Search Results (9,800)

Breast cancer, a leading global malignancy, exhibits extensive metabolic reprogramming that drives tumorigenesis, therapy resistance, and survival. Ferroptosis, an iron-dependent regulated cell death mechanism characterized by lipid peroxidation, emerges as a promising therapeutic vulnerability, particularly in aggressive subtypes like triple-negative breast cancer (TNBC). This literature review comprehensively explores the metabolic regulation of ferroptosis in breast cancer cells, focusing on how dysregulated pathways modulate sensitivity or resistance. The review will discuss iron homeostasis, including upregulated transferrin receptor 1 (TFR1), diminished ferroportin, mitochondrial dynamics, and ferritinophagy, which catalyze ROS via Fenton reactions. It will examine glutathione (GSH) metabolism through the GPX4-GSH axis, with subtype-specific reliance on cystine import via xCT or de novo cysteine synthesis. Lipid metabolism will be analyzed as the core battleground, highlighting polyunsaturated fatty acid (PUFA) incorporation by ACSL4 promoting peroxidation, contrasted with monounsaturated fatty acid (MUFA) protection via SCD1, alongside subtype adaptations. Further, the review will address tumor microenvironment influences, such as cysteine supply from cancer-associated fibroblasts and oleic acid from adipocytes. Oncogenic signaling (e.g., RAS, mTOR) and tumor suppressors (e.g., p53) will be evaluated for their roles in resistance or sensitivity. Intersections with glucose metabolism (Warburg effect) and selenium-dependent antioxidants will be explored. Therapeutically, the review will consider targeting these nodes with GPX4 inhibitors or iron overload, synergized with immunotherapy for immunogenic cell death. Future directions will emphasize multi-omics integration and patient-derived organoids to uncover subtype-specific strategies for precision medicine in breast cancer. Full article

Cellular components and inflammatory mediators involved in the transmigration of HTLV-1-infected cells across the blood–brain barrier (BBB) are not fully understood. This study proposes a BBB model to identify the immunological mechanisms associated with HTLV-1 pathogenesis. PBMCs from individuals with HTLV-1-associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) (n = 4) or HTLV-1-infected individuals without HAM/TSP (n = 4) were isolated. An indirect cell co-culture was performed between human brain microvascular endothelial (hBMEC) cells and neuroblastoma (SH-SY5Y) cells. PBMCs from healthy individuals (n = 4) were used as a negative control, and MT-2 cells were used as a positive control. Supernatants and cells were collected to quantify inflammatory cytokines and assess cell death after 24, 48, and 72 h. Multiple comparisons were performed using the Kruskal–Wallis test, followed by Fisher’s LSD post hoc analysis. We observed that the production of cytokines IL-6, IL-8, IL-1β, TNF, IL-10, and IL-12p70, as well as the rate of neuronal death, was higher in co-cultures mimicking HAM/TSP carriers compared to HTLV-1-infected individuals without HAM/TSP and controls. Our results suggest that the HAM/TSP condition induces the release of IL-6, IL-8, IL-1β, TNF, IL-10, and IL-12p70, along with the infiltration of mononuclear cells, which may lead to neuronal death. Full article

Background: Glutamate transporter 1 (GLT-1) plays a vital role in maintaining glutamate homeostasis in the body. A decreased GLT-1 expression in astrocytes can heighten neuronal sensitivity to glutamate excitotoxicity after traumatic brain injury (TBI). Despite its significance, the mechanisms behind the reduced expression of GLT-1 following TBI remain poorly understood. After TBI, the endocannabinoid 2-arachidonoyl glycerol (2-AG) is elevated several times. 2-AG is known to inhibit key positive transcriptional regulators of GLT-1. This study aims to investigate the role of 2-AG in regulating GLT-1 expression and to uncover the underlying mechanisms involved. Methods: A controlled cortical impact (CCI) model was used to establish a TBI model in C57BL/6J mice. The CB1 receptor antagonist (referred to as AM281) and the monoacylglycerol lipase (MAGL) inhibitor (referred to as JZL184) were administered to investigate the role and mechanism of 2-AG in regulating GLT-1 expression following TBI. Behavioral tests were conducted to assess neurological functions, including the open field, Y-maze, and novel object recognition tests. Apoptotic cells were identified using the TUNEL assay, while Western blot analysis and immunofluorescence were employed to determine protein expression levels. Results: The expression of GLT-1 in the contused cortex and hippocampus following TBI showed an initial decrease, followed by a gradual recovery. It began to decrease within half an hour, reached its lowest level at 2 h, and then gradually increased, returning to normal levels by 7 days. The administration of AM281 alleviated neuronal death, improved cognitive function, and reversed the reduction of GLT-1 caused by TBI in vivo. Furthermore, 2-AG decreased GLT-1 expression in astrocytes through the CB1-CREB signaling pathway. Mechanistically, 2-AG activated CB1, which inhibited CREB phosphorylation in astrocytes. This decreased GLT-1 levels and ultimately increased neuronal sensitivity to glutamate excitotoxicity. Conclusions: Our research demonstrated that the upregulation of GLT-1 expression effectively mitigated neuronal apoptosis and cognitive dysfunction by inhibiting the CB1-CREB signaling pathway. This finding may offer a promising therapeutic strategy for TBI. Full article

Human cytomegalovirus (HCMV) establishes lifelong latency following primary infection, residing within myeloid progenitor cells and monocytes. To achieve this, the virus employs multiple immune evasion strategies. It suppresses innate immune signaling by inhibiting Toll-like receptor and cGAS-STING pathways. In addition, the virus suppresses major histocompatibility complex (MHC)-dependent antigen presentation to evade T cell recognition. As the downregulation of MHC molecules may trigger NK cell activation, the virus compensates for this by expressing proteins such as UL40 and IL-10, which engage inhibitory NK cell receptors and block activating signals, thereby suppressing NK cell immune surveillance. Viral proteins like UL36 and UL37 block host cell apoptosis and necroptosis, allowing HCMV to persist undetected and avoid clearance. In settings of profound immunosuppression, such as after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or solid organ transplantation, slow immune reconstitution creates a window for viral reactivation. Likewise, immunosenescence and chronic low-grade inflammation during aging increases the risk of reactivation. Once reactivated, HCMV triggers programmed cell death, releasing viral PAMPs (pathogen-associated molecular patterns) and host-derived DAMPs (damage-associated molecular patterns). This release fuels a potent inflammatory response, promoting further viral reactivation and exacerbating tissue damage, creating a vicious cycle. This cycle of inflammation and reactivation contributes to both transplant-related complications and the decline of antiviral immunity in the elderly. Therefore, understanding the immune regulatory mechanisms that govern the switch from latency to reactivation is critical, especially within the unique immune landscapes of transplantation and aging. Elucidating these pathways is essential for developing strategies to prevent and treat HCMV-related disease in these high-risk populations. Full article

Vilobelimab, a first-in-class, human–mouse chimeric immunoglobulin G4 (IgG4) kappa monoclonal antibody, targets human complement component 5a (C5a) in plasma. Unlike upstream complement inhibitors, vilobelimab does not inhibit the generation of the membrane attack complex (C5b-9), necessary to mitigate certain infections. C5a is a strong anaphylatoxin and chemotactic agent that plays an essential role in both innate and adaptive immunity. Elevated levels of C5a have been associated with pathologic processes, including sepsis and inflammatory respiratory disorders such as acute respiratory distress syndrome (ARDS). Blocking C5a with vilobelimab has shown therapeutic promise. A randomized, multicenter placebo-controlled Phase III study of vilobelimab in patients with severe COVID-19 (PANAMO) found that patients treated with vilobelimab had a significantly lower risk of death by day 28 and 60. Based on this study, the United States Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for Gohibic^® (vilobelimab) injection for the treatment of COVID-19 in hospitalized adults when initiated within 48 h of receiving invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). In January 2025, the European Commission (EC) granted marketing authorization for Gohibic^® (vilobelimab) for the treatment of adult patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced ARDS who are receiving systemic corticosteroids as part of standard of care and receiving IMV with or without ECMO. Herein, we review the mechanism of action of vilobelimab in selectively inhibiting C5a-induced inflammation, outlining its bench-to-bedside development from the fundamental biology of the complement system and preclinical evidence through to the clinical data demonstrating its life-saving potential in the management of COVID-19–induced ARDS. Full article

Titanium and its alloys are widely used in biomedical implants due to their favorable mechanical properties and corrosion resistance; however, their natural surface lacks sufficient bioactivity and antibacterial performance. Micro-arc oxidation is a promising approach to producing bioactive coatings, and the incorporation of nanoparticles such as TiO₂ may further improve their functionality. This study aimed to determine the optimal TiO₂ nanoparticle concentration in the micro-arc oxidation electrolyte that ensures coating stability and biological safety. Calcium–phosphate coatings were fabricated on commercially pure titanium using micro-arc oxidation with two TiO₂ concentrations: 0.5 wt.% (MAO 1) and 1 wt.% (MAO 2). Surface morphology, porosity, and phase composition were analyzed by scanning electron microscopy, energy-dispersive spectroscopy, and X-ray diffraction. Corrosion resistance was evaluated via potentiodynamic polarization in NaCl and Ringer’s solutions, while biocompatibility was assessed in vitro using HOS human osteosarcoma cells and MTT assays. Increasing the TiO₂ content to 1% decreased coating porosity (13.7% vs. 26.3% for MAO 1), enhanced corrosion protection, and reduced the friction coefficient compared to bare titanium. However, MAO 2 exhibited high cytotoxicity (81% cell death) and partial structural degradation in the biological medium. MAO 1 maintained integrity and showed no toxic effects (3% cell death). These results suggest that 0.5% TiO₂ is the optimal concentration, providing a balance between corrosion resistance, mechanical stability, and biocompatibility, supporting the development of safer implant coatings. Full article

Immunogenic cell death (ICD) is a specialized form of cell death that triggers antitumor immune responses. In tumors, ICD promotes the release of tumor-associated and tumor-specific antigens, thereby reshaping the immune microenvironment, restoring antitumor immunity, and facilitating tumor eradication. However, the regulatory mechanisms of ICD and its immunological effects vary across tumor types, and a comprehensive understanding remains limited. We systematically analyzed the expression of 34 ICD-related regulatory genes across 33 tumor types. Differential expression at the RNA, copy number variation (CNV), and DNA methylation levels was assessed in relation to clinical features. Associations between patient survival and RNA expression, CNVs, single-nucleotide variations (SNVs), and methylation were evaluated. Patients were stratified into immunological subtypes and further divided into high- and low-risk groups based on optimal prognostic models built using a machine learning framework. We explored the relationships between ICD-related genes and immune cell infiltration, stemness, heterogeneity, immune scores, immune checkpoint and regulatory genes, and subtype-specific expression patterns. Moreover, we examined the influence of immunotherapy and anticancer immune responses, applied three machine learning algorithms to identify prognostic biomarkers, and performed drug prediction and molecular docking analyses to nominate therapeutic targets. ICD-related genes were predominantly overexpressed in ESCA, GBM, KIRC, LGG, PAAD, and STAD. RNA expression of most ICD-related genes was associated with poor prognosis, while DNA methylation of these genes showed significant survival correlations in LGG and UVM. Prognostic models were successfully established for 18 cancer types, revealing intrinsic immune regulatory mechanisms of ICD-related genes. Machine learning identified several key prognostic biomarkers across cancers, among which NT5E emerged as a predictive biomarker in head and neck squamous cell carcinoma (HNSC), mediating tumor–immune interactions through multiple ligand–receptor pairs. This study provides a comprehensive view of ICD-related genes across cancers, identifies NT5E as a potential biomarker in HNSC, and highlights novel targets for predicting immunotherapy response and improving clinical outcomes in cancer patients. Full article

Cannabidiol (CBD) and other phytocannabinoids are gaining attention for their therapeutic potential in cardiovascular disease (CVD), the world’s leading cause of death. This review highlights advances in understanding the endocannabinoid system, including CB1 and CB2 receptors, and the mechanisms by which CBD exerts anti-inflammatory, antioxidative, vasoprotective, and immunomodulatory effects. Preclinical and translational studies indicate that selective activation of CB2 receptors may attenuate atherogenesis, limit infarct size in ischemia–reperfusion injury, decrease oxidative stress, and lessen chronic inflammation, while avoiding the psychotropic effects linked to CB1. CBD also acts on multiple molecular targets beyond the CB receptors, affecting redox-sensitive transcription factors, vascular tone, immune function, and endothelial integrity. Early clinical trials and observational studies suggest that CBD may lower blood pressure, improve endothelial function, and reduce sympatho-excitatory peptides such as catestatin, with a favorable safety profile. However, limited bioavailability, small sample sizes, short study durations, and uncertainty about long-term safety present challenges to its clinical use. Further research is needed to standardize dosing, refine receptor targeting, and clarify the role of the endocannabinoid system in cardiovascular health. Overall, current evidence supports CBD’s promise as an adjunct in CVD treatment, but broader clinical use requires more rigorous, large-scale studies. Full article

Pertussis is an infectious disease that contributes to hundreds of thousands of deaths worldwide each year. Despite the prevalence of preventive vaccination programs, there has been an increasing number of new cases of the disease over the past few decades. This poses a particular problem for the pediatric population among whom the highest mortality from the disease is recorded. Several reasons for this phenomenon can be mentioned, but what is particularly important from the microbiological point of view is the correlation of the increased number of pertussis cases with the introduction of a new form of vaccine—the acellular vaccine in place of the whole-cell vaccine. In this review, we summarized the current state of knowledge on potential factors that may contribute to the decline in immunization efficacy against the pathogen. The post-vaccination response profile, symptomatic of vaccination with vaccination-acellular, is characterized by recruitment of Th₂ and Th₁₇ lymphocytes; it has been reported that in the long term, this results in insufficient activation of B cells and low titers of antibodies to key bacterial antigens (hemagglutinin, pertactin). Moreover, the immune response proceeds by bypassing the recruitment of tissue-resident memory T cells, resulting in a lack of protection against colonization of the nasal cavity by the bacterium despite vaccination. The decline in vaccination efficacy should also be attributed to the phenotypic variability of Bordetella. The popularization of the PtxP3 strain, characterized by its ability to incompletely activate immune mechanisms, poses a real threat to public health. The growing resistance of B. pertussis to standardly used antibiotics including macrolides also remains a problem. This makes it difficult to eradicate pathogens from the nasal cavity area and increases the pool of bacterial carriers in the population area. The increasing prevalence of the disease prompts reflection on more effective methods of prevention. Particularly promising in this field seem to be new vaccines, especially mucosally implemented, e.g., intranasal, or developed on the basis of B. pertussis antigens other than those used so far. Full article

African swine fever virus (ASFV) is an important transboundary animal pathogen with significant impacts on the global swine industry. Overwhelming proinflammatory responses are a major virulence mechanism for ASFV, but the dynamics of these changes during clinical disease are not completely understood. We constructed a detailed portrait of the innate immune responses during acute African swine fever (ASF) at the cellular, transcriptomic, and cytokine levels. Samples serially obtained from infected piglets show that progression of acute ASF is characterized by rapid increases in plasma type I interferons, TNF-α, IL-12p40, and IL-10, which coincide with the manifestation of clinical disease and viral DNAemia. Lymphocytes and natural killer (NK) cells progressively declined, with fluctuations in B cell, CD8+ T cell, and CD4+/CD8+ T cell populations. Blood monocytes and macrophages were highly variable throughout infection, with an abrupt spike in CD203+ mature macrophages immediately prior to death. Transcriptomic analysis of blood showed downregulation of cellular translation as early as 1 day post-challenge (DPC) and significant upregulation of antiviral immune processes at 5 DPC and 7 DPC, which overlapped with the onset of clinical disease. Together, these results present a detailed delineation of fatal ASF which involves an initial infection and damage of susceptible myeloid cells prior to symptomatic disease characterized by pro-inflammatory immune responses, lymphoid depletion, and clinical deterioration. Full article

Background: Dilated cardiomyopathy (DCM) and long QT syndrome (LQTS) are genetically heterogeneous cardiac disorders that contribute significantly to morbidity and sudden cardiac death. Although they are typically considered distinct entities, co-occurrence within families has been increasingly recognized, complicating diagnosis and genetic counseling. Identifying shared genetic determinants may provide insights into overlapping disease mechanisms. Methods: We investigated a multi-generational family in which several members presented with features of both DCM and LQTS. Exome sequencing was performed to identify potential disease-causing variants, and candidate findings were validated by Sanger sequencing. In silico prediction tools and evolutionary conservation analysis were used to assess the pathogenic potential of the identified variant. Results: We identified a novel heterozygous missense variant in the CRYAB gene, c.368G>A (p.Arg123Gln). This variant is located in a highly conserved region critical for protein function and was consistently predicted to be deleterious across multiple computational algorithms. Segregation analysis demonstrated co-occurrence of the variant with disease phenotypes in affected family members. Clinically, several carriers exhibited overlapping features of both DCM and prolonged QT interval, suggesting a dual cardiac phenotype associated with this mutation. Conclusions: Our findings expand the phenotypic spectrum associated with CRYAB mutations, linking them to a combined presentation of dilated cardiomyopathy and long QT syndrome. This underscores the importance of including CRYAB in comprehensive gene panels for inherited cardiac disorders and highlights the need for integrated clinical and genetic evaluation in families presenting with complex cardiac phenotypes. Full article

Dysregulation of astroglia-mediated neuroinflammation is known to be involved in neurodegenerative diseases. Amongst multiple inflammatory pathways, pyroptosis is characterized by inflammatory cell death following inflammasome activation. Recently, the omega-3 poly-unsaturated fatty acid, DHA, has been identified as a pyroptosis inducer, although the underlying mechanisms remain unclear. In this study, we investigated the role of the alternatively spliced T-isoform of Fyn kinase (FynT) in DHA-induced astroglial pyroptosis. Immortalized normal human astrocytes (iNHA) expressing wild-type FynT (FynT-WT), kinase-dead mutant FynT (FynT-KD), or empty vector (EV) controls were treated with DHA and assessed for pyroptotic activation. We found that DHA-treated FynT-WT cells exhibited significantly reduced cytosolic lactate dehydrogenase release, pyroptotic morphology and markers (cleaved caspase-1 and its substrates, cleaved caspase-3 and gasdermin-D N fragments) compared to either EV or FynT-KD cells. No significant differences in pyroptotic activation were observed between EV and FynT-KD cells. In addition, no differences in immunoreactivities of pro- or anti-apoptotic markers (Bax or Bcl-2) were observed across the DHA-treated cells. In summary, our study postulates a negative regulatory role of FynT kinase in DHA-induced pyroptosis in astrocytes, with implications for further understanding neuroinflammatory mechanisms in neurodegenerative diseases and identification of potential therapeutic targets. Full article

Background/Objectives: CD38-targeting monoclonal antibodies isatuximab and daratumumab have revolutionized multiple myeloma (MM) treatment, but a deeper understanding of their distinct mechanisms is crucial for therapeutic optimization. Methods: We used flow cytometry to assess isatuximab and daratumumab binding competition in MM cell lines and patient-derived bone marrow cells. The dynamics of CD38 expression were evaluated at different time points before and after antibody-mediated removal. The effects of IMiDs (pomalidomide, lenalidomide) on CD38 expression and isatuximab-induced apoptosis, either alone or in combination with IMiDs, were also examined. Moreover, MM cell migration was assessed through CXCR4-mediated assays, and cell adhesion was evaluated via CD49d-dependent assays. Results: Isatuximab and daratumumab did not compete for CD38 binding, confirming distinct epitope recognition. Following depletion with either antibody, CD38 expression on the MM cell surface began to recover within 2 h, suggesting a dynamic regulation of CD38 availability. While daratumumab lacked direct apoptosis, isatuximab induced significant direct cell death. Pomalidomide enhanced isatuximab-induced apoptosis by increasing CD38 expression, whereas lenalidomide had no significant effect. Additionally, both antibodies effectively inhibited MM cell migration and significantly reduced cell adhesion. Conclusions: Their non-competitive binding and shared impact on cell dynamics suggest opportunities for optimizing treatment strategies through combinatorial or sequential approaches in MM therapy. Full article

Reperfusion therapy uses thrombolysis and clot removal to restore blood flow in the brain after stroke; however, three months after reperfusion therapy, roughly 46% of stroke patients become independent again. MiRNAs (micro RNA) regulate cerebral ischemia/reperfusion injury, and their transfer between cells via exosomes may differentially affect recipient cells. We examined serum exosomal miRNA levels, stroke treatments, and functional outcomes in stroke patients, and we explored the potential role of estimated differentially expressed miRNA (DEmiRNA) target genes in the brain’s reaction to reperfusion after ischemia. The patients in the study received aspirin or reperfusion therapy with either intravenous thrombolysis (rt-PA), mechanical thrombectomy (MT), or a combination of both (rt-PA/MT). Serum samples were collected from stroke patients on days 1 and 10 post-stroke. Serum exosomes’ miRNA was analyzed using qRT-PCR. We identified DEmiRNAs, estimated their targets, and performed enrichment analysis. Functional outcomes were assessed using the modified Rankin Scale (mRS) on days 10 and 90 post-stroke. Among studied treatments, only rt-PA/MT lowered DEmiRNA by day 10 vs. other groups. Specifically, patients with unfavorable mRS score exhibited decreased levels of miR-17, miR-20, miR-186 and miR-222 after combined stroke therapy. Functional analysis identified target genes and pathways associated with cytoskeleton remodeling, cell death, autophagy, inflammation, and dementia. In conclusion, unfavorable stroke outcomes following poor rt-PA/MT response could result from lower miRNA expression levels, thus activating cell death and neurodegenerative processes in brain. Full article

Inflammation and congestion constitute fundamental mechanisms underlying heart failure (HF). Carbohydrate Antigen 125 (CA125) is a well-established biomarker in HF, primarily associated with congestion, but also it may act as a functional ligand amplifying the inflammatory response in HF. Our aim was to evaluate the potential modulatory effect of CA125 on inflammation, assessed by a set of cytokines (interleukin [IL]-6, IL-10, IL-1β, and tumor necrosis factor [TNF]). We prospectively included 284 patients admitted for acute HF in which cytokines and CA125 were assessed at admission. Study endpoints were all-cause mortality and total HF rehospitalizations. At a median follow-up of 4.2 years (interquartile range: 1.3–7.5), a total of 211 patients (74.3%) died, and 117 patients (41.2%) experienced 249 HF readmissions. In the multivariable analysis, a significant interaction between IL-6 and IL-10 and CA125 was observed for both outcomes (p-value for interactions < 0.05 for all comparisons). Among patients with CA125 > 35 U/mL, both IL-6 and IL-10 showed a positive, linear relationship with the risk of death or HF readmissions. In contrast, we did not find a significant association in patients with CA125 ≤ 35 U/mL. In conclusion, the association between IL-6 and IL-10 with long-term adverse events was significantly modulated by CA125 status, being significantly associated with poor prognosis only when CA125 was upregulated. These findings support a potential modulatory role for CA125 in the inflammatory response in HF. Full article