hematopoietic-Related Molecule Changes in Response to Hypoxic Exposure.

The Qing-Tibet Plateau is characterized by low oxygen pressure, which is an important biomedical and ecological stressor. However, the variation in gene expression during periods of stay on the plateau has not been well studied. We recruited eight volunteers to stay on the plateau for 3, 7, and 30 days. Human Clariom D arrays were used to measure transcriptome changes in the mRNA expression profiles in these volunteers' blood. Analysis of variance (ANOVA) indicated that 699 genes were significantly differentially expressed in response to entering the plateau during hypoxic exposure. The genes with changes in transcript abundance were involved in the terms phosphoprotein, acetylation, protein binding, and protein transport. Furthermore, numerous genes involved in hematopoietic functions, including erythropoiesis and immunoregulation, were differentially expressed in response to hypoxia. This phenomenon may be one of reasons why the majority of people entering the plateau do not have excessive erythrocyte proliferation and are susceptible to infection.

NOD-like receptors mediate inflammatory lung injury during plateau hypoxia exposure.

BACKGROUND: The lung is an important target organ for hypoxia treatment, and hypoxia can induce several diseases in the body. METHODS: We performed transcriptome sequencing for the lungs of rats exposed to plateau hypoxia at 0 day and 28 days. Sequencing libraries were constructed, and enrichment analysis of the differentially expressed genes (DEGs) was implemented using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, experimental validation was executed by quantitative real-time PCR (qRT-PCR) and western blot. RESULTS: The results showed that the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) signaling pathway that was involved in immunity may play a crucial function in lung injury caused by plateau hypoxia. And the expressions of NOD1, NOD2, IL-1ß, TNF-α, IL-6, and IL-18 were higher at 28 days of exposure to plateau hypoxia than that at 0 day. Similarly, CARD9, MYD88, p38 MAPK, and NF-κB p65, which are related to the NF-κB and MAPK signaling pathways, also demonstrated increased expression at 28 days exposure to plateau hypoxia than at 0 day. CONCLUSIONS: Our study suggested that the NF-κBp65 and p38 MAPK signaling pathways may be activated in the lungs of rats during plateau hypoxia. Upregulated expression of NF-κBp65 and p38 MAPK can promote the transcription of downstream inflammatory factors, thereby aggravating the occurrence and development of lung tissue remodeling.

Enhanced P-glycoprotein expression under high-altitude hypoxia contributes to increased phenytoin levels and reduced clearance in rats.

To study the effect of plateau hypoxia on the concentration of P-glycoprotein (P-gp) substrate phenytoin, Wistar rats are randomly divided into the control group and the hypoxic group, including P-gp inhibited groups respectively. Blood, cerebrospinal fluid, brain tissue, and blood-brain barrier were collected in plain areas at an altitude of 1500 m and plateau areas at an altitude of 4010 m. Evans Blue exclusion was used to assess the integrity of the blood-brain barrier. Western blot and qPCR were used to detect changes in P-gp expression. LC-MS/MS was used to determine the concentration of phenytoin in plasma and cerebrospinal fluid. In the high-altitude plateau group, phenytoin AUC0-t, MRT0-t and t1/2 increased significantly by 60%, 48%, and 61%, respectively, and clearance decreased by 67% (p <0.05 for all parameter). The protein expression of P-gp in the blood-brain barrier of the plateau group was up-regulated 1.84 times and the gene expression was up-regulated 2.21 times. The concentrations of phenytoin in the CSF of rats in the plain and high-altitude groups were 864.7 ± 348.3 and 1000±273.9 ng•mL-1, respectively. However, after inhibiting P-gp, the concentration of phenytoin in the CSF decreased significantly. It indicates that the increased expression of P-gp on the blood-brain barrier may lead to an increase in the amount of phenytoin excreted from the blood into the CSF, which may cause neurotoxic side effects. These results demonstrate significant changes in the pharmacokinetics of phenytoin under hypoxic conditions, supporting the need for careful dose titration for drugs with a narrow therapeutic range under high-altitude conditions.

Effects of Gut Microbiota on Drug Metabolism and Guidance for Rational Drug Use Under Hypoxic Conditions at High Altitudes.

BACKGROUND: Modern features of drug development such as low permeability, low solubility, and improved release affect the interplay of the gut microbiota and drug metabolism. In recent years, studies have established the impact of plateau hypoxia on gut microbiota, where drug use by plateau populations is affected by hypoxia- induced changes in intestinal microflora-mediated drug metabolism. METHODS: In this review, we summarized the effects of gut microbiota on drug metabolism, and of plateau hypoxia on the intestinal flora, with the aim of providing guidance for the rational use of drugs in high-altitude populations. RESULTS: The evidence clearly shows that alterations in gut microbiota can affect pro-drug activation, drug inactivation, and the biotransformation of xenobiotics. Additionally, plateau hypoxia alters drug metabolism by affecting intestinal flora. CONCLUSION: This review provides an overview of the effects of gut microbiota on drug metabolism and provides guidance for rational drug use under hypoxic conditions at high altitudes.

Plateau hypoxia attenuates the metabolic activity of intestinal flora to enhance the bioavailability of nifedipine.

Nifedipine is completely absorbed by the gastrointestinal tract and its pharmacokinetics and metabolism may be influenced by microorganisms. If gut microbes are involved in the metabolism of nifedipine, plateau hypoxia may regulate the bioavailability and the therapeutic effect of nifedipine by altering the metabolic activity of the gut microbiota. We herein demonstrated for the first time that gut flora is involved in the metabolism of nifedipine by in vitro experiments. In addition, based on the results of 16S rRNA analysis of feces in rats after acute plateau, we first confirmed that the plateau environment could cause changes in the number and composition of intestinal microbes. More importantly, these changes in flora could lead to a slower metabolic activity of nifedipine in the body after an acute plateau, resulting in increased bioavailability and therapeutic efficacy of nifedipine. Our research will provide basis and new ideas for changes in the fecal flora of human acutely entering the plateau, and contribute to rational drug use of nifedipine.