Research on stem cell therapy for spinal cord injury: a bibliometric and visual analysis from 2018-2023.

Objectives: The aim of this study was to conduct a bibliometric analysis of the literature on stem cell treatment for spinal cord injury to gain an intuitive understanding of how the field is progressing, discover topics of interest, and determine what development trends are emerging in this field. Background: Spinal cord injury and its complications often cause an enormous economic burden, and postinjury repair and treatment have always been challenging in clinical and scientific research. Stem cell therapy for spinal cord injury can prevent immune rejection and induce the release of neuroprotective and anti-inflammatory factors to reduce the production of stress-related proteins, reactive oxygen species, and inflammatory reactions. Methods: We analyzed the number and quality of publications in the field of stem cell therapy in spinal cord injury between 2018.01.01 and 2023.06.30 in the core collection database of Web of Science. CiteSpace and VOSviewer were used to sort and summarize these studies by country, institution, authors' publications, and collaborative networks. In addition, the research topics of interest were identified and summarized. Results: This study ultimately included 2,150 valid papers, with the number of publications showing a gradual upward trend. The country, institution, author and journal with the greatest number of publications and citations are China, the Chinese Academy of Sciences, Dai JW, and the International Journal of Molecular Sciences, respectively. The top three high-frequency keyword clusters were hereditary paraplegia, reactive astrocytes and tissue engineering. Conclusion: With the help of visual analysis, we identified general trends and research topics of interest in the field of spinal cord injury over the last 5 years. Our findings suggest that stem cell transplantation for spinal cord injury and exosome therapy may be a focus of future research. This study provides a foundation for future research on stem cell therapy as well as clinical efforts in this field.

The Role of the Notch Signaling Pathway in the Differentiation of Human Umbilical Cord-Derived Mesenchymal Stem Cells.

Human umbilical cord mesenchymal stem cells (hUCMSCs) exhibit potent self-renewal and multilineage differentiation characteristics. They have garnered substantial attention within the domain of regenerative medicine owing to their therapeutic potential, such as in tissue repair, regeneration, immunomodulation, anti-inflammation, angiogenesis, wound healing, neuroprotection, and neuroregeneration. The process of fate determination is initiated by multiple signaling molecules. During development and tissue homeostasis, the Notch signaling pathway assumes a pivotal function in cell differentiation and the renewal of stem cells. A growing body of research has revealed that the Notch signaling pathwayplays a pivotal role in hUCMSC proliferation and differentiation. The latest progress concerning the crucial functions of the Notch signaling pathway in maintaining homeostasis and determining the cell fate of hUCMSCs is summarized. Furthermore, the authors also summarized the mediators related to the Notch signaling pathway in hUCMSC differentiation, as well as the pathway alterations and mechanisms involved in hUCMSC therapy.

Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1.

PD-1 is a co-inhibitory receptor expressed by CD8+ T cells which limits their cytotoxicity. PD-L1 expression on cancer cells contributes to immune evasion by cancers, thus, understanding the mechanisms that regulate PD-L1 protein levels in cancers is important. Here we identify tumor-cell-expressed otubain-2 (OTUB2) as a negative regulator of antitumor immunity, acting through the PD-1/PD-L1 axis in various human cancers. Mechanistically, OTUB2 directly interacts with PD-L1 to disrupt the ubiquitination and degradation of PD-L1 in the endoplasmic reticulum. Genetic deletion of OTUB2 markedly decreases the expression of PD-L1 proteins on the tumor cell surface, resulting in increased tumor cell sensitivity to CD8+ T-cell-mediated cytotoxicity. To underscore relevance in human patients, we observe a significant correlation between OTUB2 expression and PD-L1 abundance in human non-small cell lung cancer. An inhibitor of OTUB2, interfering with its deubiquitinase activity without disrupting the OTUB2-PD-L1 interaction, successfully reduces PD-L1 expression in tumor cells and suppressed tumor growth. Together, these results reveal the roles of OTUB2 in PD-L1 regulation and tumor evasion and lays down the proof of principle for OTUB2 targeting as therapeutic strategy for cancer treatment.

Overexpression of NtDOGL4 improves cadmium tolerance through abscisic acid signaling pathway in tobacco.

The DELAY OF GERMINATION1-LIKE (DOGL) genes play an essential role in diverse biological processes in plants. However, their exact involvement in the response to cadmium (Cd) stress via the ABA pathway remains unclear. Here, we focused on NtDOGL4, a tobacco DOGL gene whose expression is highly induced upon exposure to Cd. Overexpression of NtDOGL4 in tobacco resulted in elevated endogenous ABA levels, reduced Cd accumulation, and increased tolerance to Cd. Moreover, NtDOGL4 overexpression led to decreased accumulation of reactive oxygen species (ROS) and improved ROS scavenging capacity under Cd stress. Further analyses revealed the direct binding of the transcription factor ABSCISIC ACID-INSENSITIVE 5 (ABI5) to the NtDOGL4 promoter, positively regulating its expression in tobacco. Notably, NtDOGL4 overexpression promoted suberin formation and deposition, while suppressing the expression of Cd transporter genes in tobacco roots, as evidenced by histochemical staining, suberin fraction determination, and qRT-PCR assays. Collectively, our results demonstrate that NtDOGL4 overexpression reduces Cd accumulation, thereby improving Cd stress tolerance through the modulation of antioxidant system, transcription of Cd transporters, and suberin deposition. Notably, the NtABI5-NtDOGL4 module functions as a positive regulator in tobacco's Cd tolerance, underscoring its potential as a molecular target for developing low-Cd crops to ensure environmental safety.

Integrated evaluation of the performance of phosphogypsum recycling technologies in China.

The Chinese government is implementing policies, such as the "Guidance on comprehensive utilization of bulk solid waste for the 14th Five-Year Plan period", to stimulate phosphogypsum (PG) reduction and recycling. Thus, the comprehensive evaluation of PG recycling technologies for sustainable development is crucial. This study proposes a novel multi-criteria decision analysis (MCDA) method that considers the criteria of resources, environment, economy, and society and risk attitudes of decision-makers and integrates game theory (GT) and utility theory for criteria weighting and ranking to assess industrial-scale PG recycling technologies in China. The results demonstrate that GT provides more reasonable criteria weights than individual weighting methods. PG-based lightweight plaster is the top performer in the resource and environmental dimensions owing to its exceptional resource and energy efficiency. PG utilized for dry-mix mortar and organic fertilizer production exhibited the best utility performance of 0.74 and 0.73, respectively. Measures, such as subsidies and product publicity, should be implemented to promote these technologies. However, technologies with poor performance, such as PG used for the co-production of sulfuric acid and fertilizer or cement, may require optimization or substitution for the sustainable recycling of PG. The proposed MCDA method is robust and can serve as a reliable decision-making tool for other waste-recycling technologies. However, caution must be exercised when determining risk attitude using the MCDA method as it may vary with the number of technologies and affect the final rankings.

New strategy for rational use of antihypertensive drugs in clinical practice in high-altitude hypoxic environments.

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.

Impact of locally delivered diphosphonates on dental implants: A systematic review and meta-analysis.

INTRODUCTION: Dental implants are a common solution for edentulous patients. This systematic review and meta-analysis aimed to determine whether locally delivered diphosphonates influence the osseointegration of dental implants in humans. MATERIAL & METHODS: In March 2023, we conducted an electronic systematic literature search using three databases (MEDLINE/PubMed, Embase, Web of Science). We included randomized trials documenting locally delivered diphosphonates in partly edentulous patients. Two independent reviewers evaluated study eligibility, extracted data, and assessed study quality. RESULTS: We have identified 752 studies, out of which 7 studies involving 154 patients met the inclusion criteria. The overall meta-analysis indicates that diphosphonates are associated with marginal bone loss during the pre-loading period (mean difference (MD) of -0.18 mm, 95% CI -0.24 to -0.12, p<0.00001; I²=83%), marginal bone loss after one year (MD -0.35 mm, 95% CI -0.56 to -0.14, p = 0.0009; I²=14%), and five years loading (MD -0.34 mm, 95% CI -0.56 to -0.13, p = 0.002; I²=0%). However, the drug did not seem to affect the implant survival rate (risk ratios (RR) of 1.02, 95% CI 0.98 to 1.08, P = 0.33; I²=9%). DISCUSSION: This study suggests that local use of diphosphonates does not affect implant survival, but it does reduce marginal bone loss and improve the osseointegration of dental implants in humans. However, future research must be more standardized and address methodological biases to draw more conclusive findings.

Iron deficiency in hepatocellular carcinoma cells induced sorafenib resistance by upregulating HIF-1α to inhibit apoptosis.

Sorafenib is the first-line therapeutic agent for hepatocellular carcinoma (HCC), but the drug resistance has become a major impediment. Previously we found that the abnormal iron metabolism in HCC led to iron deficiency, whether it induces sorafenib resistance during the treatment of HCC is not yet disclosed. In this study, we observed the effects of iron deficiency on sorafenib resistance and explored the underlying mechanisms. The results revealed that the killing effects of sorafenib on HCC cells were weakened by iron deficiency but effectively restored by iron re-supplementation. The ferroptosis indicators, including the contents of lipid hydroperoxide (LPO) and malondialdehyde (MDA), the level of intracellular reactive oxygen species (ROS), and the expression of glutathione peroxidase 4 (GPX4), were not significantly changed by iron deficiency in sorafenib-treated HCC cells. However, the sorafenib-induced apoptosis of HCC cells was inhibited by iron deficiency. Notably, the expression of anti-apoptotic protein B-cell lymphoma-2 (BCL-2) was elevated, and the expressions of other apoptotic proteins, BCL2-associated X (Bax), caspase-3, and caspase-9, were inhibited by iron deficiency. Mechanistically, iron deficiency upregulated hypoxia-inducible factor 1 alpha (HIF-1α) to increase BCL-2. Inhibition of HIF-1α suppressed the iron deficiency-induced BCL-2 and sorafenib resistance. In summary, iron deficiency in HCC cells generated sorafenib resistance by increasing HIF-1α and BCL-2, which therefore inhibited the sorafenib-induced apoptosis of HCC cells. These results identified iron deficiency as a new factor of sorafenib resistance in HCC cells, which would be an effective target to alleviate sorafenib resistance.

Iron deficiency downregulates ENPEP to promote angiogenesis in liver tumors.

The abnormal iron metabolism in liver cancer leads to iron deficiency in tumor tissues. We previously found that iron deficiency promoted liver cancer metastasis, but the mechanisms were not fully understood. In the present study, we identified that the angiogenesis-associated glutamyl aminopeptidase (ENPEP) was consistently decreased in iron-deficient liver tissues, iron-deficient liver tumors, and iron-deprived liver cancer cells. Interestingly, the lower expression of ENPEP was correlated with the poor prognosis of liver cancer patients, while the biomarkers of angiogenesis, CD31 and CD34, were increased in tumor tissues. In vivo imaging of liver-orthotopically implanted and tail vein-injected liver cancer cells showed that iron deficiency increased the pulmonary metastasis of liver cancer. The angiogenesis in iron-deficient tumors was enhanced, and the expression of ENPEP was decreased. Silencing ENPEP expression increased the migration of liver cancer cells and the proliferation of cocultured HUVECs. By sequence analysis, we found that the transcription factor SP1 possessed abundant binding sites in the ENPEP promoter region. Its combination with ENPEP promoters was verified by chromatin immunoprecipitation. The inhibition of SP1 by mithramycin A effectively restored the expression of ENPEP, which was decreased by iron deficiency. In conclusion, these results revealed that iron deficiency in liver tumors decreased the expression of ENPEP by SP1 and increased the angiogenesis and metastasis of liver tumors, which further explained the mechanism by which iron deficiency promoted liver cancer metastasis.

Rosuvastatin promotes survival of random skin flaps through AMPK-mTOR pathway-induced autophagy.

Plastic surgery frequently employs random skin flaps. However, its clinical applicability is constrained by flap necrosis brought on by ischemia-reperfusion damage. Flap survival is aided by rosuvastatin, a naturally occurring flavonoid primarily obtained from plants. In this research, we looked into the processes mediating the effects of rosuvastatin on flap survival. All experimental mice were randomly assigned to three groups: control, rosuvastatin, and 3-methyladenine (3MA) plus rosuvastatin. These groups were, respectively, treated with dimethyl sulfoxide solution, rosuvastatin, and rosuvastatin combined with 3MA. After that, the animals were euthanized so that histology and protein analyses could determine the extent of angiogenesis, pyroptosis, oxidative stress, and autophagy. In addition to lessening tissue edema, rosuvastatin promoted the survival of the skin flap. Rosuvastatin also promoted angiogenesis, reduced oxidative stress, induced autophagy, and reduced pyroptosis. According to the study's findings, rosuvastatin increases angiogenesis, prevents pyroptosis, and reduces oxidative stress by inducing autophagy, which improves the survival rate of random skin flaps.

Evidence-based guideline for the prevention and management of perioperative infection.

BACKGROUND: We have updated the guideline for preventing and managing perioperative infection in China, given the global issues with antimicrobial resistance and the need to optimize antimicrobial usage and improve hospital infection control levels. METHODS: We conducted a comprehensive evaluation of the evidence for prevention and management of perioperative infection, based on the concepts of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The strength of recommendations was graded and voted using the Delphi method and the nominal group technique. Revisions were made to the guidelines in response to feedback from the experts. RESULTS: There were 17 questions prepared, for which 37 recommendations were made. According to the GRADE system, we evaluated the body of evidence for each clinical question. Based on the meta-analysis results, recommendations were graded using the Delphi method to generate useful information. CONCLUSIONS: This guideline provides evidence to perioperative antimicrobial prophylaxis that increased the rational use of prophylactic antimicrobial use, with substantial improvement in the risk-benefit trade-off.

Relationship between blood-brain barrier changes and drug metabolism under high-altitude hypoxia: obstacle or opportunity for drug transport?

The blood-brain barrier is essential for maintaining the stability of the central nervous system and is also crucial for regulating drug metabolism, changes of blood-brain barrier's structure and function can influence how drugs are delivered to the brain. In high-altitude hypoxia, the central nervous system's function is drastically altered, which can cause disease and modify the metabolism of drugs in vivo. Changes in the structure and function of the blood-brain barrier and the transport of the drug across the blood-brain barrier under high-altitude hypoxia, are regulated by changes in brain microvascular endothelial cells, astrocytes, and pericytes, either regulated by drug metabolism factors such as drug transporters and drug-metabolizing enzymes. This article aims to review the effects of high-altitude hypoxia on the structure and function of the blood-brain barrier as well as the effects of changes in the blood-brain barrier on drug metabolism. We also hypothesized and explore the regulation and potential mechanisms of the blood-brain barrier and associated pathways, such as transcription factors, inflammatory factors, and nuclear receptors, in regulating drug transport under high-altitude hypoxia.

Iron Deficiency Increases Phosphorylation of SP1 to Upregulate SPNS2 Expression in Hepatocellular Carcinoma.

The sphingosine-1-phosphate (S1P) transporter spinster homolog 2 (SPNS2) promotes tumor progression by modulating tumor immunity and enhancing tumor cells migration and invasion. Previously we found that iron deficiency in hepatocellular carcinoma upregulated SPNS2 expression to increase tumor metastasis. The present study aimed to identify the underlying mechanism of SPNS2 upregulation. Since the mRNA of SPNS2 was significantly increased, we used a transcription factor activity microarray to find the transcription factor responsible for this. The results showed that iron deprivation in hepatoma cells increased the transcriptional activities of 14 transcription factors while only 2 were decreased. Among these, 3 transcription factors, HIF1α, SP1, and YY1, were predicted to bind with the transcription promoter region of SPNS2. But only HIF1α and SP1 transcriptional activities on SPNS2 were increased by iron deficiency, and the increase of SP1 transcriptional activity was stronger than HIF1α. The protein level of HIF1α was increased by iron deficiency, while SP1 was not changed at the protein level but the phosphorylation level was increased. The inhibitor of HIF1α, PX478, and the inhibitor of SP1, Mithramycin A, reversed the increased mRNA and protein expressions of SPNS2 by iron deficiency, with a more significant effect by Mithramycin A. These results provided a comprehensive view of changes in transcriptional activities by iron deficiency and identified that SP1 was the main regulator of iron deficiency-inducing SPNS2 expression in hepatoma cells.

Evaluation and Analysis of Design Elements for Sustainable Renewal of Urban Vulnerable Spaces.

The sustainable renewal design of urban vulnerable spaces is critical for urban space quality improvement. Taking Zhengzhou and surrounding cities as examples, a cognitive framework of urban vulnerable spaces is constructed. The three types of urban vulnerable spaces are vulnerable population, vulnerable cultural, and vulnerable forgotten spaces. Their sustainable renewal design elements comprise multidimensional factors, such as functional requirement, space organization, activity facility, urban context continuation, and material texture. The design elements for the sustainable update of urban vulnerable spaces are evaluated by grey relation analysis (GRA), and update strategies are proposed. The result shows that (1) vulnerable population spaces were shown to have the highest sensitivity to functional requirements and activity facility design elements, while vulnerable cultural spaces have high relevance to urban context continuation and functional requirement design elements. Furthermore, space organization, activity facility, and urban context continuation design elements all show high relevance and importance in vulnerable forgotten spaces. (2) The update of vulnerable population spaces should be designed to achieve functional communion; vulnerable cultural spaces can be reshaped through urban context implantation, and vulnerable forgotten spaces can use space creation to enhance ecological space continuity, achieving sustainable renewal. The study provides a reference for decision-making for improving urban vulnerable habitats and the sustainable renewal design of atypical urban space types.

The clinical implications of circulating microRNAs as potential biomarkers in screening oral squamous cell carcinoma.

Background: Recent studies have highlighted the biomarker role of circulating miRNAs in oral squamous cell carcinoma (OSCC), indicating their potential application as early diagnostic markers for OSCC. However, the diagnostic results have proven inconclusive. This study was conducted to evaluate the diagnostic value of circulating miRNAs for OSCC diagnosis. Methods: Eligible published studies were identified by a literature search carried out in several databases by using combinations of keywords associated with OSCC, circulating miRNAs, and diagnosis. The bivariate meta-analysis model was adopted to summarize the pooled parameters. Afterwards, we thoroughly explored the sources of heterogeneity after evaluating the risk of bias. Results: A total of 60 studies focusing on 41 circulating miRNAs were included. The pooled sensitivity, specificity, and AUC were 0.75 (95%CI: 0.69-0.80), 0.76 (0.70-0.81), 0.82 (0.79-0.85), respectively. Subgroup analyses showed that miRNA combinations were more accurate than single miRNAs. Additionally, plasma may be a better matrix for miRNAs assays in OSCC diagnosis as the plasma-based miRNA assay had a higher level of diagnostic accuracy than serum-based miRNA assay. Subgroup analyses also suggested that using circulating miRNAs for OSCC diagnosis is more effective in Caucasians than in Asian ethnic groups. Finally, circulating miRNA assays based on large sample sizes have superior diagnostic accuracy than small sample sizes. Conclusion: Circulating miRNAs might be applied as effective surrogate biomarkers for early diagnosis of OSCC. Nevertheless, future larger-scale prospective studies should be performed to enhance the diagnostic efficiency and investigate the miRNA combinations with more pronounced accuracy.

Mesenchymal stem/stromal cells primed by inflammatory cytokines alleviate psoriasis-like inflammation via the TSG-6-neutrophil axis.

Psoriasis is currently an incurable skin disorder mainly driven by a chronic inflammatory response. We found that subcutaneous application of umbilical cord- derived mesenchymal stem/stromal cells (MSCs) primed by IFN-γ and TNF-α, referred to as MSCs-IT, exhibited remarkable therapeutic efficacy on imiquimod (IMQ)-induced psoriasis-like inflammation in mice. Neutrophil infiltration, a hallmark of psoriasis, was significantly reduced after treatment with MSCs-IT. We further demonstrated that the effects of MSCs-IT were mediated by tumor necrosis factor (TNF) stimulating gene-6 (TSG-6), which was greatly upregulated in MSCs upon IFN-γ and TNF-α stimulation. MSCs transduced with TSG-6 siRNA lost their therapeutic efficacy while recombinant TSG-6 applied alone could also reduce neutrophil infiltration and alleviate the psoriatic lesions. Furthermore, we demonstrated that TSG-6 could inhibit neutrophil recruitment by decreasing the expression of CXCL1, which may be related to the reduced level of STAT1 phosphorylation in the keratinocytes. Thus, blocking neutrophil recruitment by MSCs-IT or TSG-6 has potential for therapeutic application in human psoriasis.

An iron-deficient diet prevents alcohol- or diethylnitrosamine-induced acute hepatotoxicity in mice by inhibiting ferroptosis.

The liver is easily injured by exogenous chemicals through reactive oxygen species (ROS), which lead to ferroptosis, a ROS-dependent programmed cell death characterized by iron accumulation and lipid peroxidation. However, whether iron restriction has a positive role in chemicals-induced liver injuries is unknown. The present study investigated the effects of an iron-deficient diet on liver injuries induced by alcohol or diethylnitrosamine (DEN). Mice were fed an iron-deficient diet for four weeks, then treated with three doses of alcohol (5 g/kg, 24 h interval, gavage) to mimic mild liver injury or five doses of DEN (50 mg/kg, 24 h interval, i. p.) to mimic severe liver failure. The results showed that mice were iron-deficient after four weeks of feeding. Interestingly, as evaluated by H&E staining of liver slices, liver/body weight ratio, serum ALT and AST, iron deficiency significantly alleviated liver injuries triggered by alcohol or DEN. The activities of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), and the expression of CYP2E1 were increased by iron deficiency. Mechanistically, iron deficiency prevented the decrease of glutathione peroxidase 4 (GPX4), which eliminated malondialdehyde (MDA) by utilizing glutathione (GSH). In summary, alcohol- or DEN-induced liver injuries were mitigated by the iron-deficient diet by inhibiting ferroptosis, which might be a promising measure for preventing liver injuries induced by alcohol, DEN, or other exogenous chemicals.

Regulation of CYP450 and drug transporter mediated by gut microbiota under high-altitude hypoxia.

Hypoxia, an essential feature of high-altitude environments, has a significant effect on drug metabolism. The hypoxia-gut microbiota-CYP450/drug transporter axis is emerging as a vital factor in drug metabolism. However, the mechanisms through which the gut microbiota mediates the regulation of CYP450/drug transporters under high-altitude hypoxia have not been well defined. In this study, we investigated the mechanisms underlying gut microbial changes in response to hypoxia. We compared 16S ribosomal RNA gene sequences of the gut microbiota from plain and hypoxic rats. As a result, we observed an altered gut microbial diversity and composition in rats under hypoxia. Our findings show that dysregulated gut microbiota changes CYP3A1 and MDR1 expressions in high-altitude hypoxic environments. Thus, our study reveals a novel mechanism underlying the functioning of the hypoxia-gut microbiota-CYP450/drug transporter axis.

High-altitude Hypoxia Influences the Activities of the Drug-Metabolizing Enzyme CYP3A1 and the Pharmacokinetics of Four Cardiovascular System Drugs.

(1) Background: High-altitude hypoxia has been shown to affect the pharmacokinetic properties of drugs. Although there is a high incidence of cardiovascular disease among individuals living in high-altitude areas, studies on the effect of high-altitude hypoxia on the pharmacokinetic properties of cardiovascular drugs are limited. (2) Methods: The aim of this study was to evaluate the pharmacokinetics of nifedipine, bosentan, simvastatin, sildenafil, and their respective main metabolites, dehydronifedipine, hydroxybosentan, simvastatin hydroxy acid, and N-desmethyl sildenafil, in rats exposed to high-altitude hypoxia. Additionally, the protein and mRNA expression of cytochrome P450 3A1 (CYP3A1), a drug-metabolizing enzyme, were examined. (3) Results: There were significant changes in the pharmacokinetic properties of the drugs in rats exposed to high-altitude hypoxia, as evidenced by an increase in the area under the curve (AUC) and the half-life (t1/2z) and a decrease in total plasma clearance (CLz/F). However, most of these changes were reversed when the rats returned to a normoxic environment. Additionally, there was a significant decrease in CYP3A1 expression in rats exposed to high-altitude hypoxia at both the protein and mRNA levels. (4) Conclusions: High-altitude hypoxia suppressed the metabolism of the drugs, indicating that the pharmacokinetics of the drugs should be re-examined, and the optimal dose should be reassessed in patients living in high-altitude areas.

Changes in the Gut Microbiota of Rats in High-Altitude Hypoxic Environments.

This study was conducted to investigate the effects of high-altitude hypoxic environments on the gut microbiota. Male Sprague-Dawley rats were randomly divided into three groups, namely, the plain, moderate-altitude hypoxic, and high-altitude hypoxic groups. On the 3rd, 7th, 15th, and 30th days of exposure, fecal samples were collected and analyzed via 16S rRNA gene sequencing technology. Fecal microbiota transplantation (FMT) experiments were also performed. The results showed significant differences between the gut microbiota structure and diversity of rats in the high-altitude hypoxic group and those of rats in the other groups. Further, compared with that of rats in the plain group, the gut microbiota of rats in the two hypoxic groups showed the most significant changes on day 7. Furthermore, the gut microbiota of the rats in the FMT groups exhibited changes and became increasingly similar to those of the rats in the hypoxic groups. We also identified the phylum Firmicutes, genus Akkermansia, and genus Lactobacillus as the core microbiota under hypoxic conditions. Phenotypic analysis indicated a decrease in the proportion of aerobic bacteria and an increase in that of anaerobic bacteria, possibly owing to the high-altitude hypoxic environment. Additionally, functional analysis showed significant differences between the different groups with respect to different metabolic pathways, including carbohydrate metabolism, energy metabolism, glycan biosynthesis, and metabolism. These findings indicated significant changes in gut microbiota structure and diversity under high-altitude hypoxia, establishing a foundation for further research on the pathogenesis and development of diseases, as well as drug metabolism, under high-altitude hypoxia. IMPORTANCE In this study, we investigated the effects of high-altitude hypoxic environments with low oxygen levels on the gut microbiota characteristics of rats. We observed that high-altitude hypoxia is an important environmental factor that can affect gut microbiota structure and diversity, thereby affecting homeostasis in the host intestinal environment. These findings provide a basis for further studies on disease initiation and development, as well as drug metabolism, in high-altitude hypoxic environments.