ObjectivesExtracorporeal Membrane Oxygenation (ECMO) is associated with high risks of bleeding and clotting. While traditional anticoagulants like heparin and bivalirudin target the coagulation cascade, prostaglandins including PGE1 and PGI2 may offer adjunctive platelet inhibition. This study evaluated whether prostaglandin use modifies the risk of severe bleeding or clotting events in pediatric ECMO patients.Material and MethodsWe used the Pediatric Health Information System database from 2004 to 2025, and included children supported with ECMO. Primary outcomes were severe bleeding and clotting events. Generalized linear mixed model regressions adjusted for site, patient and ECMO data, and pulmonary hypertension.ResultsA total of 22,061 pediatric ECMO patients were included. Pulmonary hypertension was present in 12.4% (2736/22,061). PGE1 and PGI2 were independently associated with increased risk of pulmonary hemorrhage (PGE1: adjusted OR 1.24, P = .003; PGI2: adjusted OR 1.21, P = .047). Conversely, neither PGE1 nor PGI2 were independently associated with intracranial hemorrhage (PGE1: adjusted OR 1.01, P = .92; PGI2: adjusted OR 0.96, P = .79), stroke (PGE1: adjusted OR 1.02, P = .84; PGI2: adjusted OR 0.88, P = .38), or other bleeding or thrombotic events.ConclusionIn this large multicenter cohort of more than 22,000 pediatric ECMO patients, neither PGE1 nor PGI2-modulated anticoagulation conferred measurable protection against the major bleeding or clotting complications.
Objective This study aimed to investigate the impact of human leukocyte antigen B27 (HLA-B27)/β2m gene expression on the gut microbiota and metabolites, and to elucidate its role in the pathogenesis of spinal arthritis (SpA)-associated intestinal inflammation. Methods Transgenic mice expressing HLA-B27/β2m without spontaneous inflammation were employed. Integrated multi-omics analyses, including metagenomics and metabolomics, were conducted to profile microbial and metabolic changes at prenatal, early colonization, and stable colonization stages. Inflammatory susceptibility was further assessed using a dextran sulfate sodium (DSS)-induced colitis model. Results Expression of HLA-B27/β2m significantly altered the gut microbiota structure, promoting the expansion of Gram-negative bacteria and inhibiting Gram-positive populations. Metabolomic profiling revealed enhanced arachidonic acid metabolism, elevated levels of pro-inflammatory metabolites such as prostaglandins, and a reduction in anti-inflammatory flavonoids. These findings collectively indicated a pro-inflammatory intestinal microenvironment, which was corroborated by exacerbated colitis upon DSS challenge in animal models. Conclusion The HLA-B27/β2m gene modulates gut microbial composition and metabolic balance, predisposing the intestine to inflammatory responses. These results provide novel mechanistic insights into the "gut-joint axis" in SpA pathogenesis.
Labor induction using medications such as synthetic oxytocin (synOT) and prostaglandins (PG) has become increasingly common; however, its implications for mother-to-infant bonding remain unclear. These agents may plausibly influence early bonding by altering peripartum oxytocin-related physiology and by affecting early breastfeeding establishment. We examined whether labor induction and specific induction agents are associated with postpartum mother-to-infant bonding trajectories and evaluated breastfeeding mode as a potential mediator. We analyzed data from the Japan Environment and Children's Study (JECS). Among 104,059 fetal records, we included 58,384 mother-infant dyads with complete bonding data at 1, 6, and 12 months postpartum (56.1%; complete-case analysis), restricted to liveborn, term, singleton vaginal deliveries. Mother-to-infant bonding was assessed as mothers' self-reported bonding-related feelings using the Mother-to-Infant Bonding Scale (MIBS). Induction status and induction agents (synOT, PG) were obtained from transcribed medical records. Linear mixed-effects models tested associations with bonding trajectories, and mediation analyses evaluated whether 1-month feeding mode (exclusive formula vs. any breastfeeding) accounted for observed associations. Induction was associated with a time-varying pattern in mother-to-infant bonding (time × induction: β = -0.057, 95% CI [-0.067, -0.046], p < 0.001), although contrasts at 1, 6, and 12 months were not significant (β = 0.013, p = 0.109; β = 0.005, p = 0.482; β = 0.000, p = 0.953). SynOT was associated with poorer bonding at 1 and 6 months (β = 0.027, p = 0.004; β = 0.016, p = 0.024), but not at 12 months (β = 0.010, p = 0.205). Mediation via feeding was small for induction (indirect effect = 0.001, 95% CI [0.0002, 0.001]) and not supported for synOT (indirect effect = 0.0004, 95% CI [-0.00009, 0.001]). Labor induction and synOT exposure were associated with poorer early postpartum mother-to-infant bonding, with differences attenuating over the first postpartum year. Exclusive formula feeding was associated with poorer bonding and may contribute to early postpartum differences, supporting the clinical value of proactive breastfeeding support and attention to maternal wellbeing while reassuring families that early challenges often ease over time.
Eicosanoids are lipid signaling molecules derived from arachidonic acid that play crucial roles in immune responses and the regulation of inflammation. This review explores the various eicosanoid families-prostaglandins, thromboxanes, leukotrienes, and lipoxins-and their involvement in airway inflammation and asthma pathogenesis. We performed a comprehensive PubMed search for relevant preclinical (animal) and clinical (human) studies using the keywords "eicosanoids," "asthma," "airway inflammation," and "flavonoids." Evidence from these sources highlights how eicosanoids orchestrate inflammatory pathways in the lungs, contributing to bronchoconstriction, mucus hypersecretion, and immune cell recruitment. Dysregulation of these lipid mediators can exacerbate chronic airway inflammation and asthma severity. Additionally, we examine the therapeutic potential of flavonoids-a class of polyphenolic compounds known for antioxidant and anti-inflammatory effects-in modulating eicosanoid pathways. Early findings suggest that certain flavonoids can dampen eicosanoid-mediated inflammation and oxidative stress, potentially improve airway function, and reduce asthma symptoms. Mechanistically, flavonoids may inhibit key enzymes in eicosanoid synthesis (cyclooxygenases and lipoxygenases), thereby reducing the production of pro-inflammatory mediators. We discuss how targeting lipid-based signaling pathways with flavonoid interventions might complement existing asthma therapies by addressing underlying inflammatory mechanisms. In conclusion, eicosanoid pathways play a pivotal role in asthma pathophysiology, and their modulation represents a promising avenue for intervention. This review underscores the need for further preclinical and clinical studies to deepen our understanding of eicosanoid-driven inflammation in asthma and to validate flavonoid-based therapeutic approaches in asthma management.
Aldo-keto reductase 1C3 (AKR1C3) is a drug target for the treatment of various androgen dependent malignancies, including castration-resistant prostate canceras well as hematological cancers. The enzyme plays a key role in the conversion of androgen precursors into potent androgen receptor ligands and the conversion of prostaglandins from pro-differential to pro-proliferative, facilitating progression of these malignancies. Additionally, AKR1C3 plays a role in chemotherapy resistance, reducing therapeutics to inactive forms and stabilizing expression of mutant androgen receptors. This article reviews patents, obtained from WIPO and SciFinder, published since 2020 covering AKR1C3 inhibitors, compounds that exploitAKR1C3 for prodrug activation, and the use of AKR1C3 expression levels as a biomarker for measuring disease and therapeutic response. As well as inhibitors, this article reviews the first reported AKR1C3/AR-v7 dual degrader. Multiple compounds have been reported to potently and selectively inhibit AKR1C3 eliciting tumor growth inhibition as stand-alone agents and when used in combination with clinically approved chemotherapeutics. With drug resistance an ever-present issue, exploration of alternative routes for treating malignancies via AKR1C3 targeting offers tremendous potential. Translation to clinical trials and their effect in patients is expected to be revealed in the coming years.
Bovine endometritis remains one of the most significant postpartum uterine disorders. It impairs uterine recovery, compromises fertility, and causes substantial economic losses in dairy production. Growing evidence suggests that the disease cannot be attributed solely to postpartum bacterial contamination; rather, it should be understood as a multifactorial failure to restore uterine homeostasis after calving. This review summarises the latest research findings on six interconnected aspects: the clinical significance of postpartum uterine disease; the diagnostic and biological differences between clinical and subclinical endometritis; the role of microbes in the uterus in health and disease; interactions between the host and uterine bacteria; the mechanisms of persistent inflammatory regulation; and current as well as emerging treatment strategies. Current evidence indicates that postpartum uterine disease is more strongly associated with dysbiosis, reduced microbial diversity, and disturbed microbial succession than with the presence of any single pathogen. Disease progression is driven by complex interplay among microbial ligands, epithelial and stromal immune responses, virulence-associated tissue injury, endocrine disruption, and impaired inflammatory resolution. Furthermore, persistent uterine inflammation is regulated by multilayered networks involving cytokines, prostaglandins, noncoding RNAs, extracellular vesicles, metabolic remodeling, and oxidative stress. Although conventional therapies remain relevant in certain clinical cases, microbiota-oriented approaches, particularly probiotic interventions, have emerged as promising adjunctive strategies for the prevention and control of the condition. Overall, bovine endometritis should be viewed as a disorder caused by disrupted interactions between the host, microbiota and inflammation. Future progress will depend on longitudinal, strain-resolved, and function-oriented studies to enable more precise and less antimicrobial-dependent interventions for postpartum uterine health.
Background: Acute myeloid leukemia (AML) is characterized by reduced antileukemic effector cells and increased immunosuppressive cell populations. Leukemia-derived dendritic cells (DCleu), generated from 18 leukemic whole blood (WB) ex vivo using 'Kit-M' (clinically approved: GM-CSF + PGE1), lead to improved cytotoxicity against autologous blasts after mixed lymphocyte culture (MLC) with patients' T-cells. Methods: We studied Kit-M-mediated effects on frequencies of tolerogenic, immunosuppressive DC (DCtol) and correlated findings with ex vivo-achieved antileukemic effects (increased intracellular IFNγ production/degranulation, blast lysis) and patients' clinical characteristics. Results: We show significantly decreased frequencies of DCtol (and increased frequencies of mature DCleu) without induced blast proliferation in Kit-M treated vs. untreated WB samples. After T-cell-enriched MLC with Kit-M pretreated vs. not pretreated, WB frequencies of regulatory (CD152+ T-cells) were significantly decreased, while 'activated' (IFNγ+, degranulating) non-naive, proliferating, memory, CD154+) T-cells, as well as NK and CIK-cells were (significantly) increased. We found a (significant) positive correlation of achieved improved blast lysis, frequencies of DCleu and 'activated' (IFNγ+/degranulating) T- or NK/CIK cells, and a (significant) negative correlation with frequencies of DCtol and regulatory (CD152+ T-cells). Kit-M treatment of leukemic WB increases DCleu and decreases DCtol, correlating with improved immune reactions/improved cytotoxicity against autologous blasts, and downregulated suppressive T-cells in samples before or after MLC. Conclusions: These findings demonstrate the potential of Kit-M (using clinically approved drug compositions) to treat AML patients to potentially overcome the immunosuppressive tumor microenvironment, leading to improved antileukemic responses-thereby stabilizing remission of the disease in AML patients.
Primary hyperparathyroidism (PHPT) is associated with neurological damage, which tends to improve after parathyroidectomy (PTX). Oxidative stress might play a role in these pathological changes. This study aimed to investigate oxidative stress and neuronal damage markers following PTX in patients with PHPT. The study involved 36 patients with PHPT who underwent surgical treatment. Markers for oxidative stress, including serum total antioxidant status (TAS), total oxidative status (TOS), oxidative stress index (OSI), 7-ketocholesterol (7-KC) and cholestan-3β,5α,6β-triol (C-triol) as oxysterols and 8-iso-prostaglandin F2α (8-iso-PGF2α), were measured, along with neurofilament light chain (NfL) as a marker for neuronal damage. These markers were assessed before and six months after PTX. Following PTX, a significant reduction in OSI was observed (p = 0.020), while TAS, TOS, oxysterol, 8-iso-PGF2α, and NfL levels remained unchanged. There was no correlation between baseline serum calcium and parathyroid hormone levels with baseline oxidative stress markers or NfL levels. However, baseline TAS levels showed a correlation with baseline NfL levels (r = -0.370), which was not present after surgery. These findings suggest oxidative stress is elevated in patients with PHPT and may contribute to neurological complications. Post surgery, oxidative stress levels decrease, as reflected by a significant reduction in OSI; whether this translates into better central nervous system outcomes warrants confirmation in future studies.
Background: Hypertension (HTN) is a multifactorial condition involving alterations in vascular signaling, inflammation, and oxidative stress. Women during the menopausal transition may experience increased cardiovascular risk due to hormonal fluctuations, highlighting the need for circulating biomarkers that may assist in identifying HTN-related biological changes. This study aimed to evaluate circulating biomarkers reflecting estrogen signaling, inflammation, and oxidative stress, and to assess their diagnostic accuracy in HTN. Methods: This cross-sectional study included 54 treatment-naïve hypertensive women and 30 age-matched normotensive controls, all in the menopausal transition period. Serum levels of GPER-1, 8-iso-PGF2α, raftlin-1, and estradiol were measured using ELISA. Associations between biomarkers and body mass index (BMI) were examined using Spearman correlation. Diagnostic discrimination was examined using ROC curve analysis, and optimal cut-off points were determined using the Youden index. Results: Serum levels of GPER-1, 8-iso-PGF2α, and raftlin-1 were significantly higher in the HTN group compared to controls, while estradiol showed a modest increase. No significant associations were found between BMI and any of the measured biomarkers within the HTN group. ROC analysis demonstrated that 8-iso-PGF2α and raftlin-1 showed the highest diagnostic accuracy for distinguishing HTN patients from controls, followed by GPER-1, whereas estradiol showed limited diagnostic value. High sensitivity and specificity values further supported the diagnostic potential of 8-iso-PGF2α and raftlin-1. Conclusions: These findings suggest that serum raftlin-1 and 8-iso-PGF2α levels may serve as potential biomarkers for distinguishing hypertension in women during the menopausal transition, while GPER-1 also demonstrated good diagnostic accuracy. The lack of association with BMI suggests relative independence from adiposity-related effects. However, further validation in larger and well-characterized cohorts is required.
Type 2 diabetes mellitus (T2DM) is a multidimensional metabolic disorder characterized by hyperglycemia, insulin insensitivity, and dysfunction and degeneration of β-cells. Increase in the levels of free fatty acids (FFAs) in blood plasma is a typical symptom of obesity and metabolic syndrome, which influences the mechanisms of insulin resistance and β-cell impairment. Acute increase in FFA levels blocks glucose uptake by insulin-sensitive skeletal muscles while chronic increase in FFA levels results in hepatic insulin resistance which causes gluconeogenic flux and lipotoxicity in pancreatic βcells. FFA-induced insulin resistance involves various molecular pathways and generation of lipid intermediates (diacylglycerol and ceramides), activation of serine/threonine kinases (PKC), induction of oxidative and endoplasmic reticulum stresses, and inflammatory signaling via nuclear factor-κB (NF-κB) and toll-like receptor (TLR) signaling pathways. Recent studies have indicated that the fetuin-A-FFA complex is an important endogenous ligand of TLR4 that causes inflammation and metabolic dysregulation. In addition, certain FFAs, especially ω-6 polyunsaturated fatty acids, can elicit ferroptosis which is a new form of lipid peroxidation-mediated cell death in β-cells, thereby expanding the extent of FFA-mediated lipotoxicity. This review covers recent information on the mechanisms and clinical factors related to the role of FFAs in insulin resistance and T2DM pathogenesis, and the contribution of experimental research towards developing therapeutic strategies in normalizing the levels of FFA and inhibiting downstream lipotoxicity-related pathways.
Sickness behaviors are common in cancer-associated cachexia and affect up to half of lung cancer patients. We demonstrate that among the most common cancer mutations, loss of liver kinase B1 (Lkb1) promotes the development of cachexia in preclinical models of lung cancer. In an effort to improve caloric intake with an obesogenic high-fat diet, we paradoxically observed worsened cachexia-associated sickness. We found that local production of prostaglandin E2 (PGE2), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE2 suppresses sickness and cachexia. Notably, we demonstrate that lung sensory neuron abrogation prevents PGE2-dependent cachexia. Our study establishes localized tumor-derived signals to sensory neurons, rather than circulating factors, as drivers of cachexia and highlights a previously unknown role of the peripheral nervous system in cancer cachexia.
To evaluate the efficacy of MSCs-HO-1 in pulmonary arterial hypertension (PAH) and explore the underlying mechanisms. HO-1 expression and localization in lung tissues and vessels were assessed using spatial transcriptomics and single-cell RNA sequencing analyses of human PAH. MSCs-HO-1 were intravenously administered in rat and mouse PAH models (MCT-induced and SuHx). Hemodynamics (RVSP), right ventricular hypertrophy index (RVHI), survival rate, and vascular remodeling were assessed by HE staining and α-SMA immunostaining. Inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-18, IL-10, TGF-β, IL-4, IL-1Ra), ROS levels, and endothelial molecules [nitric oxide (NO) and prostaglandin I2 (PGI2)] were measured. RNA sequencing (RNA-seq) of PAECs was followed by pathway analysis and MAPK validation. HO-1 was downregulated in PAH patients and models, mainly in the vascular endothelium. MSCs-HO-1 significantly reduced RVSP, RVHI, vascular remodeling, and improved survival compared to unmodified MSCs and HO-1 alone. MSCs-HO-1 inhibited pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-18), increased anti-inflammatory factors (IL-10, TGF-β, IL-4, IL-1Ra), reduced ROS, and restored NO/PGI2. PAEC migration and proliferation abnormalities were corrected. RNA-seq revealed multiple synergistic pathways, with MAPK playing a key role in endothelial protection. MSCs-HO-1 enhances endothelial function and pulmonary vascular remodeling by modulating antioxidant and immune responses, restoring NO-PGI2 signaling, and suppressing MAPK-mediated inflammation, providing more stable and significant effects than MSCs or HO-1 alone.
The prostaglandin D2 receptor (PTGDR) -441 C/T polymorphism has been previously associated with inflammatory diseases such as asthma. The goal of this study was to explore the association of this polymorphism with idiopathic inflammatory myopathies (IIM) and their clinical features. Seventy-two healthy subjects (HS) and forty-eight patients with IIM from Guadalajara and Mexico were recruited over three years. Clinical features and enzymes used for diagnostics and follow-up, such as creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate transaminase (AST), and alanine aminotransferase (ALT), were collected at the recruitment point and from the chart at the diagnostic point. PCR-ARMS was used to define genotypes. The Chi-square test was used to compare genotype and allele frequencies and clinical features between IIM patients and healthy subjects. A one-way ANOVA on ranks was performed to compare enzymatic levels. The allele distribution was not in Hardy-Weinberg equilibrium in the controls. There was no difference in age or gender distribution between the groups. The polymorphic (T) allele was more common in the IIM group than in the HS group. At the same time, the wild-type (CC) genotype presented more clinical features, such as heliotrope rash, fever, dyspnea, and weight loss, than the TT genotype. No significant differences were found regarding the enzyme levels. To further understand the role of this polymorphism in IIM, a bigger sample size is required along with mechanistical studies. Nevertheless, the polymorphic allele of the PTGDR -441 C/T polymorphism suggests susceptibility to IIM, whereas the wild-type CC genotype is associated with more clinical features.
The upregulation of cyclooxygenase-2 (COX-2) and the subsequent production of prostaglandin E2 (PGE2) in synovial tissue are hallmarks of autoimmune arthritis, including rheumatoid arthritis (RA). While glucosamine (GlcN) derivatives modulate RA symptoms, their specific anti-inflammatory mechanisms in synovial fibroblasts (SFBs) are poorly understood. In this study, we evaluated the anti-inflammatory efficacy of various GlcN derivatives: glucosamine hydrochloride (GlcN-HCl), glucosamine sulfate (GlcN-S), glucosaminate (GlcNA), and N-acetylglucosamine (GlcNAc). GlcN-HCl and GlcN-S inhibited IL-1β-induced PGE2 release and the expression of COX-2 at both protein and mRNA levels, whereas GlcNA and GlcNAc exhibited no such inhibitory activity. Structure-activity relationship analysis using GlcN-HCl epimers revealed that whereas the C-4 epimer, galactosamine hydrochloride (GalN-HCl), retained potent anti-inflammatory effects, the C-2 epimer, mannosamine hydrochloride (ManN-HCl), showed significantly diminished bioactivity, highlighting the critical role of the C-2 stereochemical configuration in modulating inflammatory responses. Mechanistically, we demonstrated that GlcN-HCl-mediated COX-2 suppression occurs via epigenetic silencing rather than mRNA destabilization. GlcN-HCl treatment significantly reduced the enrichment of active chromatin marks, H3K27ac and H3K4me3, at the COX-2 promoter, whereas mRNA stability remained unaffected. Given that metabolic dysregulation is intrinsically linked to inflammatory pathogenesis, we characterized the metabolic profile of GlcN-HCl-treated SFBs. We found that GlcN-HCl triggers metabolic reprogramming of the polyol pathway by modulating the expression of AKR1B1 and sorbitol dehydrogenase (SORD), resulting in elevated intracellular sorbitol levels. Pharmacological inhibition of AKR1B1 effectively abrogated the anti-inflammatory effects of GlcN-HCl, indicating that polyol pathway activation is essential for its efficacy. We confirmed the evolutionary conservation of these findings in human SFBs, demonstrating the translational relevance of the GlcN-HCl-mediated metabolic and epigenetic axis. Our findings demonstrate that GlcN-HCl induces metabolic reprogramming of the polyol pathway in synovial fibroblasts, facilitating the epigenetic silencing of inflammatory mediators. This metabolic-epigenetic axis suggests a mechanistic rationale for pharmacological metabolic intervention in RA, shifting the therapeutic paradigm toward targeted reprogramming of synovial fibroblast metabolism.
Extracellular ATP (eATP) accumulates in the tumor microenvironment (TME), where its metabolite adenosine is implicated in promoting immunosuppressive pathways. We found that immunotherapy further increased eATP concentrations in the TME. eATP directly signaled through the purinergic receptor P2RY2 in tumor cells to suppress T cell function, independently of its metabolites. Mechanistically, eATP-P2RY2 signaling drove expression of cyclooxygenase (COX)-1 and COX-2 and downstream accumulation of prostaglandin E2 (PGE₂). Genetic deletion or pharmacologic inhibition of P2RY2 reduced baseline intratumoral PGE₂ and prevented therapy-induced PGE₂ accumulation, changed the TME immune infiltrate, restored antitumor T cell responses, and overcame resistance to immune checkpoint blockade, CAR-T, and TCR-T therapies. A P2RY2 antagonist monoclonal antibody recapitulated the in vivo therapeutic benefit and enhanced human autologous tumor-infiltrating lymphocyte responses against matched tumor cells ex vivo. Thus, persistent eATP-P2RY2 signaling in the TME drives a PGE₂-mediated immunosuppressive circuit that operates at baseline and is further amplified during immunotherapy, driving adaptive resistance.
Although the main component of cell membrane is phospholipids, there are regions that are rich in glycosphingolipids and cholesterol, called membrane microdomains. Membrane microdomains are densely populated with receptors and intra/extracellular proteins that regulate signal transduction. Membrane microdomains move freely on cell membrane like floating rafts in the sea. In the presence of ligands, they associate with intracellular signaling molecules, regulating cellular functions. Most cell surface proteins including receptors and secreted proteins are glycosylated and interact with lectins that recognize specific glycan structures. Glycan-lectin binding plays an important role in regulating cellular function. Glycans on receptors and ligands and on glycosphingolipids abundant in membrane microdomains are recognized and crosslinked by endogenous lectins, regulating the behavior of cell surface molecules such as receptors. We have been investigating the in vivo function of galactose-recognizing galectins. Fifteen subtypes of galectins exist in mammals, and they are widely distributed throughout the body including the gastrointestinal tract, urogenital tract, and immune system in a tissue- and cell-specific manner. While analyzing the function of galectins in the mechanism controlling the function of the corpus luteum, which produces progesterone essential for the establishment and maintenance of pregnancy, we discovered that cell membrane lipids play a central role in regulating luteal function. Here, we introduce the involvement of cell membrane lipids, particularly a lipid-derived mediator, prostaglandin E, and the qualitative and quantitative changes in glycosphingolipids, as well as galactose-recognizing galectins in the mechanism controlling human corpus luteum function.
Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality, and immune checkpoint inhibitors have become central to systemic treatment for advanced disease. However, durable responses are limited to a subset of patients, indicating the need to clarify tumor-intrinsic mechanisms that shape immune resistance. Nuclear factor erythroid 2-related factor 2 (NRF2), encoded by Nuclear Factor Erythroid 2-Related Factor 2 Like 2 (NFE2L2), is a stress-responsive transcription factor that regulates antioxidant defense, detoxification, metabolism, and redox adaptation. Although transient NRF2 activation protects hepatocytes from oxidative injury, persistent activation in HCC may promote tumor survival, immune escape, and resistance to therapy. Emerging evidence links NRF2 activity to two biologically connected processes: suppression of ferroptosis and remodeling of the tumor immune microenvironment. Through downstream targets involved in glutathione synthesis, cystine transport, iron handling, and lipid peroxide detoxification, NRF2 can reduce ferroptotic vulnerability. In parallel, NRF2-associated inflammatory and immune-regulatory pathways, including the Cyclooxygenase-2 - Prostaglandin E2 (COX2-PGE2) axis, may contribute to immune-cold phenotypes and impaired response to immune checkpoint blockade. This review summarizes current evidence on NRF2/KEAP1 signaling in HCC, with emphasis on its role in immune escape, ferroptosis suppression, and its potential implications as a biomarker and therapeutic target for understanding and potentially improving immune checkpoint inhibitor responsiveness. We also discuss the potential of NRF2-related biomarkers and therapeutic strategies, while emphasizing the challenges of selectively targeting NRF2 in patients with underlying liver dysfunction.
Prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), prostacyclin and their analogues are widely used in clinical practice for their potent biological effects. PGE1/PGE2 analogues, including misoprostol and sulprostone, are primarily used in obstetrics for labour induction, abortion, and postpartum haemorrhage management, whereas PGI2 analogues such as iloprost and treprostinil are key drugs in pulmonary arterial hypertension treatment. Despite structural similarities, these compounds produce contrasting vascular effects due to differences in receptor selectivity, signalling pathways, and tissue distribution. PGE1/PGE2 analogues activate EP receptors, particularly EP1 and EP3 with varying selectivity profile, promoting vasoconstriction and have been associated with cardiovascular complications such as coronary vasospasm. In contrast, PGI2 analogues act mainly on IP receptors, promoting vasodilation, inhibition of platelet aggregation, and beneficial vascular remodelling, with a generally favourable cardiovascular safety profile. Although cardiovascular effects have been reported with both classes of analogues, the underlying mechanisms, and especially their direct effects on human coronary arteries (HCA) remain insufficiently explored. In this context, we combined a review of the clinical and experimental literature that integrates clinical reports with original ex vivo pharmacological investigations on isolated HCA. Both PGE2 and misoprostol induce concentration-dependent vasoconstriction, primarily via EP3 receptors, which is significantly reduced by a TP receptor antagonist, suggesting a potential EP3-TP pathway interaction. All tested PGI2 analogues consistently induced relaxation in our HCA preparations, a finding that aligns with their general improvement of cardiovascular clinical parameters, with only rare exceptions. Together, these findings summarize the cardiovascular effects of clinically-used prostanoids and provide mechanistic insights to optimize their therapeutic use while minimizing cardiovascular risk.
BackgroundAcetylsalicylic acid (aspirin) is a widely used medication with antipyretic, anti-inflammatory, and antiplatelet effects. It also exhibits antitumor properties by enhancing immune responses, downregulating proinflammatory cytokines, and interfering with platelet-tumor cell interactions that promote metastatic dissemination. Identifying effective, safe interventions for brain metastases (BMs) remains a major clinical challenge.ObjectivesThis narrative review synthesizes mechanistic, preclinical, clinical, and safety evidence on aspirin's potential role in preventing or modulating brain metastasis and proposes possible preventive and adjuvant strategies for future investigation.DiscussionThe development of BMs involves tumor-derived factors, extracellular vesicles, and recruited host cells that remodel the brain microenvironment into a premetastatic niche. Platelet activation and the COX-1/TXA2 axis promote platelet-tumor cell aggregates, immune evasion, and endothelial adhesion-key steps in metastatic seeding. Aspirin may inhibit these processes by (1) irreversibly blocking platelet COX-1 (reducing TXA2 and aggregation), (2) lowering prostaglandin E2 (PGE2)-mediated immunosuppression, and (3) preserving blood-brain barrier (BBB) integrity. Preclinical and retrospective clinical studies provide supportive but heterogeneous evidence across cancer types. Combination strategies-aspirin with radiotherapy, antioxidants (e.g., ascorbic acid), or immunotherapy-are biologically plausible and supported by limited data. Major safety concerns remain, particularly bleeding risk and intracranial hemorrhage in patients with intracranial disease.ConclusionAspirin is a low-cost, biologically plausible adjunct for metastasis prevention. However, direct evidence in brain-metastasis settings is limited. Prospective trials with mechanistic biomarkers and careful safety monitoring are required to determine optimal dosing, timing, patient selection, and combination strategies.
IM-B is a herbal formula comprising extracts derived from four medicinal herbs previously reported to exhibit antioxidant and anti-inflammatory properties. In this study, the bioactive compounds of IM-B extract, as well as its antioxidant and anti-inflammatory properties, were explored. Chemical compounds in IM-B extract were identified through phytochemical analysis using LC-ESI-QTOF-MS/MS. Fifteen compounds comprising naringenin 5-methyl ether, alpinetin, pinocembrin, 2',4',6'-trihydroxydihydrochalcone, demethoxycurcumin, curcumin, alpinetin methyl ether, caffeic acid, myrcene, bisdemethoxycurcumin, geraniol, pinostrobin, pinostrobin chalcone, cannabidiol, and astaxanthin were analyzed. Based on the total phenolic (106.20 ± 3.11 mg GAE/g extract) and flavonoid (94.65 ± 2.65 mg QE/g extract) contents of the IM-B extract, we consider it a good source of these secondary metabolites. Its antioxidant activities were 4.03 ± 0.63 μg/mL, 9.11 ± 0.57 μg/mL, and 126.84 ± 0.30 mg FeSO4/g extract based on 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power (FRAP) assays, respectively. Analyses of the association of IM-B extract with nitric oxide (NO), prostaglandin E2, and cytokines (tumor necrosis factor-α [TNF-α] and interleukin-6 [IL-6]) revealed that IM-B extract significantly inhibits the LPS-stimulated proinflammatory responses in RAW 264.7 macrophage cells. These findings support the potential effectiveness of IM-B as an herbal supplement in health promotion.