Search Results (6,731)

Stem cell-derived extracellular vesicles (EVs) hold therapeutic potential for hypoxia-associated injury, yet the molecular mechanisms underlying their protective effects remain incompletely defined. Herein, we performed comparative proteomic profiling of extracellular vesicles (EVs) secreted by human placenta-derived perivascular stem cells (hPPSCs) and human umbilical cord mesenchymal stem cells (hUCMSCs). We found that hPPSCs-EVs are enriched in proteasome-related proteins. Enzymatic activity assays further confirmed that proteasome activity in hPPSCs-EVs was significantly higher than that in hUCMSCs-EVs. Additionally, we observed that hPPSCs-EVs were efficiently endocytosed by human umbilical vein endothelial cells (hUVECs), leading to marked downregulation of hypoxia-inducible factor 1-alpha (HIF-1α) and intracellular ubiquitinated proteins. Importantly, this HIF-1α degradation persisted even when the host ubiquitin–proteasome system was blocked, indicating that hPPSCs-EVs can function independently of the host proteasomal pathway. These results reveal that hPPSCs-EVs deliver functional proteasomes to endothelial cells, thereby compensating for impaired protein degradation and protecting cells under hypoxic stress. Collectively, our findings provide evidence for an intercellular transfer of proteolytic capacity via stem cell-derived EVs, a mechanism that preserves endothelial proteostasis and highlights the therapeutic potential of proteasome-rich EVs for hypoxia-associated diseases. Full article

Background and Objectives: In-hospital cardiac arrest (IHCA) in critically ill patients with COVID-19 is among the most severe clinical outcomes, associated with high mortality and a significant risk to healthcare workers during cardiopulmonary resuscitation (CPR). The aim of this study was to evaluate the incidence, characteristics, associated factors, and outcomes of IHCA among COVID-19 patients treated in the intensive care unit (ICU), with particular emphasis on resuscitation outcomes and survival. Materials and Methods: A retrospective cohort study was conducted including critically ill patients with confirmed SARS-CoV-2 infection treated in the ICU of the Clinical-Hospital Center (KBC) in Kosovska Mitrovica between March 2020 and December 2022. Patients were categorized into two groups: (1) CA group—patients who experienced CA in the ICU, and (2) non-CA group—patients who did not experience CA during ICU treatment. Results: A total of 222 patients were analyzed, of whom 114 (51.4%) experienced IHCA. Patients with IHCA were significantly older, more frequently obese, and had a higher burden of comorbidities. They also exhibited more pronounced hematological and inflammatory abnormalities, including lower erythrocyte and hemoglobin levels, thrombocytopenia, and elevated leukocyte counts, fibrinogen, C-reactive protein, and procalcitonin levels. In addition, higher lactate and D-dimer concentrations were observed, along with a more frequent occurrence of hyperkalemia and hypernatremia. The predominant cause of IHCA was respiratory failure, most commonly associated with severe hypoxemia (59.6%), while non-shockable initial rhythms (asystole and pulseless electrical activity (PEA)) were most common (76.3%). Among patients with IHCA, return of spontaneous circulation (ROSC) was achieved in 11 patients (9.6%), and 3 patients (2.6%) survived to hospital discharge. Conclusions: Despite rapid response and CPR in the ICU setting, outcomes remained poor. More favorable outcomes were observed mainly in cases with potentially reversible etiologies (such as myocardial infarction and pulmonary embolism (PE)), in contrast to hypoxia-mediated CA. Full article

Summer hypoxia in the bottom water of the Bohai Sea is accompanied by marked changes in water-column structure and nutrient conditions, which may affect ammonia-oxidizing microorganisms and thus alter nitrification-related nitrogen cycling. To examine these responses, seawater samples were collected along an inshore–offshore transect from the coastal waters off Qinhuangdao City to the central Bohai Sea in June, July, and August 2018. Surface, middle, and bottom waters were sampled, and physicochemical variables, including temperature, salinity, dissolved oxygen (DO), and inorganic nitrogen concentrations, were measured. Ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) were then analyzed using amoA amplicon sequencing to compare their diversity, community structure, genus-level composition, and dominant OTU patterns. From June to August, along with temperature increase, the water column showed stronger stratification and oxygen depletion in the bottom water, together with shifts in salinity and inorganic nitrogen distributions. AOA and AOB showed different temporal responses. AOA diversity surpassed that of AOB in July, but AOB became more diverse in August. Principal coordinates analysis showed clear separation of AOA communities between July and August, and sampling month had a significant effect on AOA community structure (PERMANOVA, p = 0.009). In contrast, AOB communities did not show significant month-related separation (p = 0.157). According to environmental fitting analysis, AOA community structure was predominantly associated with temperature and salinity, with only a marginal link to NH₄⁺, while pH and salinity were the key factors shaping AOB communities. At the genus level, AOA was dominated by Nitrosopumilus and AOB was dominated by Nitrosospira. Overall, the results indicate that AOA showed stronger temporal variation than AOB during the development of summer hypoxia in seawater of Bohai Sea. Full article

Panvascular diseases, characterized by systemic vascular dysfunction across multiple organ systems, represent a complex interplay of genetic susceptibility and environmental triggers. Ring Finger Protein 213 (RNF213), initially identified as the principal susceptibility gene for moyamoya disease (MMD), has emerged as a central regulator of panvascular pathophysiology. This review synthesizes current evidence elucidating RNF213′s multifaceted roles in vascular homeostasis, spanning its functions as an E3 ubiquitin ligase, mechanosensor, and immune modulator. The “second-hit” hypothesis posits that RNF213 mutations establish a genetic predisposition, while secondary insults—such as infection, hypoxia, or hemodynamic stress—precipitate pathological manifestations. Mechanistically, RNF213 orchestrates critical processes including endothelial integrity, angiogenesis, and inflammatory responses through pathways such as HIF-1α/VEGF, NF-κB, and Wnt signaling. Its dysfunction disrupts vascular remodeling, promotes aberrant smooth muscle proliferation, and exacerbates hypoxia-inflammation cycles, contributing to diverse pathologies ranging from intracranial aneurysms and arterial dissections to pulmonary hypertension and coronary artery disease. Emerging insights into RNF213′s interactions with gut microbiota, lipid metabolism, and epigenetic regulators further underscore its systemic influence. Despite advancements, unresolved questions persist regarding the context-dependent duality of RNF213 variants and organ-specific regulatory mechanisms. This review highlights the imperative for integrated approaches combining genetic, molecular, and environmental perspectives to unravel RNF213′s panvascular roles. We also outline unresolved questions regarding context-dependent effects of RNF213 variants and organ-specific regulatory mechanisms, and discuss potential avenues for future research integrating genetic, molecular, and environmental perspectives to advance understanding of RNF213′s panvascular roles. Full article

Skeletal muscle dysfunction and exercise intolerance are major extrapulmonary manifestations of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), yet their severity is not fully predicted by pulmonary impairment. This narrative review examines extracellular vesicles (EVs) as candidate mediators of lung–muscle communication within a broader network of inflammatory, metabolic, vascular, nutritional, and inactivity-related mechanisms. The evidence is asymmetrical. COPD provides direct human skeletal muscle evidence for quadriceps microRNA dysregulation, impaired protein synthesis and mitochondrial function, oxidative stress, and abnormalities of the regenerative microvascular niche; however, none of these observations demonstrates delivery of pathogenic cargo from the lung by EVs. In IPF, EV-mediated epithelial–mesenchymal signalling, fibroblast activation, and profibrotic remodelling are well supported within the lung, whereas skeletal muscle effects remain indirect. Accordingly, the lung–muscle EV axis should be viewed as a biologically plausible, evidence-weighted hypothesis rather than an established causal pathway. Progress will require experiments that identify the cellular source of EVs, trace their vascular transit and skeletal muscle uptake, and demonstrate functional cargo transfer using EV-depletion, rescue, and integrated muscle readouts. Conventional size and morphology measurements do not reliably distinguish muscle- from lung-derived EVs; source discrimination currently depends more on molecular cargo and cell-associated markers. Hypoxia and transient or sustained oxygen desaturation may modify EV release and cargo through HIF- and redox-sensitive signalling, but disease-specific evidence connecting these changes to lung-to-muscle transfer in COPD or IPF remains limited. Full article

Background: Reliable intraoperative monitoring of anesthesia depth is critical for patient safety, yet standard monitors can be confounded by systemic physiological changes. Non-invasive optical modalities that measure cerebral hemodynamics offer a promising approach, but their ability to differentiate brain neurovascular activity assessment versus changes due to systemic events requires validation. This study aims to explore the robustness of diffuse correlation (DCS) and near-infrared spectroscopy (NIRS) measures in differentiating changes in cerebral signals due to changes in anesthetic depth versus those resulting from alterations in systemic hemodynamics. Methods: A neonatal piglet model (N = 18) was used to assess anesthesia states and injury models creating systemic hemodynamic changes which may lead to instability in readings of hemodynamic responses and likely cause failure to detect the true anesthesia state. We continuously measured relative cerebral blood flow (rBFI), oxyhemoglobin (HbO), deoxyhemoglobin (HbR), and total hemoglobin (HbTotal) concentrations during three distinct conditions: (1) transition from deep to light anesthesia state in healthy piglets, (2) controlled hemorrhage, and (3) hypoxia induced under maintained deep anesthesia. Linear mixed-effects models were used to compare hemodynamic signatures across conditions. Results: Transition to light anesthesia was characterized by significant increases in rBFI (p.adj < 0.01), HbO (p.adj < 0.01), and HbTotal (p.adj < 0.05). Interaction analyses confirmed this distinct cerebral hemodynamic pattern was statistically different from the patterns of hemorrhagic shock (decreased rBFI, HbO, HbTotal) and hypoxic shock (decreased rBFI, HbO; increased HbR, HbTotal), with significant differences in trends (p.adj < 0.05). Optical biomarkers distinguished the transition to lighter anesthesia from early physiological changes during systemic insults, suggesting discriminative capability beyond severe shock states. Conclusions: These findings demonstrate that a DCS-NIRS system provides quantitative biomarkers capable of distinguishing changes in anesthetic depth from specific, controlled systemic insults causing subtle to severe hemodynamic instability, supporting its potential as a robust tool for improving intraoperative monitoring and patient safety. Full article

Background/Objectives: Human breathing occurs through either the nasal or the oral route. Nasal breathing is the physiological mode of ventilation and contributes to nitric oxide delivery, upper-airway regulation, and efficient pulmonary gas exchange. In contrast, chronic oral breathing has been associated with upper-airway dysfunction, impaired nocturnal oxygenation, and chronic intermittent hypoxia, conditions increasingly associated with cardiovascular, metabolic, respiratory, neurocognitive, and oncological diseases. To determine whether adults with cancer exhibit structural and functional craniofacial characteristics associated with oral breathing patterns and altered nocturnal oxygenation. Methods: We conducted an exploratory case–control study including adults with cancer and matched controls. Participants underwent a standardized multidimensional airway assessment comprising symptom evaluation using the STOP-BANG questionnaire, structured clinical examination of upper-airway and orofacial characteristics, craniofacial assessment, cone-beam computed tomography (CBCT), and home respiratory polygraphy to characterize upper-airway phenotype and nocturnal oxygenation patterns. Results: Adults with cancer exhibited impaired nocturnal oxygenation despite comparable apnea–hypopnea index values. They also exhibited a higher prevalence of structural and functional upper-airway abnormalities, including restricted tongue mobility, anterior open bite, and reduced maxillary transverse dimensions. Conclusions: This exploratory study identifies a distinct upper-airway phenotype in adults with cancer, characterized by craniofacial and functional features associated with impaired nocturnal oxygenation. These findings suggest that upper-airway anatomy and nocturnal oxygenation may contribute to systemic disease vulnerability and warrant further investigation. Full article

Background: Antimicrobial resistance represents a growing global health challenge, necessitating the development of effective non-antibiotic antimicrobial approaches. Antimicrobial photodynamic therapy (aPDT) has emerged as a promising localized antimicrobial strategy owing to its broad-spectrum activity, biofilm-targeting capability, and low propensity to induce resistance. However, its clinical translation remains restricted by limited photosensitizer (PS) performance, insufficient light penetration, oxygen dependency, biofilm-associated barriers, and the lack of standardized treatment protocols. Methods: This narrative review summarizes recent strategies developed to enhance the efficacy and translational potential of aPDT, including PS engineering, nanomaterial- and non-nanomaterial-based delivery systems, advanced light-source technologies, hypoxia-modulating approaches, and synergistic therapeutic strategies. In addition, current challenges associated with regulatory approval, manufacturing scalability, treatment standardization, and clinical implementation are discussed. Results: Recent advances have transformed aPDT from a conventional PS–light–oxygen system into a multifunctional antimicrobial platform. Emerging approaches improve bacterial targeting, biofilm penetration, reactive oxygen species generation, oxygen utilization, and therapeutic precision. Nevertheless, many advanced systems remain at the preclinical stage due to complexity, cost, safety concerns, and insufficient clinical validation. Conclusions: aPDT should be considered a targeted therapeutic option for accessible, localized, and biofilm-associated infections rather than a replacement for systemic antimicrobial therapy. Future clinical translation will depend on balancing technological innovation with biosafety, scalability, and protocol standardization. Strategies integrating intelligent PS design, oxygen regulation, and clinically feasible synergistic approaches may provide promising pathways toward the broader application of aPDT in antimicrobial management. Full article

Background: Dangguibuxue decoction (DD), containing Angelica sinensis (Oliv.) Diels (AS) and Astragalus membranaceus (Fisch.) Bge. (AM) (1:5), is a well-known traditional Chinese medicine (TCM) used for strengthening qi and nourishing the blood. DD has shown therapeutic effects in nephropathy patients. However, the underlying mechanisms based on the traditional efficacy are still not fully elucidated. Methods: The chemical constituents in DD were identified using UPLC-MS/MS. Network pharmacology analysis was applied to predict the potential target genes and associated signaling pathways. A renal fibrosis mouse model was induced by the intraperitoneal injection of aristolochic acid I (AA I) at 3.0 mg/kg. Mice were treated with AM, AS, and DD at two dosages by oral gavage for 30 days. Body weights, serum biochemistry, hematology, and histopathology observations were assessed. The key targets predicted were validated using qRT-PCR and Western blotting. The active constituents were screened by molecular docking, and their anti-fibrotic effects were evaluated through in vitro assays. Results: DD effectively improved renal functions and alleviated AA I-induced renal fibrosis. DD alleviated anemia and upregulated the expression of Erythropoietin (EPO). Network pharmacology analysis indicated the involvement of signaling pathways, including the PI3K/Akt, hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-β (TGF-β) signaling pathways. Experimental validation further demonstrated that DD reduced the protein expression of HIF-1α, collagen I, and TGF-β, and the ratios of phosphorylated Smad2/3 to total Smad2/3. Molecular docking and in vitro assays suggested that rutin may be a potential bioactive compound in DD. Conclusions: This research indicated that DD ameliorated AA I-induced renal fibrosis in mice, which may be associated with the modulation of HIF-1α and TGF-β/Smad signaling pathways. Rutin may be a potential bioactive compound in DD with anti-fibrotic activity, but further studies are still needed to clarify the content of rutin in DD, the amount of its exposure in the body, and its contribution to the effects of DD. Full article

Anemia management in chronic kidney disease patients is a significant challenge for modern healthcare professionals. Anemia in chronic kidney disease patients has multiple causes, which include erythropoietin deficiency, abnormal iron metabolism, resistance to erythropoietin signaling, bone marrow suppression, blood loss, inflammation, nutrition deficiencies, and oxidative stress. Vadadustat, a stabilizer of hypoxia-inducible factor (HIF), is indicated for the treatment of symptomatic anemia associated with chronic kidney disease (CKD) in adults on chronic maintenance dialysis. Evidence-based pharmaceutical care services are of great importance for chronic kidney disease patients because they provide safe and cost-effective care for patients. In the present article, we outline the most important pharmaceutical aspects that may affect the efficacy and safety of drug therapy with vadadustat and other HIF stabilizers. We conclude that evidence-based pharmaceutical care is one of the criteria that promotes management of vadadustat therapeutic efficacy and safety. Such an approach will contribute to improving patient adherence to treatment and, consequently, quality of life. Special attention is paid to structure-derived side effects of widely used HIF stabilizers, including their advantages and disadvantages. Based on all available safety and efficacy data for vadadustat, the overall risk–benefit profile remains positive for the approved indications for use. Full article

Reactive oxygen species (ROS) are central regulators of cancer biology and represent a double-edged target in oncology. At physiological levels, ROS support signal transduction, proliferation, differentiation, and immune responses, whereas sustained ROS imbalance promotes DNA damage, genomic instability, metabolic reprogramming, and remodeling of the tumor microenvironment, thereby contributing to tumor initiation, progression, metastasis, and therapy resistance. Conversely, because many cancer cells operate close to the limit of tolerable oxidative stress, further ROS elevation can trigger apoptosis, ferroptosis, immunogenic cell death, and other cytotoxic programs. This review summarizes the major intracellular and microenvironmental sources of ROS, the mechanisms by which redox signaling shapes malignant transformation and tumor adaptation, and the antioxidant systems that buffer oxidative stress in cancer cells. We further discuss current therapeutic approaches based on both ROS suppression and ROS amplification, including redox-modulating small molecules, radiotherapy, photodynamic and sonodynamic therapy, catalytic nanomaterials, and ROS-responsive prodrugs and drug delivery systems. Particular attention is given to the context-dependent effects of ROS, the antioxidant paradox, tumor heterogeneity, hypoxia, off-target toxicity, and the need for robust redox biomarkers. A deeper understanding of tumor-specific redox vulnerabilities will be essential for developing precise and clinically effective ROS-oriented cancer therapies. Full article

Inadequate supply of oxygen causing hypoxic cellular stress drives metabolic reprograming across diverse physiological conditions, including cancer. The activation of hypoxia-inducible factors (HIFs) to facilitate adaptation to low oxygen environments is well-characterized; however, post-transcriptional regulation by microRNAs (miRNAs) is poorly understood. Here, we investigated the mRNA and miRNA response in hypoxia-mediating reduced growth and cellular metabolism. Next-generation sequencing revealed the impact of hypoxia in cultured human hepatocellular carcinoma cells and identified over 400 mRNAs and 140 miRNAs that were differentially expressed. Hypoxia upregulated mRNA transcripts associated with glycolysis, DNA replication and the PI3K (phosphoinositide 3-kinase)-Akt pathway, which promote anaerobic metabolism for energy production, decreased cell proliferation and genomic instability, respectively. Upregulated miRNAs included miR-197-3p and miR-766-3p, targeting genes involved in lipid biosynthesis and metabolism. Downregulated miRNAs included miR-33a-5p and miR-15a-5p, targeting genes involved in glycolysis and lactate metabolism. Notably, miR-6834 emerged as a potential regulator of mechanistic target of rapamycin (mTOR) signaling and insulin-like growth factor binding protein-1 (IGFBP-1) signaling; miR-6834 overexpression altered 4E-BP1 phosphorylation levels and IGFBP-1 secretion. These findings provide critical insights into miRNA–mRNA regulation of metabolic adaptation and highlight miRNAs as potential targets for interventions with relevance to tumor biology and other hypoxia-associated conditions. Full article

Hepatocellular carcinoma (HCC) lacks effective early diagnostic markers and is heavily driven by angiogenesis and hypoxia. Emerging evidence indicates that metabolic enzymes and noncoding RNAs coordinate these processes. Here, we reveal that phosphoserine phosphatase (PSPH), a serine biosynthesis enzyme, is significantly upregulated in HCC, correlating with angiogenic markers and poor prognosis. Clinical data and functional assays demonstrated that miR-101-3p directly targets the PSPH 3′ UTR to suppress its expression, while lncRNA GSEC acts as a competing endogenous RNA to sponge miR-101-3p. In vitro, GSEC knockdown or miR-101-3p overexpression decreased PSPH and HIF1α levels, strongly inhibiting HCC angiogenesis, migration, invasion, and proliferation. Crucially, these anti-tumor effects were reversed by restoring PSPH. In vivo, modulating the GSEC/PSPH axis significantly altered xenograft tumor growth and vascularization. Conclusively, the GSEC/miR-101-3p/PSPH regulatory axis drives HIF1α-dependent angiogenesis and HCC progression, highlighting PSPH as a promising diagnostic biomarker and therapeutic target. Full article

Theranostic nanoparticles, which integrate diagnostic imaging and therapeutic delivery within a single nanoplatform, represent a transformative paradigm in oncological nanomedicine. Despite substantial preclinical progress, the field faces persistent gaps in rational nanoparticle design informed by tumor biology, preclinical model fidelity, and clinical translation. This review critically synthesizes theranostic nanoparticle research across three underexplored domains. First, we examine tumor microenvironment features—reactive oxygen species dynamics, glutathione gradients, hypoxia, and proteasomal dysregulation—as mechanistic drivers of nanoparticle responsiveness. Second, we evaluate redox-responsive and proteasome-targeted nanoplatforms that exploit these cues for stimuli-triggered drug release and simultaneous imaging readout. Third, we address the unmet need for three-dimensional organoid and microfluidic tumor models as predictive preclinical testing environments, given the well-documented limitations of conventional two-dimensional cultures. Cancer subtype-specific applications are discussed for breast cancer, HPV-associated malignancies, colorectal cancer, and prostate cancer. Clinical translation barriers—including pharmacokinetic constraints, protein corona formation, immune clearance, anti-PEG antibodies, complement activation-related pseudoallergy, and FDA/EMA regulatory pathways—are addressed from a clinical oncology perspective. The review concludes with a research roadmap integrating proteomics-guided nanoparticle engineering, patient-derived organoid biobanks, and artificial intelligence-assisted design as priority areas for next-generation oncological theranostics. Full article

Background/Objectives: Multiple myeloma (MM) is an incurable, hematological malignancy caused by the abnormal proliferation of terminally differentiated plasma cells in the bone marrow. Current research indicates that N-azacytidine, as an epigenetic drug and nucleoside metabolic inhibitor, can be efficient in MM treatment. However, data on bone marrow mesenchymal stromal cells (BMSCs), as a critical cell population in the hematopoiesis and bone remodeling processes, are limited. Methods: The effect of N-azacytidine on the myeloma cell line AMO-1, bone marrow mesenchymal stromal cells from MM patients (MM-MSCs) and patients undergoing hip arthroplasty (BMSCs) as a healthy control in hypoxia (3% O₂) were examined. Cellular functions such as viability, proliferation, phenotype, and differentiation were determined by in vitro tests and flow-cytometry. Results: N-azacytidine (100 nM to 1000 nM) significantly inhibited metabolic activity, cell cycle, CFSE dilution and CD138+/CD38+ expression levels by myeloma cells after 72 h. No viability changes were detected in MM-MSCs and BMSCs treated with N-azacytidine. As for both BMSCs and MM-MSCs differentiation potential, N-azacytidine did not affect alkaline phosphatase (ALP) activity and adipogenesis but inhibited matrix mineralization (500 nM and 1000 nM). However, when BMSCs were pretreated with N-azacytidine for 72 h, changes in ALP activity and mineralization level were not detected. Conclusions: N-azacytidine, along with the suppressive effect on myeloma cells, did not change the differentiation potential of MSCs, but rather preserved their capacity. These findings are of particular importance considering MM progression and bone tissue destruction, suggesting that N-azacytidine may represent a promising therapeutic agent for myeloma disease. Full article