Search Results (4,778)

Acute myeloid leukemia (AML) develops within a bone marrow environment that influences leukemic stem cell behavior, residual disease, and response to therapy. This review examines evidence that the marrow microenvironment is not only a site of leukemic growth, but can actively shape AML initiation, maintenance, and treatment resistance. Clinical observations such as donor cell leukemia after allogeneic transplantation, together with experimental models in which stromal or osteolineage abnormalities induce myeloid disease, suggest that altered niches may contribute to leukemogenesis in selected settings. In established AML, vascular and endosteal compartments provide adhesive, chemokine, inflammatory, and metabolic signals that promote leukemic-cell retention, quiescence, survival, and chemotherapy tolerance. AML cells also remodel the surrounding marrow, suppressing normal hematopoiesis and generating stromal, endothelial, osteoblastic, adipocytic, and immune-cell programs that favor leukemic persistence. These interactions are especially relevant to drug resistance, including resistance to venetoclax-based therapy, where cytokine-mediated changes in apoptotic dependence, fatty-acid metabolism, mitochondrial adaptation, and stromal support may all contribute. Several therapeutic approaches have attempted to disrupt niche-mediated protection, including targeting CXCL12/CXCR4 signaling, adhesion pathways, inflammatory circuits, Hedgehog signaling, and metabolic dependencies. Although early-phase studies have shown activity in some AML subsets, randomized evidence remains limited and results have been inconsistent. We discuss how a better understanding of microenvironmental biology may help define when niche-directed therapy is most likely to complement conventional and molecularly targeted AML treatment. Full article

Polyploid giant cancer cells (PGCCs) are increasingly recognized as major drivers of therapy resistance and tumor relapse, yet the conserved molecular programs underlying their persistence remain incompletely defined. To identify genes consistently deregulated across eight independent datasets, we performed an integrative transcriptomic analysis of PGCCs derived from prostate, ovarian, and breast cancers. By focusing on consistently up- or down-regulated genes that were expressed in at least five datasets and showed a concordant direction of expression across more than 70% of datasets and met a significance threshold of adjusted p < 0.05, we defined the core regulatory architecture stabilizing the PGCC state under therapeutic stress. Our analysis reveals that PGCCs exhibit a paradoxical ranscriptomic signature consistent with cytolytic activity alongside reduced immune detection. These cells activated pro-inflammatory cytokine and chemokine signaling while simultaneously engaging immune-evasion mechanisms, including PD-L1-associated and virus-like escape programs. Concurrently, PGCCs displayed transcriptional features characteristic of immune-privileged cellular states, including embryonic development, reproductive programs, senescence-associated survival, apoptosis resistance, and deep dormancy marked by coordinated suppression of major housekeeping processes. Notably, PGCCs also activated neuronal differentiation and neurodegeneration-associated pathways, including axon guidance, neurogenesis, and calcium signaling. This neuron-like, calcium-dependent stress adaptation program may further enhance immune privilege and long-term survival capacity. We propose that PGCCs represent an immune-adaptive polyploid survival state in which inflammatory and ontogenetic pathways are repurposed to support immune evasion and tumor persistence. By identifying actionable vulnerabilities within calcium signaling, neuronal mimicry, and checkpoint-associated pathways, this study provides a framework for therapeutic strategies aimed at dismantling the PGCC reservoir and preventing tumor relapse. Full article

Background: The C-X-C chemokine receptor type 7 (CXCR7), also known as atypical chemokine receptor 3 (ACKR3), primarily signals through β-arrestin and plays a pivotal role in tumor progression, inflammation, and neurodegenerative diseases. CXCR7 antagonists block chemokine binding and dampen β-arrestin signaling. Accordingly, identification of such antagonists is highly desirable for therapeutic development against CXCR7 driven pathologies. Methods: Through microscale thermophoresis (MST) screening of a Food and Drug Administration (FDA)-approved drug library, entacapone was identified as a CXCR7 binder. The NanoBit complementation assay was employed to evaluate the effect of entacapone on CXCR7 mediated β-arrestin 1/2 recruitment. Molecular docking was performed to predict the binding pocket and binding sites. Results: Entacapone specifically bound to CXCR7 with a Kd value of 6.04 µM. Although entacapone did not directly activate CXCR7, it selectively inhibited CXCL12 and VUF11207 induced β-arrestin 1 recruitment with no significant effect on β-arrestin 2 recruitment. Molecular docking suggested that entacapone interacted with key residues via hydrophobic contacts, including Trp100, Phe124, Gln301, and Leu305, and formed hydrogen bonds with Ser103, Asn108, and Tyr51 in the transmembrane core, collectively suggesting a possible binding mode compatible with stabilizing the receptor in an inactive conformation. Conclusions: Entacapone, a clinically well established COMT inhibitor, is reported for the first time as a novel biased antagonist of CXCR7, providing a new candidate molecule for drug repurposing. Full article

Donor liver scarcity is exacerbated by preservation-related injury, particularly ischemia-reperfusion injury (IRI), which reduces organ utilization and increases discard rates. Liver sinusoidal endothelial cells (LSECs) play a critical role in mediating IRI, yet their response to static cold storage (SCS) remains poorly understood. Here, we investigate the impact of SCS on isolated rat LSECs. Isolated rat hepatocytes, stellate cells, Kupffer cells, and LSECs were subjected to up to 3 days of SCS followed by up to 2 days of recovery, with LSECs also receiving apoptosis and/or oxidative stress inhibition. Afterwards, changes in survivability, functionality, and morphology were measured. Additionally, changes in gene, cytokine, and chemokine expression were also measured. We found that SCS reduced cell viability by approximately 40%, accompanied by a 60% reduction in metabolic activity and ATP levels, indicating substantial impairment in cellular energetics. SCS also doubled reactive oxygen species (ROS) production and upregulated oxidative stress and apoptosis-related genes, leading to functional decline in LSECs. Importantly, combined inhibition of apoptosis and oxidative stress improved LSEC viability by 20% and metabolic activity and ATP levels by 30% and 40%, respectively, and reduced ROS production by 50%. These findings highlight LSEC vulnerability to preservation injury and the importance of understanding LSEC-specific injury mechanisms to provide a foundation for the development of endothelial-targeted preservation strategies to significantly improve liver transplantation outcomes, subsequently increasing access to this life-saving treatment. Full article

Sjögren’s disease (SjD) is a chronic autoimmune disease characterized by lymphocytic infiltration and dysfunction of the exocrine glands, with manifestations extending beyond glandular sicca symptoms to multiple extraglandular systems. Although the pathogenesis of SjD remains incompletely understood, growing evidence indicates that a complex cytokine network involving both innate and adaptive immune pathways plays a central role in disease development. This narrative review summarizes recent updates on cytokine signaling in SjD across three clinically relevant domains. In glandular inflammation, activation of salivary gland epithelial cells through Toll-like receptor pathways triggers type I interferon (IFN) signaling via plasmacytoid dendritic cells, while IFN-γ, Th17-related cytokines (IL-6, IL-17, IL-22), BAFF/APRIL, and chemokines (CXCL10, CXCL12, CXCL13) collectively sustain local inflammation and ectopic lymphoid organization. The BAFF/APRIL axis, a systemic type I IFN signature, and IL-21–follicular helper T cell–B cell interactions primarily drive systemic immune activation, which together underlie autoantibody production, hypergammaglobulinemia, and a lymphoma-prone phenotype. In contrast, constitutional symptoms such as fatigue, pain, and dryness frequently dissociate from classical inflammatory activity and are better explained by neuroimmune–metabolic mechanisms, including the IFN-γ–IDO–kynurenine pathway and symptom-associated proteomic signatures. Collectively, these findings underscore the heterogeneous nature of SjD, in which glandular inflammation, systemic immune activation, and constitutional symptoms are driven by distinct yet partially overlapping cytokine pathways. Recognizing this heterogeneity has direct implications for cytokine-targeted therapy, suggesting that future trials should stratify patients by disease phenotype (IFN-high, B cell-dominant, and symptom-dominant) rather than treating SjD as a uniform population. Full article

Background/Objectives: The chemokine receptor CXCR4 plays a pivotal role in tumor progression, metastasis, and therapy resistance and is frequently overexpressed in hematologic malignancies, including multiple myeloma and lymphoma. This study investigates a CXCR4-targeted theranostic platform comprising a PET imaging agent and two therapeutic radioconjugates derived from the high-affinity CXCR4 antagonist LY2510924. Methods: The PET tracer [¹⁸F]AlF-NOTA-SC and therapeutic radioconjugates [¹⁷⁷Lu]Lu-BL02 and [¹⁶¹Tb]Tb-BL02 were synthesized and evaluated. Radiolabeling efficiency, molar activity, and in vitro binding affinity were assessed. Specificity and uptake were evaluated in CXCR4-expressing U87.CD4.CXCR4 and MM.1S cells, with cytotoxic potential being analyzed via clonogenic survival assays. In vivo biodistribution and pharmacokinetics were evaluated in MM.1S xenograft mouse models, supported by longitudinal SPECT imaging. Results: All radioconjugates were obtained with high radiochemical purity (>98%). The constructs showed nanomolar affinity for human CXCR4; in vitro assays confirmed specific uptake in CXCR4-positive cells, and both therapeutic agents demonstrated dose-dependent cytotoxicity. In vivo, all compounds displayed comparable tumor uptake with low off-target accumulation. Co-injection studies confirmed consistent pharmacokinetics across agents, while SPECT/CT imaging demonstrated gradual tumor clearance of [¹⁷⁷Lu]Lu-BL02 over seven days. Conclusions: The radiopharmaceutical trio [¹⁸F]AlF-NOTA-SC, [¹⁷⁷Lu]Lu-BL02, and [¹⁶¹Tb]Tb-BL02 demonstrates the feasibility of a CXCR4-targeted theranostic approach for imaging and treating hematologic malignancies. The observed tumor washout highlights the need for further structural optimization to enhance tumor retention and therapeutic efficacy, providing a clear direction for future development toward clinical translation. Full article

Short-chain fatty acids (SCFAs), acetate, propionate, and butyrate, are typically produced in a 3:1:1 ratio, respectively, via microbial fermentation of non-digestible carbohydrates, and to a lesser degree, from undigested protein. The effects of individual SCFAs on adipocyte function have been described; however, the effects of SCFAs in combination on adipocyte function remain unknown. Mature 3T3-L1 adipocytes were treated with a 1 mM total dose of acetate, propionate, and butyrate combined in a 3:1:1 ratio, respectively, for 24 h ± lipopolysaccharide (LPS, 10 ng/mL) under both normoxic and hypoxic (via the addition of 100 µM cobalt chloride) environmental conditions. In both normoxic and hypoxic LPS-stimulated conditions, SCFAs increased the secretion of adiponectin and reduced the secretion of resistin, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1/C-C motif chemokine ligand (CCL)2, and RANTES/CCL5, in addition to reducing intracellular protein levels of activated (i.e., the ratio of phosphorylated-to-total) nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) p65 and signal transducer and activator of transcription 3 (STAT3) (p < 0.05). Additionally, SCFA treatment reduced leptin secretion only in LPS-stimulated normoxic environmental conditions compared to control (p < 0.05). In normoxic conditions, SCFA + LPS increased mRNA expression of genes involved in fat storage), fatty acid recycling, and lipolysis, whereas in hypoxic conditions, SCFA + LPS decreased mRNA expression of genes involved in fat storage and triglyceride synthesis (p < 0.05), indicating different effects of SCFAs on adipocyte metabolic function depending on hypoxia status. Collectively, combined SCFAs in a 3:1:1 ratio beneficially modify the adipocyte adipokine secretory profile under both normoxic and hypoxic environmental conditions. Full article

Chlorophenylacetonitriles are known as one of the emerging nitrogenous disinfection byproducts (N-DBPs) in chlorinated drinking water due to their concerned cytotoxicity and genotoxicity compared to regulated carbonaceous DBPs. However, under low-dose exposure, the in vivo pathological consequences of chlorophenylacetonitriles remain largely unresolved. Here, C57BL/6J mice were exposed to 2-chlorophenylacetonitrile (2-CPAN) via drinking water (100 ug/L) for six months, and an integrated histopathological and genome-wide transcriptomic approach was employed to mechanistically characterize its multi-organ toxicological consequences. 2-CPAN ingestion significantly suppressed body weight (35.9 ± 2.0 g vs. 47.6 ± 11.6 g, p < 0.05) and induced severe gastroenteropathy—including gastric lamina propria inflammatory infiltration, intestinal villous blunting, crypt disorganization, transmural mononuclear infiltration, and abrogating epithelial barrier integrity. Intestinal barrier failure drove portal translocation of luminal PAMPs, potentially triggering splenic white pulp atrophy, red/white pulp boundary dissolution, and parenchymal changes consistent with fibrotic remodeling. Splenic RNA sequencing revealed a bipartite transcriptomic reprogramming: upregulated pathways were enriched in the ribosome, MAPK signaling, cytokine–cytokine receptor interaction, and chemokine signaling pathways. A proteotoxic stress module (Hspa1a, 9.4-fold; Hspa1b, 10.2-fold) and a chemokine effector hub (Ccl2, 3.43-fold; Ccl5, 2.9-fold; Ccl19, 2.58-fold; Ccl21a, 2.15-fold) were identified by the STRING network. Downregulated pathways converged on cell cycle suppression, with concurrent loss of Ccne1/Ccne2 and Cdc6 (G1/S block), Ccnb1 and Plk1 (G2/M arrest), and Rrm2/Tars3/TrnM (dNTP and aminoacyl-tRNA starvation), collectively forcing splenic lymphocytes into irreversible proliferative failure. These findings provide the first mechanistically resolved in vivo evidence that chronic 2-CPAN exposure drives a potential gut–spleen toxicological axis, underscoring the urgent need to incorporate organ endpoints by long-term exposure into N-DBP risk assessment. Full article

Background/Objectives: To date, the antineoplastic effect of cabozantinib in in vitro anaplastic thyroid cancer (ATC) cells has not yet been investigated. We aim to evaluate the antineoplastic and immunomodulatory effect of cabozantinib in both primary and continuous ATC cell cultures in vitro. Methods: The antineoplastic activity of cabozantinib was evaluated in ATC cell lines (8305C; CAL62) and in five different primary ATC cells obtained directly from patients. Results: Increasing concentrations of cabozantinib were tested showing a significant decrease in viability/proliferation and an increase in apoptosis in the treated cells vs. control. A scratch assay was also performed to evaluate the effect of cabozantinib on migration showing a significant inhibition of it vs. control. Moreover, we showed a decrease in the secretion of both CXCL10 and CCL2 (T-helper (Th)1 and (Th)2 chemokines) under the treatment with cabozantinib, thus suggesting an immunomodulatory effect of the drug. Conclusions: A personalized approach for each patient can be achieved by using primary human ATC cells obtained directly from the patient, since in vitro studies permit assessing the chemosensitivity of cells obtained from each subject. These results in our opinion are very promising for a future in vivo evaluation of cabozantinib in patients with ATC. Full article

HIV-associated neurocognitive disorders (HAND) persist despite effective antiretroviral therapy, indicating that chronic neuroimmune dysfunction extends beyond active viral replication. Among HIV-1-derived factors, the viral proteins Tat and gp120 are contributors to sustained brain inflammation. Nevertheless, their comparative impact in genetically vulnerable neural environments remains unclear. Here, we performed a secondary transcriptomic analysis of publicly available RNA-seq data derived from the striatal tissue of hSNCA^A53T Gba1^+/L444P mice, a model combining α-synuclein overexpression with Gba1-associated lysosomal impairment, following unilateral intrastriatal injection of Tat or gp120. Both proteins induced robust transcriptional remodelling selectively in the injected striatum. Tat primarily elicited a broad inflammatory amplification programme encompassing innate immune sensing, chemokine recruitment, adaptive immune engagement, and loss of homeostatic support. gp120 preferentially activated antigen presentation, complement, oxidative stress, and lysosomal–phagocytic effector pathways consistent with immune-mediated synaptic stress. Despite these distinct profiles, Tat and gp120 converged on a shared microglia-centred effector core. Contralateral striatal tissue was analyzed as distal non-injected tissue to explore the spatial distribution of transcriptional responses and minimal and protein-specific effects were reported. These findings provide a mechanistic framework for HAND heterogeneity and suggest that HIV protein-driven neuroimmune transcriptional programmes may create a molecular environment compatible with increased neurodegenerative vulnerability in lysosome-compromised, α-synuclein-sensitized brains. Full article

Probiotic strains with multifunctional skin-beneficial properties represent promising candidates for next-generation cosmetic ingredients. In this study, a systematic stepwise screening strategy was applied to an in-house bacterial library comprising 302 isolates to identify candidates with antioxidant, anti-inflammatory, antimicrobial, wound-healing, and skin barrier-supportive activities. From this library, 33 strains were selected based on preliminary assessments and subjected to comprehensive in vitro evaluation. Cell viability and cytotoxicity assays confirmed the safety of all selected strains in RAW264.7 macrophages and HaCaT keratinocytes. Several strains exhibited strong DPPH radical scavenging activity and significantly inhibited nitric oxide production in LPS-stimulated macrophages. Among the selected candidates, Lacticaseibacillus rhamnosus DM073 demonstrated the most potent anti-inflammatory activity, whereas Lactiplantibacillus plantarum DM043 exhibited the greatest wound-healing capacity. All five selected strains displayed antimicrobial activity against Cutibacterium acnes. Furthermore, selected strains, particularly Lactiplantibacillus plantarum DM175 and Ligilactobacillus salivarius DM079, enhanced the expression of skin barrier-related genes, including zonula occludens-1 (ZO-1), occludin (OCLN), claudin-1 (Cla-1), and filaggrin (FLG), and partially restored their expression under TNF-α/IFN-γ-induced inflammatory conditions. Selected strains also reduced the expression of inflammatory chemokines in stimulated keratinocytes. Collectively, these findings demonstrate that the selected probiotic strains possess complementary multifunctional activities associated with skin health. In particular, DM073 exhibited superior anti-inflammatory activity, DM043 showed strong wound-healing potential, and DM175 demonstrated remarkable skin barrier-supportive effects. These strain-specific properties support their potential application in the development of probiotic-derived postbiotic cosmetic ingredients for skin soothing, barrier reinforcement, skin recovery, and microbiome-friendly skincare formulations. Further studies are warranted to evaluate their efficacy and safety in advanced skin models and clinical cosmetic applications. Full article

Respiratory medicine is transitioning from symptom-driven, standardized care to a more precise, patient-specific approach guided by molecular profiling. This evolution is being enabled by advances in liquid biopsy, multiomics, and artificial intelligence (AI) analytics. Fractional exhaled nitric oxide (FeNO) and blood eosinophils, the two commonly used markers in asthma, are now being joined by more precise airway markers such as galectin-10, which could aid clinicians in making more informed decisions for biological treatments. In chronic obstructive pulmonary disease (COPD) similar progress is underway, with treatment now emphasizing inflammation endotypes, especially eosinophilic patterns, to direct therapeutic choices. Alongside these developments, routine blood-based ratios (e.g., platelet-to-lymphocyte and neutrophil-to-lymphocyte) are being explored as predictors of exacerbation risk, and forced oscillation testing (FOT) is proving useful for picking up early disease shifts. In more severe conditions, biomarkers are linked to an early and better prognosis, enabling timely intervention. Markers like Matrix metalloproteinase-7 (MMP-7) and CC chemokine ligand 18 (CCL18) have proven to be reliable indicators of mortality and disease progression in idiopathic pulmonary fibrosis. Meanwhile, in lung cancer, liquid biopsies, especially those measuring circulating tumor DNA and micro-RNA (miRNA) panels, are enhancing screening accuracy while helping to cut down on the high false-positive rates seen with low-dose computerised tomography (CT). Other respiratory conditions such as bronchiectasis, pulmonary embolism, pneumonia, and acute respiratory distress syndrome (ARDS) are also benefiting from biomarker advances. At the same time there is a growing push to standardize how these biomarkers are measured. AI-based clinical decision support systems are also playing an increasingly important role in the translation of all these complicated data into actionable clinical insights. Together these developments pave the way for improved respiratory care that is precise and responsive to individual patient needs. Full article

Background/Objectives: Watercress (Nasturtium officinale), a cruciferous vegetable rich in phenethyl isothiocyanate (PEITC) and bioactive phytochemicals, has demonstrated anti-inflammatory and cytoprotective activities in multiple disease models; however, its effects on colitis remain insufficiently characterized. In the present study, we investigated the effects of watercress extract supplementation in dextran sulfate sodium (DSS)-induced experimental colitis. Methods: Male C57BL/6 mice were fed either a standard AIN-93G diet or a diet supplemented with 0.5% (w/w) watercress extract for 4 weeks, followed by DSS administration to induce acute colitis. Colonic histopathological injury, immune responses, barrier integrity, and gut microbiota composition were evaluated. In addition, the activity of PEITC, a major bioactive constituent of watercress, was examined in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages in vitro. Results: Watercress extract attenuated DSS-induced colon shortening and reduced histopathological injury. The supplementation of watercress extract also decreased colonic immune cell accumulation, suppressed the expression of pro-inflammatory mediators, and preserved intestinal barrier integrity. The 16S rRNA gene amplicon sequencing further revealed that watercress extract reshaped gut microbial composition, including increased abundance of Monoglobus and Adlercreutzia, and reduced abundance of microbial taxa such as Enterococcus and Enterorhabdus. Moreover, PEITC suppressed LPS-induced inflammatory activation in RAW264.7 macrophages by reducing nitric oxide production, inhibiting p38 MAPK phosphorylation, and downregulating multiple inflammatory cytokines and chemokines. Conclusions: These findings demonstrate that watercress extract alleviates experimental colitis through attenuating mucosal inflammation, preserving intestinal barrier function, and modulating the gut microbiota, highlighting watercress as a promising dietary strategy for improving gut health and mitigating intestinal inflammation. Full article

Chronic low-grade aging-associated inflammation, or inflammaging, is a central pillar of age-related decline in quality of life. Inflammaging is partially mediated by impaired intestinal, immune, and microbiome function, and it has been hypothesized that probiotics could be used to promote healthy aging. SBD121, a defined synbiotic containing food-derived microbial strains and prebiotic fibers, has previously been shown to improve grip strength in male rats, an important indicator of healthspan, and is under evaluation in a clinical trial of 143 newly diagnosed rheumatoid arthritis patients (NCT06005220). However, the mechanisms underlying its potential benefits have not been determined. Here, we examined the function of SBD121 in microbial, cellular, and animal models relevant to inflammaging. SBD121 inhibited the growth of potential microbial pathogens, produced immunomodulatory metabolites in vitro, and improved human intestinal cell barrier function under both basal and challenge conditions, while reducing inflammatory chemokine secretion following inflammatory challenge. SBD121 also reduced the secretion of multiple chemokines in lipopolysaccharide-stimulated human intestinal and immune cells. Finally, SBD121 improved survival and locomotor activity in a C. elegans longevity model, providing evidence of benefits to lifespan and healthspan. Together, these data demonstrate that SBD121 exhibits beneficial microbial, epithelial, immune, and longevity effects and support continued investigation of SBD121 as a candidate intervention for healthy aging. Full article

Campylobacteriosis is one of the leading foodborne bacterial illnesses worldwide, with poultry meat representing its principal source of human infection. Broiler chickens are a key reservoir for Campylobacter jejuni, where the bacterium persists in the gastrointestinal tract without disease. Understanding this host–pathogen interaction is essential to clarify mechanisms of persistence and food safety implications. This study investigated persistent C. jejuni colonisation and systemic immune responses in experimentally infected broiler chickens. Following oral challenge with the virulent ST-403 strain, animals were monitored under controlled conditions. Caecal bacterial loads were determined at 13, 27, 35 and 41 days post-infection, alongside serum total and antigen-specific IgY levels and circulating cytokines and chemokines using ELISA and multiplex assays. C. jejuni rapidly colonised the caecum and persisted throughout the study, although bacterial loads gradually declined over time but remained high. Total IgY increased early after infection and then stabilized. Antigen-specific antibodies were higher in infected chickens than in controls. Cytokine profiling revealed distinct temporal patterns, with increased IL-6 and MIP-1β, decreased IL-2 and MIP-3α, and persistently low IFN-γ levels. C. jejuni established stable intestinal colonisation with a detectable but non-clearing systemic immune response. These findings further support the role of broiler chickens as a persistent reservoir for human exposure to C. jejuni. Full article