Search Results (319)

The retina is highly sensitive to oxygen and blood supply, and hypoxia plays a key role in retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Müller glial cells, which are essential for retinal homeostasis, respond to injury and hypoxia with reactive gliosis, characterized by the upregulation of the glial fibrillary acidic protein (GFAP) and vimentin, cellular hypertrophy, and extracellular matrix changes, which can impair retinal function and repair. The retinal pigment epithelium (RPE) supports photoreceptors, forms part of the blood–retinal barrier, and protects against oxidative stress; its dysfunction contributes to retinal degenerative diseases such as AMD, retinitis pigmentosa (RP), and Stargardt disease (SD). Extracellular vesicles (EVs) play a crucial role in intercellular communication, protein homeostasis, and immune modulation, and have emerged as promising diagnostic and therapeutic tools. Understanding the role of extracellular vesicles’ (EVs’) signaling machinery of glial cells and the retinal pigment epithelium (RPE) is critical for developing effective treatments for retinal degeneration. In this study, we investigated the bidirectional EV-mediated crosstalk between RPE and Müller cells under hypoxic conditions and its impact on cellular metabolism and retinal cell integrity. Our findings demonstrate that RPE-derived extracellular vesicles (RPE EVs) induce time-dependent metabolic reprogramming in Müller cells. Short-term exposure (24 h) promotes pathways supporting neurotransmitter cycling, calcium and mineral absorption, and glutamate metabolism, while prolonged exposure (72 h) shifts Müller cell metabolism toward enhanced mitochondrial function and ATP production. Conversely, Müller cell-derived EVs under hypoxia influenced RPE metabolic pathways, enhancing fatty acid metabolism, intracellular vesicular trafficking, and the biosynthesis of mitochondrial co-factors such as ubiquinone. Proteomic analysis revealed significant modulation of key regulatory proteins. In Müller cells, hypoxic RPE-EV exposure led to reduced expression of Dyskerin Pseudouridine Synthase 1 (DKc1), Eukaryotic Translation Termination Factor 1 (ETF1), and Protein Ser/Thr phosphatases (PPP2R1B), suggesting alterations in RNA processing, translational fidelity, and signaling. RPE cells exposed to hypoxic Müller cell EVs exhibited elevated Ribosome-binding protein 1 (RRBP1), RAC1/2, and Guanine Nucleotide-Binding Protein G(i) Subunit Alpha-1 (GNAI1), supporting enhanced endoplasmic reticulum (ER) function and cytoskeletal remodeling. Functional assays also revealed the compromised barrier integrity of the outer blood–retinal barrier (oBRB) under hypoxic co-culture conditions. These results underscore the adaptive but time-sensitive nature of retinal cell communication via EVs in response to hypoxia. Targeting this crosstalk may offer novel therapeutic strategies to preserve retinal structure and function in ischemic retinopathies. Full article

Diabetic wounds are a devastating complication that cause chronic pain, recurrent infections, and limb amputations due to impaired healing. Despite advances in wound care, existing therapies often fail to address the underlying molecular dysregulation, highlighting the need for innovative and safe therapeutic approaches. Among these, D-amino acids such as D-tryptophan (D-Trp) have emerged as key regulators of cellular processes; however, their therapeutic potential in diabetic wounds remains largely unexplored. Here, we investigate the therapeutic potential of D-Trp in streptozotocin (STZ)-induced diabetic mice, comparing it with phosphate-buffered saline (PBS) controls and vascular endothelial growth factor (VEGF) as a positive control. Wound healing, inflammation, and histopathology were assessed. Protein and gene expression were analyzed via Western blot and RT-qPCR, respectively. Biolayer interferometry (BLI) measured the binding of D-Trp to hypoxia-inducible factor-1α (HIF-1α). D-Trp accelerated wound healing by modulating extracellular matrix (ECM) remodeling, signaling, and apoptosis. It upregulated matrix metalloproteinases (MMP1, MMP3, MMP-9), Janus kinase 2 (JAK2), and mitogen-activated protein kinase (MAPK) proteins while reducing pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], IL-6). D-Trp also suppressed caspase-3 and enhanced angiogenesis through HIF-1α activation. These findings suggest that D-Trp promotes healing by boosting ECM turnover, reducing inflammation, and activating MAPK/JAK pathways. Thus, D-Trp is a promising therapeutic for diabetic wounds. Full article

Belzutifan is a hypoxia-inducible factor-2α (HIF-2α) inhibitor that received FDA approval in 2021 for treating cancers resulting from von Hippel-Lindau (VHL) disease, including clear cell renal cell carcinoma (ccRCC), followed by approval in 2023 for sporadic ccRCC that has progressed through multiple lines of therapy. HIF-2α is a promising drug target, as VHL is commonly inactivated in ccRCC, which results in HIF-2α-mediated signaling that is considered central to tumorigenesis. Belzutifan has demonstrated efficacy in clinical trials in the first-line and subsequent line settings, and in combination with tyrosine kinase inhibitors. Despite being overall well tolerated, belzutifan has a distinct safety profile because of its unique mechanism of action. Anemia was the most common adverse event observed in clinical trials and is considered an on-target effect. Hypoxia is also frequently observed and commonly results in dose reductions, treatment discontinuation, and supplemental oxygen use. This review summarizes the rates of hypoxia seen in clinical trials of belzutifan in ccRCC. As the cause of hypoxia is not well understood, this review also discusses possible mechanisms of hypoxia based on preclinical studies of the HIF pathway and HIF-2α inhibitors. Finally, this review proposes monitoring and management recommendations for clinicians prescribing belzutifan to ccRCC patients. Full article

Background: Astrocytes are not only structural cells but also play a pivotal role in neurogenesis and neuroprotection by secreting a variety of neurotrophic factors that support neuronal survival, growth, and repair. This study investigates the time-dependent responses of primary rat cortical astrocytes to oxygen–glucose deprivation (OGD) and evaluates the neuroprotective potential of astrocyte-conditioned medium (ACM). Methods: Primary rat cortical astrocytes and neurons were obtained from postnatal Sprague Dawley rat pups (P1–3) and embryos (E17–18), respectively. Astrocytes exposed to 6, 24, and 48 h of OGD (0.3% O₂) were assessed for viability, metabolic function, hypoxia-inducible factor 1 and its downstream genes expression. Results: While 6 h OGD upregulated protective genes such as Vegf, Glut1, and Pfkfb3 without cell loss, prolonged OGD, e.g., 24 or 48 h, led to significant astrocyte death and stress responses, including elevated LDH release, reduced mitochondrial activity, and increased expression of pro-apoptotic marker Bnip3. ACM from 6 h OGD-treated astrocytes significantly enhanced neuronal survival following 6 h OGD and 24 h reperfusion, preserving dendritic architecture, improving mitochondrial function, and reducing cell death. This protective effect was not observed with ACM from 24 h OGD astrocytes. Furthermore, 6 h OGD-ACM induced autophagy in neurons, as indicated by elevated LC3b-II and decreased p62 levels, suggesting autophagy as a key mechanism in ACM-mediated neuroprotection. Conclusions: These findings demonstrate that astrocytes exhibit adaptive, time-sensitive responses to ischemic stress and secrete soluble factors that can confer neuroprotection. This study highlights the therapeutic potential of targeting astrocyte-mediated signalling pathways to enhance neuronal survival following ischemic stroke. Full article

Background: The retina, a light-sensitive tissue of the central nervous system that is located at the posterior part of the eye, is particularly vulnerable to alterations in oxygen levels. In various retinal diseases, such as central retinal vein occlusion, glaucoma, and diabetic retinopathy, hypoxia (a condition of low oxygen levels) is commonly observed. Müller glia, the principal glial cells in the retina, play a crucial role in supporting the metabolic needs of retinal neurons. They are also responsible for sensing oxygen levels and, in response to hypoxia, express Hypoxia-Inducible Factor 1 (HIF-1), a transcription factor that activates signaling pathways related to hypoxia. Methods: In this study, primary rat Müller glial cells were cultured and exposed to a 1% oxygen for 72 h. Following this, immunohistochemical assays were conducted to assess the effects of hypoxia on various parameters, including HIF-1α expression, cell survival, Müller glia-specific markers (CRALBP and GS), gliosis (GFAP expression), apoptosis (caspase-3 expression), cell proliferation (Ki-67 expression), and metabolic stress (indicated by the number of mitochondria per cell). Results: Under hypoxic conditions, a decrease in Müller glial survival and proliferation was observed. Conversely, there was an increase in HIF-1α expression, GFAP expression, caspase-3-positive cells, and the number of mitochondria per cell. However, no significant changes were noted in the expression of the Müller glial markers GS and CRALBP. Conclusions: In conclusion, hypoxia resulted in reduced proliferation and survival of Müller glial cells, primarily due to increased apoptosis and heightened metabolic stress. Full article

The hypothalamic-pituitary-adrenal (HPA) axis plays an important regulatory role in inflammatory responses to systemic or local infection in the host. A high-calorie diet, which can aggravate pediatric pneumonia and delay recovery, is intimately associated with HPA axis disorder; however, its underlying mechanisms remain unknown. This study examined whether the mechanism by which a high-calorie diet aggravates pneumonia is related to HPA axis disorder. In this study, juvenile rats were fed a high-calorie diet and/or nebulized with lipopolysaccharide (LPS) for model construction. Our data shows that a high-calorie diet increases interleukin-1 beta(IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels in lung tissues and aggravates LPS-induced inflammatory injury in the lungs of juvenile rats. Additionally, we found that a high-calorie diet decreases the expression level of serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in juvenile rats with pneumonia, resulting in HPA axis disorder. Hypothalamus proteomics and Western blot results proved that a high-calorie diet upregulated the expression level of hypothalamus hypoxia-inducible factor-1 alpha (HIF-1α) in juvenile rats with pneumonia, and this mechanism is associated with reduced HIF-1α ubiquitination. We further observed that HPA axis disorder was significantly abated and inflammatory damage in rat lung tissues was significantly alleviated after in vivo HIF-1α pathway inhibition. This shows that pneumonia aggravation by a high-calorie diet is associated with interference in the HIF-1α-mediated HPA axis. A high-calorie diet boosts HIF-1α signaling in the hypothalamus and exacerbates LPS-induced pneumonia by disrupting the HPA axis. This sheds light on lung inflammation and strengthens the lung-brain connection. Full article

High-altitude pulmonary edema (HAPE) is a severe condition associated with high-altitude environments, and its molecular mechanism has not been fully elucidated. This study systematically analyzed the DNA methylation status of HAPE patients and healthy controls using reduced-representation bisulfite sequencing (RRBS) and 850K DNA methylation chips, identifying key differentially methylated regions (DMRs). Targeted bisulfite sequencing (TBS) revealed significant abnormalities in DMRs of five genes, azurocidin 1 (AZU1), growth factor receptor bound protein 7 (GRB7), mannose receptor C-type 2 (MRC2), RUNX family transcription factor 3 (RUNX3), and septin 9 (SEPT9). The abnormal expression of AZU1 was validated using peripheral blood leukocytes from HAPE patients and normal controls, as well as rat lung tissue, indicating its potential importance in the pathogenesis of HAPE. To further validate the function of AZU1, we conducted experimental studies using a hypobaric hypoxia injury model in Human Umbilical Vein Endothelial Cells (HUVEC). The results showed that AZU1 was significantly upregulated under hypobaric hypoxia. Knocking down AZU1 mitigates the reduction in HUVEC proliferation, angiogenesis, and oxidative stress damage induced by acute hypobaric hypoxia. AZU1 induces cellular oxidative stress via the p38/mitogen-activated protein kinase (p38/MAPK) signaling pathway. This study is the first to elucidate the mechanism of AZU1 in HAPE via the p38/MAPK pathway, offering novel insights into the molecular pathology of HAPE and laying a foundation for future diagnostic and therapeutic strategies. Full article

Background: Bladder cancer ranks ninth among the most commonly diagnosed cancers, with urothelial carcinoma (UC) accounting for more than 90% of all cases. Given the high recurrence rate and progression risk of bladder cancer, investigating alternative adjunct therapies is imperative. One potential candidate is isoliensinine, which has shown antitumor potential in various cancers; however, the effectiveness of isoliensinine on UC is largely unknown. Methods: In the present study, the effects of isoliensinine on UC cells were examined in a variety of in vitro experiments, including MTT assays, colony formation assays, flow cytometry assays, RNA sequencing analysis, and Western blotting. Results: The isoliensinine-treated T24 and UMUC3 UC cell lines showed cell growth inhibition and proliferation in the MTT and colony formation assays and an apoptotic effect in the flow cytometry assays. RNA sequencing analysis, performed to explain the underlying mechanisms, revealed a significant regulation of cell functions, including apoptosis, the cell cycle, hypoxia-inducible factor 1 (HIF-1) signaling, tumor necrosis factor (TNF) signaling, and ferroptosis. Subsequent Western blotting results verified all these findings. Conclusions: Overall, our data indicate that isoliensinine inhibits UC cell growth and proliferation by inducing apoptosis through alterations in the TNF and HIF1 pathways and ferroptosis. Overall, isoliensinine shows potential for use in new or combined adjunct therapies for the treatment of bladder cancer. Full article

Plateau environments present unique mental health challenges owing to stressors including hypoxia, low temperatures, and intense ultraviolet (UV) radiation. These factors induce structural and functional alterations in the gut microbiota, disrupting gut-brain axis homeostasis and contributing to the higher prevalence of depression in plateau regions relative to flatland areas. For example, studies report that 28.6% of Tibetan adults and 29.2% of children/adolescents on the Qinghai-Tibet Plateau experience depression, with increasing evidence linking this trend to alterations in the gut microbiota. Dysbiosis contributes to depression through three interconnected mechanisms: (1) Neurotransmitter imbalance: Reduced bacterial diversity impairs serotonin synthesis, disrupting emotional regulation. (2) Immune dysregulation: Compromised gut barrier function allows bacterial metabolites to trigger systemic inflammation via toll-like receptor signaling pathways. (3) Metabolic dysfunction: Decreased short-chain fatty acid levels weaken neuroprotection and exacerbate hypothalamic-pituitary-adrenal axis stress responses. Current interventions—including dietary fiber, probiotics, and fecal microbiota transplantation—aim to restore microbiota balance and increase short-chain fatty acids, alleviating depressive symptoms. However, key knowledge gaps remain in understanding the underlying mechanisms and generating population-specific data. In conclusion, existing evidence indicates an association between plateau environments, the gut microbiota, and depression, but causal relationships and underlying mechanisms require further empirical investigation. Integrating multiomics technologies to systematically explore interactions among high-altitude environments, the microbiota and the brain will facilitate the development of precision therapies such as personalized nutrition and tailored probiotics to protect mental health in high-altitude populations. Full article

Background: The hypoxia-inducible factor 1α (HIF-1α) pathway plays a key role in promoting glycolysis and tumor progression under hypoxic conditions in cancer cells. Purple potato (PP) extract, which is a polyphenol-rich natural product, has previously been shown to enhance mitochondrial function and suppress tumor growth in several cancer models. We hypothesized that PP extract could counteract hypoxia-induced glycolysis by targeting the HIF-1α pathway. Methods: Human colonic epithelial Caco-2 cells were treated with PP extract under hypoxic conditions, and its effects on glycolysis, oxidative phosphorylation, and HIF-1α signaling were evaluated. Results: Under hypoxia PP extract suppressed glycolysis, as evidenced by reduced lactate production and lower phosphorylated pyruvate dehydrogenase levels. In parallel, genes associated with oxidative phosphorylation were upregulated by PP extract, suggesting a metabolic shift under hypoxia. Additionally, PP extract reduced the protein accumulation of HIF-1α and its transcriptional activator XBP1 induced by hypoxia. Correspondingly, the expression of several HIF-1α downstream target genes, including Vegfa, Pdk1, Ldha, Hk1, and Glut1, was markedly reduced. Functionally, PP extract inhibited cell proliferation, migration, and drug resistance under hypoxic stress, indicating a broader inhibitory effect on hypoxia-driven malignant phenotypes. Conclusion: These findings suggest that PP extract disrupts cancer cell adaptation to hypoxia and supports its potential as a dietary approach against hypoxia-driven colorectal cancer, through further preclinical studies are warranted. Full article

Malignant tumors of the digestive system are widespread and pose a serious threat to humans. Immune escape is an important factor promoting the deterioration of malignant tumors in the digestive system. Natural killer cells (NK cells) are key members of the anti-tumor and immune surveillance system, mainly exerting cytotoxic effects by binding to the activating receptor natural killer cell group 2D (NKG2D) on their cell surface with the corresponding ligands (major histocompatibility complex class I chain-related protein A/B, MICA/B) on the surface of tumor cells. Malignant tumors of epithelial origin usually highly express NKG2D ligands such as MICA, which can attract NK cells to kill tumor cells and also serve as an important basis for NK cell-based immunotherapy. Tumor cells highly express hypoxia-inducible factor-1α (HIF-1α), which promotes the expression of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs). These metalloproteinases hydrolyze MICA and other ligands on the surface of tumor cells to generate soluble molecules. These soluble ligands, when binding to NKG2D, cannot activate NK cells and also block the binding of NKG2D to MICA on the surface of tumor cells, enabling tumor cells to evade the killing effect of NK cells. Almost all organs in the digestive system originate from epithelial tissue, so the soluble ligands generated by the HIF-1α/MMPs or HIF-1α/ADAMs signaling pathways play a crucial role in evading NK cell killing. A comprehensive understanding of this immune escape process is helpful for a deeper understanding of the molecular mechanism of NK cell anti-tumor activity. This article reviews the molecular mechanisms of common digestive system malignancies evading NK cell killing, providing new insights into the mechanism of tumor immune escape. Full article

Prenatal hypoxia (PH) adversely affects the development of the fetal heart, contributing to persistent cardiovascular impairments in postnatal life. A key component in regulating cardiac physiology is the nitric oxide (NO) system, which influences vascular tone, myocardial contractility, and endothelial integrity during development. Exposure to PH disrupts NO-related signaling pathways, leading to endothelial dysfunction, mitochondrial damage, and an escalation of oxidative stress—all of which exacerbate cardiac injury and trigger cardiomyocyte apoptosis. The excessive generation of reactive nitrogen species drives nitrosative stress, thereby intensifying inflammatory processes and cellular injury. In addition, the interplay between NO and hypoxia-inducible factor (HIF) shapes adaptive responses to PH. NO also modulates the synthesis of heat shock protein 70 (HSP70), a critical factor in cellular defense against stress. This review emphasizes the involvement of NO in cardiovascular injury caused by PH and examines the cardioprotective potential of NO modulators—Angiolin, Thiotriazoline, Mildronate, and L-arginine—as prospective therapeutic agents. These agents reduce oxidative stress, enhance endothelial performance, and alleviate the detrimental effects of PH on the heart, offering potential new strategies to prevent cardiovascular disorders in offspring subjected to prenatal hypoxia. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease with limited therapeutic options. This review focuses on the role of retinoids, particularly all-trans retinoic acid (atRA), and hypoxia in the pathogenesis of IPF. Despite an established understanding of genetic and environmental factors in IPF, the interplay between retinoid signaling and the response to hypoxia remains poorly explored due to its complexity. Preclinical evidence suggests that atRA could help reduce pulmonary fibrosis by modulating TGF-β signaling pathways and epithelial-to-mesenchymal transition (EMT). Additionally, we mention other diseases where a relationship between hypoxia and retinoids has been observed. We review how hypoxia, a key factor in the progression of IPF, may influence the efficacy of retinoid therapy. Combination strategies are explored to overcome hypoxia-induced treatment resistance. Finally, we address the complex role of retinoids in lung regeneration, balancing their potential benefits against the risk of exacerbating fibrotic processes. This review suggests that retinoids have potential as a treatment or adjuvant for IPF and highlights the need for further research to elucidate the precise mechanisms of retinoid action in IPF, particularly in hypoxia. Full article

Shock is a life-threatening condition characterized by inadequate tissue perfusion leading to systemic hypoxia and metabolic failure. Ischemia/reperfusion (I/R) injury exacerbates shock progression through oxidative stress and immune dysregulation, contributing to multi-organ dysfunction. This narrative review synthesizes current evidence on the interplay between I/R injury, oxidative stress, and immune modulation in shock states. We analyze the classification of shock, its progression, and the molecular pathways involved in ischemic adaptation, inflammatory responses, and oxidative injury. Shock pathophysiology is driven by systemic ischemia, triggering adaptive responses such as hypoxia-inducible factor (HIF) signaling and metabolic reprogramming. However, prolonged hypoxia leads to mitochondrial dysfunction, increased reactive oxygen species (ROS) and reactive nitrogen species (RNS) production, and immune activation. The transition from systemic inflammatory response syndrome (SIRS) to compensatory anti-inflammatory response syndrome (CARS) contributes to immune imbalance, further aggravating tissue damage. Dysregulated immune checkpoint pathways, including CTLA-4 and PD-1, fail to suppress excessive inflammation, exacerbating oxidative injury and immune exhaustion. The intricate relationship between oxidative stress, ischemia/reperfusion injury, and immune dysregulation in shock states highlights potential therapeutic targets. Strategies aimed at modulating redox homeostasis, controlling immune responses, and mitigating I/R damage may improve patient outcomes. Future research should focus on novel interventions that restore immune balance while preventing excessive oxidative injury. Full article

Endometriosis is a chronic gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus, leading to inflammation, pain, and infertility. Emerging evidence indicates that endometriotic lesions exhibit cancer-like properties, including metabolic reprogramming marked by increased glucose uptake, enhanced Warburg’s effect, and altered mitochondrial function. These metabolic adaptations support cell survival under hypoxic conditions and contribute to immune evasion and sustained proliferation. This review summarizes current findings on the molecular mechanisms driving metabolic reprogramming in endometriosis, including the roles of mitochondrial dysfunction, hypoxia-inducible factor (HIF) signaling, the PI3K/AKT/mTOR pathway, inflammatory cytokines, and genetic and epigenetic regulators. In addition, we discuss therapeutic strategies targeting glycolytic pathways using both synthetic inhibitors and natural compounds, which represent promising non-hormonal options. Finally, we highlight the need for further preclinical and clinical studies to validate metabolic interventions and improve outcomes for patients with endometriosis. Full article