Molecular Mechanisms of High-Altitude Acclimatization

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1698 - 1698

Published: Jan. 15, 2023

High-altitude illnesses (HAIs) result from acute exposure to high altitude/hypoxia. Numerous molecular mechanisms affect appropriate acclimatization hypobaric and/or normobaric hypoxia and curtail the development of HAIs. The understanding these is essential optimize hypoxic for efficient prophylaxis treatment This review aims link outcomes either adverse effects high-altitude/hypoxia or developing tolerance with acclimatization. After summarizing systemic physiological responses high-altitude exposure, associated acclimatization, epidemiology pathophysiology various HAIs, article focuses on adjustments maladjustments during Pivotal modifying include orchestrated by transcription factors, most notably inducible reciprocal mitochondrial functions REDOX homeostasis. In addition, discussed are genetic factors resultant proteomic profiles determining hypoxia-modifying culminating in successful Lastly, discusses practical considerations related aspects altitude training strategies.

Language: Английский

---

Altitude illnesses

Nature Reviews Disease Primers, Journal Year: 2024, Volume and Issue: 10(1)

Published: June 20, 2024

Language: Английский

---

Paeoniflorin attenuates cuproptosis and ameliorates left ventricular remodeling after AMI in hypobaric hypoxia environments

Journal of Natural Medicines, Journal Year: 2024, Volume and Issue: 78(3), P. 664 - 676

Published: March 1, 2024

Abstract This study investigates the cardioprotective effects of Paeoniflorin (PF) on left ventricular remodeling following acute myocardial infarction (AMI) under conditions hypobaric hypoxia. Left post-AMI plays a pivotal role in exacerbating heart failure, especially at high altitudes. Using rat model AMI, aimed to evaluate potential PF Ninety male rats were divided into four groups: sham-operated controls normoxia/hypobaria, an AMI group, and treatment group. was administered for 4 weeks after induction. function assessed using cardiac magnetic resonance imaging. Biochemical assays cuproptosis, oxidative stress, apoptosis, inflammation, fibrosis performed. Results demonstrated significantly improved Mechanistically, decreased FDX1/DLAT expression serum copper while increasing pyruvate. It also attenuated by modulating Bcl-2, Bax, NLRP3, stress markers. Thus, exhibits therapeutic altitude inhibiting apoptosis fibrosis. Further studies are warranted optimize dosage duration elucidate PF’s mechanisms action.

Language: Английский

---

A time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 10, 2024

Abstract High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we use sheep as an animal model for low-to-high altitude translocation. We generate multi-omics data including whole-genome sequences, time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues well phenotypic 20 bio-indicators. characterize transcriptional changes of all genes each tissue, examine multi-tissue temporal dynamics interactions among genes. Particularly, identify critical functional regulating short response to tissue (e.g., PARG cerebellum HMOX1 colon). further TAD-constrained cis -regulatory elements, which suppress activity most under hypoxia. Phenotypic evidence indicate that antenatal could improve tolerance offspring. Furthermore, provide time-series expression candidate associated with human mountain sickness BMPR2 ) high-altitude adaptation HIF1A ). Our study provides valuable resources insights future hypoxia-related studies mammals.

Language: Английский

---

Ligustrazine hydrochloride Prevents Ferroptosis by Activating the NRF2 Signaling Pathway in a High-Altitude Cerebral Edema Rat Model

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1110 - 1110

Published: Jan. 27, 2025

High-altitude cerebral edema (HACE) is a disorder caused by low pressure and hypoxia at high altitudes. Nevertheless, as of now, there still scarcity safe effective prevention treatment methods. The active component Ligusticum Chuanxiong, namely Ligustrazine hydrochloride (LH), has shown potential in the HACE due to its anti-inflammatory, antioxidant, neuroprotective effects nervous system disorders. Consequently, protective effect LH on mechanism need be further explored. Prior modeling, 90 male Sprague-Dawley rats were pretreated with different doses drugs, including (100 mg/kg 50 mg/kg), dexamethasone (4 ML385 (30 mg/kg). Subsequently, placed low-pressure anoxic chamber simulating plateau environment establish rat model. mechanisms elucidated through determination brain water content, HE staining, ELISA, immunofluorescence, molecular docking, dynamics simulation, western blot, other techniques. results showed, first all, that pretreatment can effectively reduce content; down-regulate expression AQP4, HIF-1α, VEGF proteins; alleviate damage tissue nerve cells. Secondly, compared group, significantly MDA levels increase GSH SOD levels. Additionally, decreased inflammatory factors IL-1β, IL-6, TNF-α; reduced total iron content tissue; increased ferroptosis-related proteins such SLC7A11, GPX4, FTH1; alleviated ferroptosis occurrence. Molecular docking simulations show strong binding affinity for NRF2 signaling. Western blot analysis confirmed promotes translocation from cytoplasm nucleus activates signaling pathway exert an antioxidant effect. inhibitor reverse anti-oxidative stress tissue. In summary, may have activating pathway, inhibiting ferroptosis, resisting oxidative stress.

Language: Английский

---

Global, regional, and national temporal trends in prevalence, deaths and disability-adjusted life years for chronic pulmonary disease, 1990–2021: an age-period-cohort analysis based on the global burden of disease study 2021

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 12

Published: March 4, 2025

Background Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality globally, with significant disparities in burden across countries socioeconomic regions. Despite advancements public health, the global COPD remains substantial, particularly low- middle-income countries. This study aims to provide comprehensive analysis global, regional, national trends COPD-related prevalence, deaths, disability-adjusted life years (DALYs) from 1990 2021 using an age-period-cohort (APC) model. Methods Data Global Burden Disease Study were analyzed for 204 territories, stratified by five Sociodemographic Index (SDI) levels. An APC model was employed assess temporal effects age, time periods, birth cohorts on burden. Trends DALYs evaluated through metrics such as Net Drift, Local risk ratios. Results Globally, 2021, age-standardized rates demonstrated decline −1.46% (95% UI: −3.36 0.39%) −37.12% −43.37% −27.68%) −36.98% −42.37% −28.54%) DALYs. After adjusting age cohort effects, annual changes −0.35% −0.39% −0.32%) −3.87% −4.00% −3.74%) − 2.95% −3.02% −2.89%) Notably, middle, low-middle, low SDI regions, prevalence showed increase compared 1990, respective 4.03% 2.00–5.89%), 0.13% −2.90 2.84%), 6.71% 4.25–8.91%). However, deaths significantly decreased all From effect perspective, over 50% concentrated among individuals aged 65 older, high-middle have shown declining trend groups. period indicates that earlier periods associated higher disease, while highlight around 1920 had pronounced impact Both exhibited notable heterogeneity different regions countries, Conclusion The concerning. Compared stable or slightly increasing trend, half experiencing during 1990–2021 period. 1990. this likely linked differences development. Countries middle found be more affected effects. population aging has undoubtedly exacerbated Regarding stronger contribution While Higher levels development can mitigate adverse cohorts.

Language: Английский

---

High altitude hypoxia and oxidative stress: The new hope brought by free radical scavengers

Life Sciences, Journal Year: 2023, Volume and Issue: 336, P. 122319 - 122319

Published: Nov. 29, 2023

Language: Английский

---

The Brain at High Altitude: From Molecular Signaling to Cognitive Performance

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(12), P. 10179 - 10179

Published: June 15, 2023

The brain requires over one-fifth of the total body oxygen demand for normal functioning. At high altitude (HA), lower atmospheric pressure inevitably challenges brain, affecting voluntary spatial attention, cognitive processing, and attention speed after short-term, long-term, or lifespan exposure. Molecular responses to HA are controlled mainly by hypoxia-inducible factors. This review aims summarize cellular, metabolic, functional alterations in at with a focus on role factors controlling hypoxic ventilatory response, neuronal survival, metabolism, neurogenesis, synaptogenesis, plasticity.

Language: Английский

---

Dexmedetomidine ameliorates diabetic cardiomyopathy by inhibiting ferroptosis through the Nrf2/GPX4 pathway

Journal of Cardiothoracic Surgery, Journal Year: 2023, Volume and Issue: 18(1)

Published: July 10, 2023

Abstract Objective Dexmedetomidine (DEX) has been shown to have anti-apoptotic effects in diabetes mellitus, but its role mitigating diabetic cardiomyopathy (DCM) through ferroptosis regulation is unclear. Methods An vitro DCM model was established using H9C2 cells induced with high glucose (HG) and treated DEX at varying doses a nuclear factor erythroid 2-realated 2 (Nrf2) specific inhibitor ML385. Cell viability evaluated the MTT method after treatment or mannitol (MAN), dosage of used subsequent experimentation determined. The HG-induced osmotic pressure were assessed MAN as control. apoptosis flow cytometry. Protein levels Bcl2, Bax, Nrf2, glutathione peroxidase 4 (GPX4) measured Western blot. Superoxide dismutase (SOD) activity, malondialdehyde (MDA) levels, Fe 2+ concentration reactive oxygen species (ROS) corresponding kits dichlorodihydrofluorescein diacetate, respectively. Results Treatment had no effect on cell viability. HG induction reduced viability, increased apoptosis, upregulated , MDA, ROS, downregulated Bcl2 protein SOD Nrf2 GPX4. inhibited promoted translocation, activated Nrf2/GPX4 pathway. Inhibition partially reversed protective against HG-evoked injury. Conclusion Our findings demonstrate that attenuates cardiomyocyte injury by inhibiting pathway, providing potential therapeutic targets for treatment.

Language: Английский

---

Empagliflozin protects against heart failure with preserved ejection fraction partly by inhibiting the senescence-associated STAT1–STING axis

Cardiovascular Diabetology, Journal Year: 2024, Volume and Issue: 23(1)

Published: July 23, 2024

Abstract Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. Empagliflozin (EMPA) improves cardiovascular outcomes in HFpEF patients, but the underlying mechanism remains elusive. Here, mice were fed high-fat diet (HFD) supplemented L-NAME for 12 weeks and subsequently intraperitoneally injected EMPA another 4 weeks. A 4D-DIA proteomic assay was performed to detect protein changes failing hearts. We identified 310 differentially expressed proteins (DEPs) (ctrl vs. group) 173 DEPs (HFpEF group). The regulation of immune system processes enriched all groups interferon response genes (STAT1, Ifit1, Ifi35 Ifi47) upregulated downregulated after administration. In addition, treatment suppressed increase levels aging markers (p16 p21) Further bioinformatics analysis verified STAT1 as hub transcription factor during pathological mice. next treated H9C2 cells IFN-γ, primary agonist phosphorylation, investigate whether plays beneficial role by blocking activation. Our results showed that IFN-γ caused cardiomyocyte senescence activation, which inhibited Notably, inhibition significantly reduced cellular possibly regulating STING expression. findings revealed mitigates cardiac inflammation inhibiting STAT1–STING axis may act pivotal pathogenesis HFpEF, especially under inflammatory conditions. Graphical abstract schematic figure depicts model (this drawn using FigDraw software).

Language: Английский

---