Search Results (1,669)

Background/Objectives: Chronic hypoxia promotes a shift in smooth muscle cells from a quiescent, contractile state to a highly proliferative phenotype, contributing to persistent vascular remodeling. This study examines primary human esophageal smooth muscle cells (HEsSMCs) exposed to hypoxia mimics, desferoxamine (DFO) and dimethyloxallyl glycine (DMOG), and their interaction with angiotensin II (AngII). Methods: We utilized HEsSMCs to assess the effects of DFO, DMOG, and AngII through MTT metabolic activity assays, Western blotting analyses, and flow cytometry to evaluate various cellular functions. Additionally, we reanalyzed the public RNA sequencing dataset GSE193817 to explore the contextual influences of DFO-induced responses in HEsSMCs. Results: Our findings indicate that both DFO and DMOG stabilize hypoxia-inducible factor-1 alpha proteins at different time intervals, revealing distinct cell cycle profiles and varied protein responses. DFO was shown to increase mitochondrial reactive oxygen species (ROS) while simultaneously suppressing cytosolic ROS, suggesting the involvement of multiple pathways beyond those activated by hypoxic stress. Flow cytometry analysis revealed that DFO triggers late-stage apoptosis, along with increases in overall hypoxia, ROS, autophagy, lipid peroxidation, and mitochondrial membrane depolarization in HEsSMCs. Furthermore, AngII was observed to inhibit the activation of nuclear factor-κB induced by DFO. The analysis of the GSE193817 dataset illuminated the transitional dynamics between quiescent and proliferative states in smooth muscle cells, indicating that AngII signaling is modular and does not simply counteract DFO-induced effects. Conclusions: This research enhances our understanding of hypoxia and ROS responses in HEsSMCs and underscores the potential for personalized medicine informed by sequencing data. Full article

The renin–angiotensin system (RAS) and vasopressin system (VAS) play an essential role in the regulation of multiple vital body functions. A survey of the literature provides evidence that the central and systemic RAS and VAS are activated during pregnancy and cooperate in the regulation of blood circulation and in the exchange of substrates and metabolites between the mother and fetus. The present review is focused on the engagement of the RAS and VAS in the regulation of blood circulation in healthy pregnant women and fetuses and in gestations complicated by cardiovascular, metabolic and psychogenic diseases. The presence of several components of the RAS and VAS, such as renin, angiotensin-converting enzymes (ACE1, ACE2), angiotensins [Ang II, Ang-(1–7)], angiotensin receptors (AT1R, AT2R), and AVP receptors (V1aR), in the placenta and the myometrium allows us to assume that the RAS and VAS play a prominent role in function of the maternal–placental–fetal unit. Gestation is also associated with the activation of components of the RAS and VAS in appropriate regions of the central nervous system that are involved in the regulation of blood pressure. Experimental studies suggest that the RAS and VAS participate in the autonomic control of blood circulation and in the regulation of emotional aspects of pregnancy and maternity. Abnormal functioning of the RAS and/or VAS was found in eclampsia, metabolic diseases (diabetes mellitus) and psychogenic disorders (anxiety, stress, and depression). Some of these abnormalities may have an immunological or genetic background. In eclampsia, the presence of specific agonistic angiotensin receptor autoantibodies (AT1-AA) and altered genotypes of AGT, ACE2, AT1R, and AT2R were reported. Polymorphism of the AVP promoter was also described. Inappropriate pharmacotherapy or toxic environmental pollution may disturb the regulation of the cardiovascular system of the mother and fetus by the RAS and VAS during gestation. Further studies are necessary to better recognize the mechanisms of action of the RAS and VAS in healthy and pathological pregnancies. Full article

Long non-coding RNAs (lncRNAs) are emerging as important regulators of cellular adaptation to environmental and molecular stress, but the extent to which their responses remain reproducible and stress-type-dependent across human stress conditions remains unclear. Here, we performed an integrative transcriptomic meta-analysis of human stress-response datasets from ASTRA and GEO, focusing on normal, non-cancerous, wild-type human cell lines exposed to oxidative stress (H₂O₂), hypoxia, heat stress, or UV-induced DNA damage. Gene Ontology (GO) enrichment analysis of differentially expressed (DE) protein-coding mRNAs confirmed that the resulting stress-stratified comparison captured biologically coherent transcriptional programmes to oxidative stress signaling, hypoxic and metabolic adaptation, heat-induced proteostasis, UV-induced DNA damage signaling, apoptosis, and cell-cycle regulation. Differential expression analysis was subsequently integrated with Weighted Gene Co-expression Network Analysis (WGCNA) -based module–treatment associations to rank network-supported lncRNA candidates. By prioritizing candidates for recurrence across at least two different stress studies, we identified lncRNAs with increased recurrence and consistent stress-type-dependent expression regulation, embedded within coordinated stress-associated mRNA programs. Full article

Fracture healing depends on coordinated osteogenesis and restoration of the vascular microenvironment. Endothelial cells support skeletal repair through angiogenesis, tissue perfusion and angiocrine signaling that regulates osteoprogenitor recruitment and differentiation. This narrative review examines endothelial dysfunction (ED) as a potential systemic contributor to impaired fracture healing by integrating evidence from vascular biology, experimental models and clinical studies. ED is characterized by reduced nitric oxide (NO) bioavailability, oxidative stress, inflammation and impaired vascular repair. These changes may disrupt angiogenic–osteogenic coupling through altered hypoxia-inducible factor 1-alpha subunit (HIF-1α)/vascular endothelial growth factor (VEGF) signaling, endothelial Notch activity, platelet-derived growth factor (PDGF)-mediated vascular remodeling and endothelial progenitor cell (EPC) mobilization. Conditions associated with endothelial dysfunction, including diabetes, aging, chronic kidney disease (CKD), smoking, obesity and chronic inflammatory disease, are also linked to delayed union, nonunion and poorer orthopedic outcomes. Cardiovascular disease and perioperative cardiovascular instability may further impair perfusion and physiological reserve during repair. However, the available evidence is predominantly experimental or observational, and direct causal evidence in fracture patients remains limited. Prospective studies combining standardized endothelial assessments with fracture-healing outcomes are needed to clarify clinical relevance and identify potential therapeutic targets. Full article

Acute myeloid leukemia (AML) persistence is sustained by leukemic stem cells (LSCs) that survive metabolic deprivation, oxidative stress, hypoxia, proteotoxic burden, and therapeutic pressure. The integrated stress response (ISR) has emerged as a central adaptive network in this process. Through phosphorylation of a subunit of eukaryotic initiation factor 2 (eIF2α) and selective translation of activating transcription factor 4 (ATF4), the ISR coordinates stress-responsive transcriptional programs that may either preserve cellular fitness or promote apoptotic commitment, depending on the intensity, duration, and biological context of activation. In AML, ATF4 occupies a critical position at the interface between stemness, metabolic adaptation, redox control, ferroptosis resistance, and treatment response. In primitive leukemic compartments, ISR–ATF4 signaling appears to support stress tolerance, amino acid metabolism, serine biosynthesis, autophagy, and leukemic persistence. At the same time, pharmacologic or sustained ISR activation may lower the apoptotic threshold by inducing pro-apoptotic mediators such as CHOP, PUMA, and NOXA, thereby modulating MCL-1 dependency and enhancing sensitivity to venetoclax-based strategies. Conversely, adaptive ISR signaling may promote resistance through mechanisms such as ATP-binding cassette subfamily B member 1 (ABCB1) enhancer activation and mitochondrial stress tolerance. This duality creates a therapeutic paradox: ISR–ATF4 signaling may need to be inhibited in adaptive, resistance-promoting states but amplified in apoptosis-permissive contexts. This review discusses the biological and therapeutic relevance of ISR–ATF4 dysregulation in AML and highlights the need for biomarkers capable of distinguishing adaptive ATF4 dependency from inducible apoptotic vulnerability. Full article

High-altitude hypoxic environments constrain yaks’ survival capacity and metabolic adaptability. Subcutaneous adipose tissue helps yaks withstand cold and resist hypoxic stress, and ADM participates in cellular stress and metabolic regulation. To explore the regulatory role of ADM in the hypoxia adaptation of yak subcutaneous preadipocytes in high-altitude environments, we established three cell culture groups (normoxia, physiological hypoxia, and hypoxia). We further systematically examined cell proliferation, apoptosis, adenosine triphosphate (ATP) production, and lipid metabolic markers, and we performed transcriptome sequencing to reveal their regulatory effects. ADM exhibited a bidirectional regulatory effect: Low doses alleviated hypoxia-induced cell damage and restored energy and lipid synthesis, whereas high doses, in conjunction with hypoxia, activated multiple metabolic pathways and altered cellular energy-supply patterns. Under physiological hypoxia, cells emphasized metabolic regulation, while under hypoxia, they prioritized stress defense. This study demonstrates that under hypoxic stress, ADM regulates the survival and physiological function of yak subcutaneous preadipocytes in a dose-dependent manner, with cells relying on staged stress-defense and metabolic-remodeling responses to achieve adaptation to hypoxia, providing important experimental and theoretical insights into the mechanisms of high-altitude hypoxia adaptation in yaks. Full article

Background: Contrast media are essential tools in diagnostic and interventional imaging, but their relationship with acute kidney injury remains clinically relevant and conceptually debated. This narrative review aimed to synthesize current evidence on contrast media-associated nephrotoxicity, including terminology, epidemiology, pathophysiology, risk stratification, prevention, pharmacotherapeutic management, and clinical decision-making. Methods: A structured literature search was conducted in major biomedical databases and complemented by international guidelines and consensus statements addressing contrast-associated and contrast-induced acute kidney injury in adults exposed to intravascular contrast media. Discussion: Contemporary evidence emphasizes the distinction between contrast-associated acute kidney injury, which reflects a temporal association after exposure, and contrast-induced acute kidney injury, which implies causality. The renal risk directly attributable to modern intravenous iodinated contrast media appears to have been historically overestimated, although clinically relevant risk persists in vulnerable patients. Proposed mechanisms include renal vasoconstriction, medullary hypoxia, oxidative stress, mitochondrial dysfunction, tubular epithelial injury, endothelial dysfunction, and inflammatory or apoptotic pathways. Preventive strategies should be individualized, with isotonic saline remaining the main intervention when indicated, whereas routine pharmacologic prophylaxis is not supported by consistent clinically meaningful benefit. Conclusions: Renal safety in contrast-enhanced imaging requires a balanced approach that minimizes avoidable kidney injury in high-risk patients without unnecessarily delaying clinically indicated diagnostic or therapeutic procedures. Full article

Background/Objectives: The PIM kinase family, comprising three serine/threonine kinase isoforms (PIM1, PIM2, and PIM3), plays a fundamental role in various cancer types, where they are frequently described as regulators of proliferation, survival, and metabolic pathways. Acute leukemia is a group of hematological malignancies characterized by the uncontrolled clonal proliferation of hematopoietic stem cells, encompassing myeloid (AML) and lymphoblastic (ALL) lineages, which together present limited therapeutic options and poor clinical outcomes. This study investigated the correlation between PIM kinase signaling pathways and the clinicopathological features, molecular pathway interactions, and cytogenetic risk stratification of patients with acute leukemia. Methods: Microarray data and clinical information from AML and ALL patients were retrieved from the Gene Expression Omnibus database. The expression levels of PIM1, PIM2, and PIM3 were assessed across leukemia subtypes and cytogenetic risk groups using ANOVA or Kruskal–Wallis tests, with Bonferroni post hoc correction, performed in R (v4.5.1). A transcriptome-wide co-expression analysis was conducted using Spearman’s rank correlation to identify genes correlated with each PIM isoform. Subsequently, Gene Set Enrichment Analysis (GSEA) was performed on pre-ranked gene lists using the clusterProfiler (v4.16.0) package and Hallmarks of Cancer gene signatures, with pathway significance determined by Benjamini–Hochberg-adjusted FDR < 0.05. Results: Transcriptomic analysis revealed distinct expression patterns of the PIM kinase family between AML and ALL subtypes, identifying PIM3 as the predominantly dysregulated isoform, marked by significant overexpression across both lineages. Risk-stratified analysis further demonstrated that PIM expression is highly context-dependent, exhibiting dynamic variation across cytogenetic risk groups. Functional enrichment analysis highlighted a potential functional redundancy and compensatory mechanisms among PIM isoforms, with enriched pathways predominantly associated with stress tolerance, hypoxia adaptation, and inflammatory signaling, rather than classical proliferative signatures. Conclusions: Collectively, these findings position the PIM kinase family as a dynamically regulated axis in acute leukemia, deeply integrated with cytogenetic risk profiles and stress-adaptation mechanisms. The consistent upregulation of PIM3 and its correlation with inflammatory and hypoxic signatures suggest a potential role in facilitating tumor survival within adverse microenvironments. Full article

Glioblastoma (GBM) is one of the most aggressive and treatment-resistant cancers, shaped by a tumor microenvironment (TME) that is both metabolically demanding and strongly immunosuppressive. GBM relies heavily on fatty acid (FA) metabolism to sustain growth of rapidly dividing tumor cells and survive metabolic stress. GBM cells enhance lipid uptake, activate sterol regulatory element-binding protein 1 (SREBP-1)-driven lipogenesis, store excess lipids in droplets to prevent toxicity, and depend on fatty acid oxidation (FAO) to generate adenosine triphosphate (ATP) and maintain redox balance, particularly under nutrient-limited conditions. GBM TME is also consistently enriched with regulatory T cells (Tregs), which maintain suppressive activity despite the nutrient restrictions that impair effector T cells (Teffs). In hypoxia and nutrient limitation within the TME, Tregs can adapt by using FAO, lactate oxidation, and OXPHOS, supported by forkhead box P3 (Foxp3)-dependent metabolic programming, cluster of differentiation 36 (CD36)-mediated FA uptake, and hypoxia-related signals. At the same time, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling reduces glycolytic activity in Teffs and contributes to metabolic dysfunction, while also supporting the stability of oxidative metabolism in Tregs. Evidence from pre-clinical and clinical studies suggests a possible association between Treg enrichment in GBM and reduced responsiveness to immune checkpoint inhibitors (ICIs), although this relationship is not yet fully defined. Overall, current findings point to FA metabolism as a shared metabolic axis that supports both tumor progression and Treg-mediated immune resistance. Targeting lipid-driven pathways may offer an opportunity to disrupt these advantages and improve the effectiveness of existing immunotherapies for GBM. Full article

Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive follicular cell-derived malignancy characterized by rapid progression, profound dedifferentiation, and marked resistance to conventional therapy. Despite frequent involvement of major oncogenic pathways, ATC does not exhibit a universal driver mutation, suggesting that its pathogenesis reflects convergence upon shared biological hallmarks rather than dependence on a single molecular event. This review describes the principal mechanistic programs that define the ATC phenotype: disruption of cell-cycle and apoptotic control through alterations in TP53, CDKN2A/B, and aberrant MAPK activation; metabolic adaptations involving glycolysis, glutaminolysis, and mitochondrial one-carbon metabolism; reprogramming of canonical stress response pathways including ER stress and hypoxia signaling; and dynamic remodeling of the tumor microenvironment through cytokine-driven paracrine networks and immune modulation. Collectively, these processes cooperate to generate a highly proliferative, stress-tolerant, immune-inflamed yet immunosuppressed tumor state. A mechanistic understanding of these convergent pathways is essential for rational therapeutic development and for overcoming the profound clinical resistance that defines ATC. Full article

The management of estuarine ecosystem sustainability is a complex problem that requires models that are physically sound, socially meaningful, and interpretable from a mechanistic standpoint. Even though classical AI has demonstrated promise in environmental forecasting, black-box models typically fall short of meeting basic conservation requirements or accounting for anthropogenic stresses that alter water quality. This work introduces a novel framework based on Deep Physics-Informed Neural Networks (Deep PINNs) to predict the dynamics of dissolved oxygen (DO) in the Bouregreg Estuary (Morocco). We advance baseline standards by directly integrating the non-linear advection–diffusion–reaction (ADR) transport equations into the loss function of a deep residual architecture (ResNet with 12–20 layers). This integration ensures that the model takes into account two important aspects of estuarine hydrodynamics: gravitational circulation and the salt wedge effect. The incorporation of a socio–hydro–physical nexus, which uses regional water-pricing indices and urban wastewater discharge volumes from the Rabat-Salé municipal area $(\sim \mathrm{120,000} {\mathrm{m}}^3/\mathrm{d}\mathrm{a}\mathrm{y})$ as proxy variables for anthropogenic pressure, is a unique aspect of this work. The Deep PINN achieves a better coefficient of determination ($R^2=0.998$) and a Nash–Sutcliffe efficiency ($\mathrm{N}\mathrm{S}\mathrm{E}=0.997$), outperforming the traditional ANFIS and ANN baselines by $89.1\%$ in terms of predictive error reduction ($\mathrm{R}\mathrm{M}\mathrm{S}\mathrm{E}=0.041\pm 0.002 \mathrm{m}\mathrm{g}/\mathrm{L}$). In situations where unconstrained data-driven models fall short, the framework exhibits physical robustness in capturing vertical DO stratification in addition to numerical accuracy. Urban effluent volumes have a significant impact on predictive variance, accounting for 28% of the model internal attribution—more than the relative influence of thermal solubility, according to mechanistic feature attribution analysis using SHAP (Shapley Additive exPlanations). Finally, exploratory management scenarios suggest that summer hypoxia could hypothetically be mitigated through a $20\%$ reduction in discharge volumes. This study bridges the gap between scientific modeling and policy implementation by providing a physics-consistent digital twin framework for environmental stewardship in support of UN SDG 6 and Morocco’s National Water Plan. Full article

Background/Objectives: Sphagneticola trilobata is a phytochemically rich medicinal plant, yet its antioxidant-active fractions and redox-related mechanisms remain incompletely characterized. This study combined metabolite profiling, antioxidant screening, network pharmacology, pharmacokineticprediction, and molecular docking to characterize active flower and leaf fractions and prioritize antioxidant-related targets. Methods: Petroleum ether, methylene chloride, and ethyl acetate fractions of S. trilobata flowers and leaves were analyzed by ultra-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC–ESI–MS/MS). The predominant metabolite was isolated and spectroscopically characterized. Antioxidant activity was assessed using 2,2′-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) and ferric reducing antioxidant power (FRAP). Metabolites from the most active fractions were investigated by target prediction, protein–protein interaction (PPI) analysis, enrichment analysis, SwissADME, and docking. Results: UPLC–ESI–MS/MS tentatively identified 59, 18, and 16 metabolites in the petroleum ether, methylene chloride, and ethyl acetate fractions, respectively, including diterpenes, phenolic acids, flavonoids, fatty acids, triterpenes, and coumarin-related metabolites. Butein was isolated as the predominant metabolite from the ethyl acetate flower fraction, which showed the strongest antioxidant activity, with IC₅₀ values of 5.85 ± 0.14 µg/mL in ABTS and 9.11 ± 0.75 µg/mL in FRAP, followed by the ethyl acetate leaf fraction. Network analysis identified 61 and 82 antioxidant-relevant targets for the flower and leaf ethyl acetate fractions, respectively, with enrichment in inflammation-, apoptosis-, transcription-, hypoxia-, lipid stress-, and kinase-related pathways. Docking suggested fraction-specific compatibility with EGFR/PTGS2/STAT3 for flower metabolites and AKT1/PTGS2 for leaf metabolites. Conclusions: S. trilobata ethyl acetate fractions, particularly the flower fraction, represent promising antioxidant sources with experimentally supported activity and computationally prioritized redox-related hypotheses requiring further validation. Full article

Coronavirus disease 2019 (COVID-19) is increasingly recognized as a multisystem disorder associated with persistent metabolic complications extending beyond the acute phase of infection. Accumulating evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may disrupt glucose homeostasis through mechanisms involving pancreatic β-cell dysfunction, insulin resistance, chronic inflammation, oxidative stress, mitochondrial dysfunction, and hypoxia-related signalling. This review summarizes current evidence regarding the molecular and cellular mechanisms linking SARS-CoV-2 infection to impaired insulin secretion and post-COVID metabolic disturbances. Particular emphasis is placed on the regulation of insulin secretion, β-cell compensation and failure, oxidative stress, inflammatory signalling, mitochondrial dysfunction, and the development of the post-COVID metabolic phenotype. Emerging evidence indicates that persistent metabolic abnormalities after COVID-19 may range from transient dysglycaemia to new-onset diabetes mellitus and metabolic syndrome. The review also discusses clinical implications, biomarkers, therapeutic perspectives, and unresolved questions regarding the reversibility of post-COVID β-cell dysfunction. A better understanding of the mechanisms underlying post-COVID metabolic dysfunction may improve risk stratification, facilitate early intervention, and support development of targeted therapeutic strategies aimed at preserving β-cell function and long-term metabolic health. Full article

Background: Endometriosis-associated ovarian cancers (EAOCs), encompassing clear cell (CC) and endometrioid carcinomas (EC), constitute distinct biological entities yet lack robust biomarkers for precise classification, prognostication, and therapeutic decision-making in women. Therefore, we aimed to describe novel biomarkers. Methods: In this study, we conducted an integrated transcriptomic analysis, powered by machine learning, to discover novel consensus biomarkers and delineate cancer hallmark signatures specific to EC and CC. Drawing on gene expression profiles from EAOC specimens, we merged differential expression analysis with LASSO regression and Random Forest classification to generate a reliable biomarker panel that effectively distinguishes EC from CC. Kaplan–Meier survival analyses and mutation analyses have been performed for selected biomarker genes. Results: Novel biomarkers, among others, the genes RPS28, EPAS1, ALKBH2, and DCLRE1A, uncover extensive transcriptional alterations tied to hypoxia signaling, oxidative stress, DNA repair, and metabolic reprogramming. Gene Ontology and pathway enrichment analyses revealed synchronized upregulation of epithelial–mesenchymal transition, TNF-α/NF-κB signaling, oxidative stress, hypoxia, and KRAS signaling pathways. Conclusions: Our work establishes novel exploratory transcriptomic candidates for innovative consensus biomarkers, yielding novel diagnostic and prognostic insights into EAOC and supporting further study of subtype-associated expression programs. The current study was designed primarily as an integrative computational investigation aimed at identifying candidate genes and molecular pathways distinguishing CC from EC. Full article

Climate change and increasing instability in coastal marine environments have intensified stressors such as elevated temperature, hypoxia, salinity variation, and pollutant exposure, posing major challenges to the survival, health, and culture performance of bivalves. As economically important aquaculture species and key components of coastal ecosystems, bivalves are highly sensitive to environmental fluctuations, making their metabolic responses highly relevant to both physiological adaptation and aquaculture sustainability. Increasing evidence indicates that metabolic remodeling is an important adaptive strategy supporting bivalve tolerance to environmental stress, with amino acid metabolic remodeling emerging as one of its most sensitive and functionally important components. This review summarizes the major response patterns, key pathways, and potential regulatory mechanisms of amino acid metabolism in bivalves under different stress conditions. Different environmental stressors induce distinct yet integrated shifts in amino acid metabolism, including enhanced catabolism, carbon–nitrogen redistribution, osmotic regulation, and antioxidant defense, thereby supporting energy homeostasis and physiological stress tolerance in bivalves. By highlighting amino acid metabolic remodeling as a central mechanism of bivalve adaptation to environmental stress, this review provides insights into adaptive responses, metabolite-based indicators for monitoring aquaculture environments and bivalve health, and management strategies for improving resilience in bivalve aquaculture. Full article