Search Results (111)

The relationship between exercise and immune function has been widely studied, yet findings remain inconsistent regarding how different exercise modalities and intensities influence acute and chronic immunological responses. Previous reviews have often focused on single exercise types or limited outcomes, leaving a gap for an integrated synthesis. This narrative review aims to address this gap by summarizing and comparing immunological effects across aerobic exercise, resistance training, high-intensity interval training (HIIT), blood flow restriction (BFR), isometric exercise, mind–body interventions, and hypoxic training. A structured narrative approach was adopted. Literature published between January 2000 and December 2024 was searched in PubMed, Scopus, and Web of Science. Experimental and observational studies on humans and animal models were included, with study selection and data extraction performed by two reviewers. Findings were synthesized thematically by exercise modality to capture both acute and chronic immune responses. Twenty-four eligible studies were identified. Aerobic and mind–body exercises consistently demonstrated anti-inflammatory and immunoprotective effects, including increased IL-10 production, improved T cell profiles, and reduced inflammatory markers. Isometric training showed favorable modulation of cytokines and T cell balance, while resistance training evidence was limited but suggested cortisol-lowering benefits. HIIT, BFR, and hypoxic exercise produced mixed results, often combining transient pro-inflammatory responses with immunological benefits. Acute and chronic immunological responses to exercise are highly modality- and intensity-dependent. Aerobic and mind–body interventions provide the most consistent benefits, whereas HIIT, BFR, and hypoxic training show variable effects. Further high-quality trials are needed to clarify mechanisms and guide exercise-based immune recommendations. Full article

Magnesium (Mg) alloys, particularly Mg AZ31, have emerged as promising biomaterials for orthopedic applications due to their biodegradability and favorable mechanical characteristics. Among these, the Mg AZ31+SPF alloy, subjected to hydrothermal (HT) treatment, has demonstrated enhanced bioactivity. Our previous research established that this surface modification supports the osteogenic differentiation of human mesenchymal stem cells (hMSCs) by modulating both canonical and non-canonical signaling pathways, including those implicated in osteogenesis, hypoxic response, exosome biogenesis, and lipid metabolism. In the present study, we extended our investigation to assess the effects of Mg AZ31+SPF+HT and Mg AZ31+SPF extracts on murine pre-osteoclasts (RAW 264.7 cells) over 3- and 6-day treatment periods. The primary objectives were to evaluate biocompatibility and to investigate potential impacts on osteoclastogenesis induction and miRNA expression profiles. Methods: To assess cytocompatibility, metabolic activity, DNA integrity, and morphological alterations in RAW 264.7 cells were evaluated. Osteoclast differentiation was quantified using TRAP staining, alongside the assessment of osteoclastogenic marker expression by qRT-PCR and ELISA. The immunomodulatory properties of the extracts were examined using multiplex BioPlex assays to quantify soluble factors involved in bone healing. Additionally, global miRNA expression profiling was performed using a specialized panel targeting 82 microRNAs implicated in bone remodeling and inflammatory signaling. Results: Mg AZ31+SPF+HT extract exhibited high biocompatibility, with no observable adverse effects on cell viability. Notably, a significant reduction in the number of TRAP-positive and multinucleated cells was observed relative to the Mg AZ31+SPF group. This effect was corroborated by the downregulation of osteoclast-specific gene expression and decreased MMP9 protein levels. Cytokine profiling indicated that Mg AZ31+SPF+HT extract promoted an earlier release of key cytokines involved in maintaining the balance between bone formation and resorption, suggesting a beneficial role in bone healing. Furthermore, miRNA profiling revealed a distinct regulatory signature in Mg AZ31+SPF+HT-treated cells, with differentially expressed miRNAs associated with inflammation, osteoclast differentiation, apoptosis, bone resorption, hypoxic response, and metabolic processes compared to Mg AZ31+SPF-treated cells. Conclusions: Collectively, these findings indicate that hydrothermal treatment of Mg AZ31+SPF (resulting in Mg AZ31+SPF+HT) attenuates pre-osteoclast activation by influencing cellular morphology, gene and protein expression, as well as post-transcriptional regulation via modulation of miRNAs. The preliminary identification of miRNAs and the activation of their regulatory networks in pre-osteoclasts exposed to hydrothermally treated Mg alloy are described herein. In the context of orthopedic surgery—where balanced bone remodeling is imperative—our results emphasize the dual significance of promoting bone formation while modulating bone resorption to achieve optimal implant integration and ensure long-term bone health. Full article

Adipose tissue enlargement in obesity leads to hypoxia, which may promote premature aging. This study aimed to understand the hypoxic response in 3D cultures of SGBS cells, a model for brown-like adipose tissue expressing uncoupling protein 1 (UCP1). Single-nucleus RNA sequencing of SGBS organoids revealed a heterogeneous composition and sub-population-specific responses to hypoxia. The analysis identified a cluster of transcriptional repression, indicating dying cells, and implied a role of ferroptosis in this model. Further experiments with SGBS cells and white adipose tissue-derived stem/progenitor cells showed that Acyl-CoA synthetase long-chain family member 4 (ACSL4), a key enzyme in ferroptosis, is expressed only in the presence of browning factors. Hypoxia downregulated ACSL4 protein in SGBS organoids but induced an inflammaging phenotype. Analysis of brown-like epicardial adipose tissue from cardiac surgery patients revealed a significant positive correlation of ACSL4 mRNA with UCP1 and hypoxia-inducible pro-inflammatory markers, while ACSL4 protein appeared to be inversely correlated. In conclusion, this study demonstrates that adipocytes’ capability to undergo ACSL4-mediated ferroptosis is linked to brown-like adipogenesis, suggesting an opportunity to modulate ferroptotic signaling in adipose tissue. The dual role of hypoxia by inhibiting ACSL4 but promoting inflammaging indicates a relationship between ferroptosis and aging that warrants further investigation. Full article

Cytokine storm (CS) is associated with poor prognosis in COVID-19 patients. Hypoxic signaling has been proposed to influence proinflammatory pathways and to be involved in the development of CS. Here, for the first time, the role of hypoxia in coronavirus-mediated inflammation has been investigated, using transcriptomic and proteomic approaches. Analysis of the transcriptome of A549 lung epithelial cells using RNA sequencing revealed 191 mRNAs which were synergistically upregulated and 43 mRNAs which were synergistically downregulated by the combination of human Betacoronavirus OC43 (HCoV-OC43) infection and hypoxia. Synergistically upregulated mRNAs were strongly associated with inflammatory pathway activation. Analysis of the expression of 105 cytokines and immune-related proteins using antibody arrays identified five proteins (IGFBP-3, VEGF, CCL20, CD30, and myeloperoxidase) which were markedly upregulated in HCoV-OC43 infection in hypoxia compared to HCoV-OC43 infection in normal oxygen conditions. Our findings show that COVID-19 patients with lung hypoxia may face increased risk of inflammatory complications. Two of the proteins we have identified as synergistically upregulated, the cytokines VEGF and CCL20, represent potential future therapeutic targets. These could be targeted directly or, based on the novel findings described here by inhibiting hypoxia signaling pathways, to reduce excessive inflammatory cytokine responses in patients with severe infections. Full article

RKIP and LKB1, encoded by PEBP1 and STK11, respectively, have emerged as key regulators of cancer pathophysiology. However, their role in shaping tumor progression through modulation of the tumor microenvironment (TME) is not yet fully understood. To address this, we performed a comprehensive pan-cancer analysis using TCGA transcriptomic data across 33 cancer types, grouped by their tissue of origin. We investigated PEBP1/STK11 co-expression and its association with transcriptomic reprogramming in major TME components, including immune, mechanical, metabolic, and hypoxic subtypes. Our results revealed both positive and inverse correlations between PEBP1/STK11 co-expression and TME-related molecular signatures, which did not align with classical cancer categorizations. In a subset of tumors, PEBP1/STK11 co-expression was significantly associated with improved overall survival and reduced mortality (HR < 1). Notably, we predominantly observed inverse correlations with pro-inflammatory and immunosuppressive chemokines, immune checkpoints, extracellular matrix components, and key regulators of epithelial-to-mesenchymal transition. In contrast, we found positive associations with anti-inflammatory chemokines and their receptors. Importantly, PEBP1/STK11 co-expression was consistently linked to reduced expression of drug resistance genes and greater chemosensitivity across multiple tumor types. Our findings underscore the co-expression of PEBP1 and STK11 as a promising target for future studies aimed at elucidating its potential as a biomarker for prognosis and therapeutic response in precision oncology. Full article

Objectives: Saffron, a traditional Chinese medicine, is renowned for its pharmacological effects in promoting blood circulation, resolving blood stasis, regulating menstruation, detoxification, and alleviating mental disturbances. Trans-crocetin, its principal bioactive component, exhibits significant anti-hypoxic activity. The clinical development and therapeutic efficacy of trans-crocetin are limited by its instability, poor solubility, and low bioavailability. Conversion of trans-crocetin into trans-sodium crocetinate (TSC) enhances its solubility, stability, and bioavailability, thereby amplifying its anti-hypoxic potential. Methods: This study integrates network pharmacology with in vivo and in vitro validation to elucidate the molecular targets and mechanisms underlying TSC’s therapeutic effects against high-altitude acute lung injury (HALI), aiming to identify novel treatment strategies. Results: TSC effectively reversed hypoxia-induced biochemical abnormalities, ameliorated lung histopathological damage, and suppressed systemic inflammation and oxidative stress in HALI rats. In vitro, TSC mitigated CoCl₂-induced hypoxia injury in human pulmonary microvascular endothelial cells (HPMECs) by reducing inflammatory cytokines, oxidative stress, and ROS accumulation while restoring mitochondrial membrane potential. Network pharmacology and pathway analysis revealed that TSC primarily targets the EGFR/PI3K/AKT/NF-κB signaling axis. Molecular docking and dynamics simulations demonstrated stable binding interactions between TSC and key components of this pathway. ELISA and RT-qPCR confirmed that TSC significantly downregulated the expression of EGFR, PI3K, AKT, NF-κB, and their associated mRNAs. Conclusions: TSC alleviates high-altitude hypoxia-induced lung injury by inhibiting the EGFR/PI3K/AKT/NF-κB signaling pathway, thereby attenuating inflammatory responses, oxidative stress, and restoring mitochondrial function. These findings highlight TSC as a promising therapeutic agent for HALI. Full article

Acute lung injury (ALI), a life-threatening clinical syndrome with multifactorial origins, is characterized by uncontrolled pulmonary inflammation and disrupted alveolar–capillary barrier integrity, leading to progressive hypoxemia and respiratory failure. In this hypoxic setting, hypoxia-inducible factor (HIF)-1 is activated, acting as a central regulator of the inflammatory response and reparative processes in injured lung tissue during ALI. The role of HIF-1 is distinctly dualistic; it promotes both anti-inflammatory and reparative mechanisms to a certain extent, while potentially exacerbating inflammation, thus having a complex impact on disease progression. We explore the latest understanding of the role of hypoxia/HIF-mediated inflammatory and reparative pathways in ALI and consider the potential therapeutic applications of drugs targeting these pathways for the development of innovative treatment strategies. Therefore, this review aims to guide future research and clinical applications by emphasizing HIF-1 as a key therapeutic target for ALI. Full article

Background and Objectives: Chronic mucosal infection with Helicobacter pylori (H. pylori) plays a key role in the development of gastroduodenal disorders such as chronic gastritis, peptic ulcers, gastric lymphoma, and gastric cancer by triggering local immune responses and inducing hypoxic and inflammatory conditions in the gastric mucosa. This study aims to evaluate the potential diagnostic value of hypoxia-inducible factors HIF-1α and HIF-2α, along with transmembrane prolyl 4-hydroxylase (P4H-TM), as biomarkers in H. pylori-positive patients. Additionally, the study investigates the association between these markers and alterations in lipid profiles, as well as their involvement in the molecular mechanisms underlying gastric conditions like gastritis, particularly in the context of H. pylori infection. Materials and Methods: This study was conducted at Istanbul Avcılar Murat Kölük State Hospital’s General Surgery Outpatient Clinic. A total of 60 participants were included: 40 patients diagnosed with chronic gastritis (20 H. pylori-positive and 20 H. pylori-negative) and 20 healthy controls confirmed negative by 13C-urea breath test. Blood samples were collected for ELISA analysis of HIF-1α, HIF-2α, and P4H-TM levels. Additionally, lipid profiles were measured and compared among the groups. Results: No significant differences were found among the groups in terms of demographic factors such as age, sex, or body mass index (BMI). However, significant variations were observed in the levels of HIF-1α, HIF-2α, and P4H-TM across all groups (p < 0.001 for each marker). These markers were substantially elevated in the H. pylori-positive gastritis group compared to both the H. pylori-negative and healthy control groups. Receiver Operating Characteristic (ROC) curve analysis revealed that all evaluated markers exhibited strong diagnostic accuracy in differentiating H. pylori-positive individuals from other groups. HIF-1α (AUC: 0.983) and HIF-2α (AUC: 0.981) both achieved 100% sensitivity with specificities of 93.3% and 91.1%, respectively. P4H-TM showed an AUC of 0.927, with 85% sensitivity and 95.6% specificity. Conclusions: These findings indicate that HIF-1α, HIF-2α, and P4H-TM may serve as effective biomarkers for diagnosing H. pylori-positive patients and may be linked to changes in lipid metabolism. The elevated expression of these markers in response to H. pylori infection highlights their potential roles in the inflammatory and hypoxic pathways that contribute to the pathogenesis of gastric diseases such as gastritis. Full article

Reactive oxygen species (ROS) play a dual role in cancer progression, acting as both signaling molecules and drivers of oxidative damage. Emerging evidence highlights the intricate interplay between ROS, microRNAs (miRNAs), and exosomes within the tumor microenvironment (TME), forming a regulatory axis that modulates immune responses, angiogenesis, and therapeutic resistance. In particular, oxidative stress not only stimulates exosome biogenesis but also influences the selective packaging of redox-sensitive miRNAs (miR-21, miR-155, and miR-210) via RNA-binding proteins such as hnRNPA2B1 and SYNCRIP. These miRNAs, delivered through exosomes, alter gene expression in recipient cells and promote tumor-supportive phenotypes such as M2 macrophage polarization, CD8⁺ T-cell suppression, and endothelial remodeling. This review systematically explores how this ROS–miRNA–exosome axis orchestrates communication across immune and stromal cell populations under hypoxic and inflammatory conditions. Particular emphasis is placed on the role of NADPH oxidases, hypoxia-inducible factors, and autophagy-related mechanisms in regulating exosomal output. In addition, we analyze the therapeutic relevance of natural products and herbal compounds—such as curcumin, resveratrol, and ginsenosides—which have demonstrated promising capabilities to modulate ROS levels, miRNA expression, and exosome dynamics. We further discuss the clinical potential of leveraging this axis for cancer therapy, including strategies involving mesenchymal stem cell-derived exosomes, ferroptosis regulation, and miRNA-based immune modulation. Incorporating insights from spatial transcriptomics and single-cell analysis, this review provides a mechanistic foundation for the development of exosome-centered, redox-modulating therapeutics. Ultimately, this work aims to guide future research and drug discovery efforts toward integrating herbal medicine and redox biology in the fight against cancer. Full article

In this study, we developed a novel theranostic nanomedicine formulation that integrates multimodal imaging with controlled drug release in reactive oxygen species (ROS)-rich microenvironments. A fluorinated oxalate compound (FOC) was synthesized through a one-step condensation reaction between 1,1,1,3,3,3-hexafluoro-2-propanol and oxalyl chloride, characterized by ¹H, ¹³C, and ¹⁹F NMR spectroscopy. The FOC and luminophore-incorporated nanomedicine formulations reacted rapidly with hydrogen peroxide via the peroxyoxalate chemiluminescence (POCL) mechanism, producing strong chemiluminescence and inducing a notable 19-fold increase in ratiometric ¹⁹F NMR signal upon conversion to fluorinated alcohol (FAH), demonstrating promising potential for high-contrast ¹⁹F MRI in deep tissue. Following ROS stimulation, the chemical conversion from hydrophobic FOC to hydrophilic FAH led to the degradation of the nanomedicines, facilitating payload release. In vitro experiments with A-431 cancer cells under hypoxic conditions confirmed ROS-responsive drug release, evidenced by enhanced fluorescence from model luminophores. Additionally, doxorubicin-loaded FOC nanomedicines reduced cell viability to 32% under hypoxia while remaining non-toxic in normoxic conditions. These results indicate that FOC-based nanomedicine formulations provide a promising platform for combined chemiluminescence and ¹⁹F MRI with targeted therapeutic efficacy in ROS-rich inflammatory and cancerous tissues. Full article

The disruption of microglial homeostasis and cytokine release are critical for neuroinflammation post-injury and strongly implicated in retinal neurodegenerative diseases like glaucoma. This study examines microglial responses to chemical hypoxia induced by cobalt chloride (CoCl₂) in BV-2 murine microglial cells, focusing on signaling pathways and proteomic alterations. We assessed the protective effects of monoclonal antibodies against TNFα and IL-1β. CoCl₂ exposure led to decreased cell viability, reduced mitochondrial membrane potential, increased lactate dehydrogenase release, elevated reactive oxygen species generation, and activation of inflammatory pathways, including nitric oxide synthase (iNOS), STAT1, and NF-κB/NLRP3. These responses were significantly mitigated by treatment with anti-TNFα and anti-IL-1β, suggesting their dual role in reducing microglial damage and inhibiting inflammatory reactivity. Additionally, these treatments reduced apoptosis by modulating ATF4 and the p38 MAPK/caspase-3 pathways. Label-free quantitative mass spectrometry-based proteomics and Gene Ontology revealed that CoCl₂ exposure led to the upregulation of proteins primarily involved in endoplasmic reticulum and catabolic processes, while downregulated proteins are associated with biosynthesis. Anti-TNFα and anti-IL-1β treatments partially restored the proteomic profile toward normalcy, with network analysis identifying heat shock protein family A member 8 (HSPA8) as a central mediator in recovery. These findings offer insights into the pathogenesis of hypoxic microglial impairment and suggest potential therapeutic targets. Full article

Background: The majority of gliomas are astrocytic in nature. Gliomas have the lowest survival rate among all tumors of the central nervous system (CNS), characterized by high aggressiveness and poor response to treatment. The tumor microenvironment is a source of cytokines such as IL-6, IFN-γ, VEGF, and PDGF-BB, secreted mainly by tumor and immune cells. These cytokines play a significant role in angiogenesis, invasion, and metastasis formation. In vitro and in vivo studies have shown that Brazilian green propolis, derived from Baccharis dracunculifolia DC and rich in artepillin C, exhibits anti-inflammatory, antimicrobial, chemopreventive, and anticancer activities. Additionally, it can penetrate the blood–brain barrier, demonstrating neuroprotective effects. The aim of the present study was to determine the concentration of selected cytokines produced by astrocytes of the CCF-STTG1 cell line, isolated from the brain of a patient with stage IV glioma (astrocytoma). Methods: The cytotoxicity of the EEP-B was evaluated using the MTT assay. Astrocytes were stimulated with LPS at a final concentration of 200 ng/mL and/or IFN-α at 100 U/mL, followed by incubation with EEP-B (25–50 µg/mL) and artepillin C (25–50 µg/mL) under 2-h hypoxia and normoxia conditions. Cytokine concentrations were measured using the xMAP Luminex Multiplex Immunoassay and the Multiplex Bead-Based Cytokine kit. Results: The absence of cytotoxic effects of EEP-B and artepillin C on human astrocytes of the CCF-STTG1 lineage was demonstrated. Stimulation with LPS, IFN-α, and their combination (LPS + IFN-α) significantly increased the secretion of the tested cytokines compared to the control cell line. The most pronounced and statistically significant reduction in cytokine levels, particularly IL-6 and VEGF, was observed following EEP-B treatment at both tested concentrations under both hypoxic and normoxic conditions. Conclusions: Brazilian green propolis may serve as a potential immunomodulator in combination therapies for gliomas of varying malignancy grades. Full article

Background/Objectives: The chronic metabolic condition of hyperglycemia in type-2 diabetics is known to cause various neurological disorders and compromise recovery from brain insults. Previously, we reported a delayed and reduced glial cell response and a greater neuronal cell death in different brain regions of diabetic, db/db, mice following cerebral hypoxic- ischemic injury. In this study, we explored the changes in baseline activation of astrocytes and microglia and its impact on vascular permeability in different brain regions. Methods: The numbers of activated astrocytes (GFAP-positive) and microglia/macrophage (Iba-1-positive) in the motor cortex, caudate and hippocampal regions of 12-week old, type-2 diabetic db/db and non-diabetic db/+ mice were quantitated. The leakage of serum IgG and loss of occludin, a tight junctional protein observed in the cortex and caudate of db/db mice, indicated a compromised blood brain barrier. Results: Results indicated significant differences in activation of glial cells in the cortex and caudate along with increased vessel permeability in diabetic mice. Conclusions: The study suggests that a constant activation of glial cells in the diabetic brain may be the cause of impaired inflammatory response and/or degenerating cerebral blood vessels which contribute to neuronal cell death upon CNS injury. Full article

Neonatal encephalopathy suspected to be due to hypoxic ischaemic encephalopathy (NESHIE) carries the risk of death or severe disability (cognitive defects and cerebral palsy). Previous genetic studies on NESHIE have predominantly focused on exomes or targeted genes. The objective of this study was to identify genetic variants associated with moderate–severe NESHIE through whole-genome, unbiased analysis. Variant filtering and prioritization were performed, followed by association testing both on a case–control basis and to compare the grades of severity and/or progression. Association testing on neonates with NESHIE (N = 172) and ancestry-matched controls (N = 288) produced 71 significant genetic variants (false discovery rate corrected p-value < 6.2 × 10⁻⁴), all located in non-coding regions and not previously implicated in NESHIE. Disease-associated variants in non-coding regions are considered to affect regulatory functions, possibly by modifying gene expression, promoters, enhancers, or DNA structure. The most significant variant was at position 6:162010973 in the Parkin RBR E3 ubiquitin protein ligase (PRKN) intron. Intronic variants were also identified in genes involved in inflammatory processes (SLCO3A1), DNA repair (ZGRF1), synaptogenesis (CNTN5), haematopoiesis (ASXL2), and the transcriptional response to hypoxia (PADI4). Ten variants were associated with a higher severity or lack of improvement in NESHIE, including one in ADAMTS3, which encodes a procollagen amino protease with a role in angiogenesis and lymphangiogenesis. This analysis represents one of the first efforts to analyze whole-genome data to investigate the genetic complexity of NESHIE in diverse ethnolinguistic groups of African origin and provides direction for further study. Full article

Ophthalmic diseases such as glaucoma, age-related macular degeneration (ARMD), and optic neuritis involve complex molecular and cellular disruptions that challenge current diagnostic and therapeutic approaches. Advanced artificial intelligence (AI) and machine learning (ML) models offer a novel lens to analyze these diseases by integrating diverse datasets, identifying patterns, and enabling precision medicine strategies. Over the past decade, applications of AI in ophthalmology have expanded from imaging-based diagnostics to molecular-level modeling, bridging critical gaps in understanding disease mechanisms. This paper systematically reviews the application of AI-driven methods, including reinforcement learning (RL), graph neural networks (GNNs), Bayesian inference, and generative adversarial networks (GANs), in the context of these ophthalmic conditions. RL models simulate transcription factor dynamics in hypoxic or inflammatory environments, offering insights into disrupted molecular pathways. GNNs map intricate molecular networks within affected tissues, identifying key inflammatory or degenerative drivers. Bayesian inference provides probabilistic models for predicting disease progression and response to therapies, while GANs generate synthetic datasets to explore therapeutic interventions. By contextualizing these AI tools within the broader framework of ophthalmic disease management, this review highlights their potential to transform diagnostic precision and therapeutic outcomes. Ultimately, this work underscores the need for continued interdisciplinary collaboration to harness AI’s potential in advancing the field of ophthalmology and improving patient care. Full article