Search Results (1,312)

Gao-shan-hong-jing-tian (GSHJT) Oral Liquid is a phytochemical-rich preparation derived from Rhodiola, yet its anti-hypoxic active constituents and molecular mechanisms remain poorly understood. This study aimed to identify the key anti-hypoxic phytochemicals in GSHJT Oral Liquid and clarify their mechanisms of action to support its potential use in managing acute mountain sickness (AMS). We first established and validated an HPLC method for quality control, then comprehensively profiled the chemical composition using LC-MS. Network pharmacology and molecular docking were applied to predict the core anti-hypoxic components, candidate targets and signaling pathways. The primary bioactivity was further verified through an in vitro carbonic anhydrase (CA) inhibition assay. A total of 71 constituents were identified, with kaempferol and ellagic acid emerging as the primary anti-hypoxic phytochemicals. These compounds target seven core proteins (SRC, PIK3R1, ESR1, EGFR, PTK2, IGF1R, and LYN) to regulate vascular tone, inflammation, oxidative stress, blood–brain barrier integrity, and cell survival under hypoxic conditions. By modulating pathways such as HIF-1α, PI3K/AKT, FAK/PTK2, SRC, and IGF1R, these phytochemicals ultimately influence the onset and alleviation of AMS. Enzyme inhibition assays demonstrated that kaempferol and ellagic acid inhibited CA with IC₅₀ values of 34.05 μM and 119.1 μM, respectively. Molecular docking further revealed that both compounds suppressed CA activity through a combination of hydrogen bonding and hydrophobic interactions, consistent with a zinc-bound water-anchoring mechanism. This study elucidates the phytochemical basis and molecular mechanism responsible for the anti-hypoxic effects of GSHJT Oral Liquid, providing scientific support for its potential application as a natural, plant-derived intervention for preventing and alleviating acute mountain sickness, providing scientific support for its potential application and offering a reproducible paradigm for the rational development of other Rhodiola-based phytomedicines, though further in vivo validation is required to confirm the anti-hypoxic efficacy. Full article

In the myocardium of rats of two phenotypes (low and high resistance to hypoxia), the dependence of the reaction of catalytic subunits of mitochondrial enzyme complexes I–V and the severity of ultrastructural changes in mitochondria upon exposure to repeated hypoxia (20 days—three daily hourly exposures to hypoxic mixtures of −14% O₂, 10.5% O₂ and 8% O₂, equivalent to 3000 m, 5000 m and 7000 m). The dynamics of expression of catalytic subunits of mitochondrial complexes I–V and ultrastructural changes in three subpopulations of mitochondria were analyzed. During the course of exposure to hypoxia (training sessions) each repeated hypoxic exposure under any regimen caused an activation of mitochondrial complex II and mitochondrial complexes III–V. At 14–10.5% O₂, this reaction was repeated with each hypoxic exposure during 8–12 training sessions. After 20 sessions, ATP synthesis returned to its initial level, indicating the completion of adaptation. These changes correlated with optimization of the mitochondrial ultrastructure, which was most pronounced at 14% O₂. On the contrary, at 8% O₂ under conditions of inhibition of succinate dehydrogenase (mitochondrial complex II), ATP synthesis was suppressed; and pronounced structural disorders of mitochondria developed. Thus, we have demonstrated that mitochondrial enzymes and the ultrastructure of subpopulations of myocardial mitochondria are informative indicators of the functional and metabolic state of the heart. Full article

Post-exercise release of cardiac biomarkers reflects physiological adaptations of the myocardium to exercise; however, data on their kinetics after exhaustive exercise under hypoxia remain scarce. We determined the kinetics of cardiac biomarker changes following a single bout of exercise to volitional exhaustion under normoxia and moderate normobaric hypoxia (2000 m and 3000 m a.s.l.) in trained (n = 12; VO_2max 64.2 ± 2.9 mL·kg⁻¹·min⁻¹) and untrained (n = 12; VO_2max 44.1 ± 7.4 mL·kg⁻¹·min⁻¹) men. Participants performed a graded exercise test (GXT) followed by a constant-workload exercise test (CXT) at the lactate threshold under three conditions (FiO₂ = 20.9%, 16.5%, 14.4%). Venous blood was sampled at rest, immediately post-exercise, and at 2, 6, and 24 h of recovery for determination of cardiac troponin T (cTnT) and I (cTnI), myoglobin (Mb), creatine kinase MB isoform (CK-MB), heart-type fatty acid-binding protein (H-FABP), ischemia-modified albumin (IMA), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) by ELISA. Exhaustive exercise induced significant elevations in all biomarkers, peaking at 2–6 h post-exercise and largely returning to resting values by 24 h. Moderate normobaric hypoxia did not augment the cardiac biomarker response; rather, it attenuated the increases in Mb, NT-proBNP, and IMA, likely due to earlier peripheral fatigue and lower absolute mechanical work. The inhibitory effect of hypoxia on cTnI release was observed exclusively in trained men, suggesting an interaction between training-related cardiac adaptations and the hypoxic stimulus. These findings support the safety of high-intensity exercise at simulated altitudes of 2000–3000 m a.s.l. Full article

Osteoarthritis is a chronic degenerative joint disease characterized by inflammation and cartilage degradation, for which current treatments are mainly symptomatic and unable to halt disease progression. Adipose-derived mesenchymal stem cells (ASCs) represent a promising therapeutic option due to their regenerative and immunomodulatory properties, which may be further enhanced through specific priming strategies. In this study, primary human ASCs were exposed to interleukin-1 beta (IL1β), interferon-gamma (IFNγ), or hypoxic priming, and subsequently analyzed using a multi-omics approach integrating RNA sequencing, proteomics of secretome, and exosomal miRNA profiling. Differential gene expression, protein abundance, and miRNA signatures were assessed together with functional enrichment and network analyses. IL1β priming induced marked transcriptional reprogramming of ASCs, while hypoxia and IFNγ priming produced limited changes. IL1β also profoundly reshaped the ASC secretome and exosomal miRNA cargo, revealing coordinated regulation of pathways involved in immune modulation and cartilage remodeling. In contrast, the other priming conditions showed minimal and less integrated molecular effects. Overall, IL1β priming consistently generated a multi-layered molecular signature linking immunoregulatory and regenerative pathways. These findings suggest that IL1β priming enhances the functional properties of ASCs and provides mechanistic insight supporting their potential use in osteoarthritis therapy. Full article

Despite advances in lifestyle-based therapy, achieving clinically meaningful reductions in blood lipid levels remains a major challenge in obese men with secondary hypercholesterolemia. Hypoxic exposure encompassing both training sessions and nocturnal rest may offer a novel adjunct to conventional interventions; however, no study has evaluated such a protocol in this population. Twenty sedentary men with obesity-related hypercholesterolemia were randomly allocated to a hypoxic group (H) or normoxic control group (C). Both groups completed an identical two-week high-intensity training program under an individualized calorie-restricted diet, residing at the same lowland location (~100 m above sea level). The H group trained and rested under normobaric hypoxia (FiO₂ = 14.4%, simulated altitude ~3000 m, 8 h nightly); C remained under normoxic conditions. The H group demonstrated significantly greater reductions in body mass (−4.1%) and fat mass (−11.0%). Significant reductions in total cholesterol (−20.1%), low-density lipoprotein cholesterol (−21.3%), non-high-density lipoprotein cholesterol (−23.1%), atherogenic index of plasma (−42.4%), and Castelli Risk Index I (−19.4%) occurred exclusively in the H group, accompanied by a strong downward trend in Castelli Risk Index II (p = 0.072). High-density lipoprotein cholesterol did not change; for triglycerides, a clear downward trend was observed in the H group, approaching statistical significance within-group (p = 0.052). The magnitude of cholesterol reduction was significantly associated with body mass and fat loss (r = 0.61–0.67). A two-week intervention combining hypoxic training with nocturnal normobaric hypoxic exposure and caloric restriction produces clinically relevant improvements in lipid profile and body composition in men with obesity-related hypercholesterolemia. Full article

Perinatal asphyxia is a major contributor to neonatal morbidity and mortality, particularly among preterm infants, whose brains are highly vulnerable to hypoxic–ischemic injury. The germinal matrix (GM), owing to its vascular fragility and high metabolic demand, is especially susceptible in this context. This study analyzed 118 germinal matrix samples from neonates, stratified into three groups according to gestational age—Extremely Preterm (EP), Late Preterm (LP), and Term (T)—to investigate the immunopositivity of hypoxia-inducible factor 1-alpha (HIF-1α) and brain-derived neurotrophic factor (BDNF), correlating these findings with gestational age, the presence of asphyxia, neuronal injury, and survival time. BDNF expression showed a positive association with postnatal survival in neonates without neuronal injury (ρ = 0.309; p = 0.012). Linear regression analysis further demonstrated that BDNF immunopositivity was a significant predictor of survival time, with each 11.82% increase in positive staining corresponding to an additional predicted hour of survival (p < 0.001). HIF-1α expression was positively associated with survival in asphyxiated extremely preterm neonates (ρ = 0.492; p = 0.024) and demonstrated a strong correlation that approached, but did not reach, conventional statistical significance in late preterm neonates with neuronal injury (ρ = 0.949; p = 0.051). Collectively, these findings suggest a complementary role for BDNF and HIF-1α in neonatal neuroprotective responses, with BDNF showing potential as a prognostic biomarker in neonates without neuronal injury and HIF-1α reflecting adaptive responses to hypoxic–ischemic stress in a gestational age-dependent manner. However, additional studies are required to validate these associations and further clarify their prognostic and therapeutic relevance in neonatal hypoxic–ischemic conditions. Full article

Radiotherapy remains a central component of standard treatment for glioblastoma (GBM), yet recurrence is common because GBM radioresistance is reinforced by enhanced DNA damage repair, glioma stem cells (GSCs), hypoxia, extracellular matrix remodeling, and an immunosuppressive tumor microenvironment. FLASH radiotherapy (FLASH-RT), delivered at ultra-high dose rates, has shown reproducible normal-tissue-sparing effects in preclinical models, including the brain. In GBM models, however, available evidence indicates that FLASH-RT generally preserves tumor control at levels comparable to conventional radiotherapy rather than providing clearly superior eradication of hypoxic or stem-like tumor compartments. In parallel, endoplasmic reticulum (ER)-targeted interventions have emerged as a candidate strategy for disturbing tumor proteostasis, modulating unfolded protein response (UPR) signaling, impairing synthesis of repair-associated proteins, and promoting immunogenic cell death. This narrative review summarizes representative mechanisms of GBM radioresistance, appraises the opportunities and limitations of FLASH-RT in intracranial disease, and explains why ER targeting is discussed here as a lead but unproven biological axis for radiosensitization. We further compare ER-directed approaches with mitochondrial-, lysosomal-, and delivery-enabled radiosensitization strategies, and outline the translational variables that would determine clinical testability, including beam modality, blood–brain barrier heterogeneity, pharmacokinetics, treatment sequencing, and biomarker development. In this review, “physical precision” refers primarily to dose-rate-driven ultra-rapid delivery and the possibility of widening the normal-tissue therapeutic window under FLASH conditions, rather than to a universal depth–dose advantage shared by all FLASH platforms. Direct experimental evidence for combining FLASH-RT with ER-targeted therapy in GBM is currently lacking. We therefore present this model as a hypothesis-generating conceptual and translational framework for future preclinical testing rather than as an established therapeutic advance. Full article

Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults. Necrosis, and by inference hypoxia, is a pathognomonic feature of GBM tumors, where hypoxia significantly contributes to chemoresistance, leading to local treatment failure and disease progression. Although temozolomide (TMZ) is the main treatment option, 60–75% of GBM patients do not benefit from it. This study aimed to evaluate the therapeutic potential of Tetrandrine (TET) in combination with or compared to TMZ in treating GBM cells (M010b and U87) under both normoxic and hypoxic conditions. The therapeutic potential was assessed using qRT-PCR, MTT assay, combination index analysis, flow cytometry for apoptosis and cell cycle analysis, scratch assay, gelatin zymography, measurement of mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) production, and molecular docking. Under both normoxic and hypoxic conditions, TET showed significant cytotoxicity in both cell lines compared to TMZ. A synergistic effect was observed only under normoxia at 2× IC₅₀ concentrations in M010b cells, and at 4× IC₅₀ concentrations in U87 cells. TET significantly increased the sub-G1 cell population and apoptosis compared to TMZ in both cell lines under normoxic and hypoxic conditions, while TMZ induced G2/M arrest in U87 cells under both conditions. TET significantly increased ROS production in both cell lines under normoxia. Under both conditions, ΔΨm was significantly reduced by TET in M010b cells and by TMZ in both cell lines. TET and TMZ significantly reduced pro-MMP-2 levels in M010b cells under both conditions and in U87 cells under normoxia. In conclusion, given the limited therapeutic potential of TMZ, our findings suggest that TET could be a viable alternative treatment option for GBM. Full article

Pancreatic cancer remains one of the most lethal malignancies worldwide, with pancreatic ductal adenocarcinoma accounting for the vast majority of cases and characterized by extensive desmoplasia, immune exclusion, and resistance to systemic therapies. Increasing evidence implicates lysosomal cathepsins as important regulators of these defining features of pancreatic tumor biology. Cathepsin-dependent proteolysis and lysosome-associated signaling pathways contribute to extracellular matrix remodeling, regulate immune cell trafficking, and influence antigen processing and presentation. Beyond their classical degradative functions, cathepsins participate in stress-adaptive cellular programs linked to autophagy, metabolic regulation, and proteostasis, supporting tumor cell survival under hypoxic, nutrient-limited, and therapy-induced stress conditions. Within the tumor microenvironment, dysregulated cathepsin activity promotes immune evasion by reshaping cytokine networks, impairing effective antigen presentation, and reinforcing physical and functional barriers to cytotoxic T-cell infiltration. Collectively, these mechanisms position the lysosome–cathepsin system as a central regulator of proteolytic remodeling, immune exclusion, and adaptive therapy resistance in pancreatic cancer, highlighting its potential relevance for emerging combinatorial therapeutic strategies. Full article

The body’s microbiota plays a fundamental role in maintaining homeostasis and influences immune function, metabolism, and tissue integrity. A growing body of research suggests that fluctuations in the composition and abundance of individual microbiota populations may influence cancer development and the effectiveness of therapy. The condition of microbiota dysbiosis has been demonstrated to induce chronic inflammation, immune system dysregulation, and, most significantly, modulation of molecular pathways that promote tumorigenesis. The efficacy and toxicity of cancer treatment can be influenced by the composition of the microbiota. Bacteria can modify the effectiveness and toxicity of chemotherapy and immunotherapy by affecting drug metabolism and the body’s immune response. In contrast, the development of anticancer therapies that utilize bacteria is gaining increasing interest. This alternative to conventional treatment utilizes the natural ability of certain bacterial species to selectively colonize hypoxic and necrotic environments. The exploration of natural and genetically modified bacteria as vectors for the delivery of cytotoxins, immunomodulators, or therapeutic genes in the combat of cancer is a current area of research. In addition, their capacity to stimulate an antitumor immune response is also exploited. Preclinical investigations in animals have demonstrated the efficacy of this therapeutic approach, underscoring the promise of bacterial therapies as either an adjunct to conventional treatment or as a standalone strategy for combating cancer. This article synthesizes the current knowledge regarding the role of microbiota in carcinogenesis in animals and discusses recent developments in the field of bacterial therapies. The text also addresses the challenges, safety considerations, and future perspectives associated with translating microbiota-targeted and bacterial therapies into veterinary and comparative oncology. Full article

In light of the indispensable role of diesel engines in critical sectors such as heavy transportation, agricultural machinery, and shipping and the gradual depletion of fossil fuels, the strategic value of blended fuels has become increasingly prominent. However, the cold-start performance of diesel engines operating on blended fuels remains unclear. This study conducts a comprehensive simulation of the impact of various blended fuel ratios on the cold-start characteristics of diesel engines, focusing on low-temperature fluidity, combustion characteristics, and emissions. The research findings indicate that E30 and E50, as preferred blended fuels, exhibit excellent economic performance and environmental adaptability. Specifically, E30 demonstrates superior combustion performance and higher cylinder peak pressure under low-temperature conditions. In contrast, E50 shows a significant advantage in emissions performance, achieving 17.34% reductions in NOx and 9.7% in HC emissions compared to E30. In addition, a decrease in ambient temperature could help mitigate both NOx and HC emissions. Under simulated high-altitude conditions, E50 exhibits superior hypoxic adaptability compared to E30, achieving significant reductions in NOx (16.3%) and HC (9.7%). This study helps advance the development of clean alternative fuels for diesel engines by providing a theoretical foundation and practical guidelines for biodiesel selection across diverse environmental conditions. Full article

Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver malignancy with a rising global incidence and limited therapeutic options. Vascular invasion (VI) is a hallmark of advanced disease, correlating with early recurrence and dismal prognosis, yet its tumor microenvironment (TME) drivers remain elusive. We analyzed single-cell RNA sequencing (scRNA-seq) data from 25 ICC samples to systematically characterize the cellular composition and molecular features related to VI. By integrating bulk RNA-seq data, spatial transcriptomics, and multiplex immunofluorescence, we identified a distinct subset of tumor-like cancer-associated fibroblasts (CAFs), termed tCAFs, enriched in VI-positive tumors. Functional enrichment analyses revealed that tCAFs were prominently associated with hypoxia and angiogenesis pathways, findings corroborated by the significant upregulation of tCAF markers (MME and NT5E) in ICC-derived CAFs under hypoxic conditions in vitro. Cell–cell communication analysis and spatial mapping uncovered that tCAFs might promote VI primarily through VEGF signaling interactions with endothelial cells. Integrative bioinformatics and RT-qPCR validation identified three key functional genes in tCAFs: SLC2A1, PTGS2, and PLOD2. In endothelial sprouting assays, pharmacological inhibition of SLC2A1 exerted a pronounced suppressive effect. Consistently, sprouting assays using ICC-derived CAFs with SLC2A1 knockdown confirmed that its downregulation significantly reduced endothelial sprouting capacity. Importantly, administration of the SLC2A1 inhibitor BAY-876 effectively suppressed tumor progression and intrahepatic metastasis in the orthotopic ICC mouse model. Our findings define a VI-associated cellular ecosystem and molecular landscape in ICC, unveiling a novel hypoxia–tCAFs–endothelial cells axis. Furthermore, we identify SLC2A1 as a clinically relevant therapeutic target, offering new insights into tumor VI. Full article

The treatment of full-thickness skin defects remains a major challenge in clinical medicine. Accelerating wound healing and promoting the restoration of tissue function are of paramount importance. Stem cell therapy has been applied in clinical practice to facilitate wound repair. However, the low survival rate of transplanted stem cells in an ischemic and hypoxic microenvironment severely limits the effectiveness of their clinical application. Microspheres, owing to their excellent biocompatibility and drug delivery capabilities, can serve as effective carriers for oxygen transport. It is worthwhile to evaluate the timing and process of oxygen release under hypoxic conditions. In this study, core–shell structured oxygen-releasing microspheres were prepared and incorporated with the photosensitizer hypericin (HYP) to enable dynamic tracking of the oxygen release process via fluorescent signals. The effects of the oxygen-releasing microspheres on cells under hypoxic conditions were analyzed, focusing primarily on the characterization of the microspheres, their biocompatibility, luminescent properties, and oxygen-releasing capacity. Furthermore, the efficacy of the oxygen-releasing microspheres in combination with bone marrow mesenchymal stem cells (BMSCs) in promoting wound healing was evaluated in vivo. The results indicate that the addition of the microspheres improved cell survival rates in hypoxic environments; meanwhile, their luminescent properties demonstrated the potential of fluorescence intensity as a visual indicator of oxygen release. Full article

Hypoxia is one of the most important factors limiting the effectiveness of modern anticancer therapies, particularly photodynamic therapy (PDT). The hypoxia of the tumor microenvironment results from abnormal angiogenesis and the high metabolic demand of cancer cells, which leads to reduced oxygen availability necessary for generating reactive oxygen species (ROS). Consequently, conventional therapeutic approaches, mainly based on the type II PDT mechanism, show limited effectiveness under hypoxic conditions. In response to these limitations, strategies are being developed to increase oxygen availability within the tumor. Of particular importance are nanocarriers based on perfluorocarbons (PFCs), which, due to their high gas solubility, can effectively transport and release oxygen in the tumor microenvironment. Research indicates that the use of such systems leads to improved PDT efficiency by increasing the production of singlet oxygen and enhancing cancer cell damage. Parallelly, alternative approaches independent of high oxygen concentration, including type I photosensitizers, are being developed. Unlike classical type II mechanisms, they generate free radicals through electron transfer reactions, which allows effective action even under conditions of significant hypoxia. This approach significantly expands the possibilities of using PDT in the treatment of tumors with low oxygen levels. Current research directions focus on integrating various therapeutic strategies to achieve a synergistic effect. Hybrid systems combining oxygen delivery (e.g., using PFCs) with the use of type I photosensitizers and other treatment methods, such as chemotherapy or immunotherapy, show the greatest clinical potential. Such multifunctional approaches simultaneously allow improving tumor oxygenation and increasing the efficiency of ROS generation, which makes them a promising strategy for the future of anticancer therapies. Full article

Hypoxia is a prevalent pathophysiological condition. Prolonged exposure to hypobaric hypoxia can lead to maladaptation, increasing the risk of chronic hypoxic diseases such as high-altitude polycythemia (HAPC). Dauricine, an alkaloid derived from the root of Menispermum dauricum DC, has been demonstrated to possess anti-hypoxic properties; however, its underlying molecular mechanisms remain elusive. In this study, a potential multi-target anti-hypoxic mechanism of dauricine was proposed and computationally evaluated using an integrated approach combining network pharmacology, molecular docking, and molecular dynamics simulations. Common targets between dauricine and hypoxia-related genes were identified through network pharmacology screening. A protein–protein interaction (PPI) network was constructed to identify core targets, followed by Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Molecular docking was subsequently employed to evaluate the binding affinities between dauricine and the candidate core targets, while molecular dynamics simulations were performed to assess the dynamic stability of the resulting complexes. Additionally, the drug-likeness and safety profiles of dauricine were assessed. The results suggest that dauricine may exert its anti-hypoxic effects by modulating candidate core targets, including ESR1, PIK3CA, and MTOR, and by acting on key signaling pathways such as PI3K-Akt, MAPK, and mTOR. This study provides a theoretical foundation for the further investigation of dauricine as a multi-target candidate for intervention in hypoxia and establishes a bioinformatics basis for subsequent experimental validation. Full article