Search Results (553)

Nephrolithiasis, predominantly driven by calcium oxalate (CaOx) crystal deposition, poses a significant global health burden due to its high prevalence and recurrence rates and limited preventive/therapeutic options. Recent research has underscored a pivotal role for macrophage polarization in nephrolithiasis pathogenesis. Pro-inflammatory phenotype macrophages exacerbate crystal-induced injury and foster stone formation by amplifying crystal adhesion via an NF-κB–IL-1β positive-feedback axis that sustains ROS generation and NLRP3 inflammasome activation, whereas anti-inflammatory phenotype macrophages facilitate crystal clearance and tissue repair. We have summarized the research on treating nephrolithiasis and related renal injury by targeting macrophage polarization in recent years, including therapeutic approaches through pharmacological methods, epigenetic regulation, and advanced biomaterials. At the same time, we have critically evaluated the novel therapeutic strategies for macrophage reprogramming and explored the future development directions of targeting macrophage reprogramming for nephrolithiasis treatment, such as using single-cell/spatial omics to reveal the heterogeneity of macrophages in the stone microenvironment, chimeric antigen receptor macrophages (CAR-Ms) as a potential therapy for specific crystal phagocytosis in certain areas, and multi-omics integration to address inter-patient immune differences. This review highlights that macrophage reprogramming is a transformative frontier in nephrolithiasis management and underscores the need for further research to translate these molecular insights into effective clinical applications. Full article

Crotoxin (CTX), the main toxin in Crotalus durissus terrificus venom, is a heterodimeric complex known for its antitumoral, anti-inflammatory, and immunomodulatory properties. In macrophages, CTX stimulates energy metabolism, pro-inflammatory cytokines, superoxide production, and lipoxin A₄ secretion while inhibiting macrophage spreading and phagocytosis. These effects are completely blocked by Boc-2, a selective formyl peptide receptors (FPRs) antagonist. Despite the correlation between FPRs and CTX-mediated effects, their involvement in mediating CTX entry into macrophages remains unclear. This study aimed to investigate the involvement of FPRs in CTX entry into monocytes and macrophages. For this, THP-1 cells were silenced for FPRs or treated with Boc-2. Results demonstrated that FPR-related signaling pathways, which influence macrophage functions such as ROS release, phagocytosis, and spreading, were reduced in FPR-silenced cells. However, even in the absence of FPRs, CTX was efficiently internalized by macrophages. These findings suggest that FPRs are essential for the immunomodulatory effects of CTX, but are not involved in CTX internalization. Full article

Adoptive cell therapies have transformed the treatment landscape for hematologic malignancies. Yet, translation to solid tumors remains constrained by antigen heterogeneity, an immunosuppressive tumor microenvironment (TME), and poor persistence of conventional CAR-T cells. In response, innate immune cell platforms, particularly chimeric antigen receptor–engineered natural killer (CAR-NK) cells and chimeric antigen receptor–macrophages (CAR-MΦ), have emerged as promising alternatives. This review summarizes recent advances in the design and application of CAR-NK and CAR-MΦ therapies for solid tumors. We highlight key innovations, including the use of lineage-specific intracellular signaling domains (e.g., DAP12, 2B4, FcRγ), novel effector constructs (e.g., NKG7-overexpressing CARs, TME-responsive CARs), and scalable induced pluripotent stem cell (iPSC)-derived platforms. Preclinical data support enhanced antitumor activity through mechanisms such as major histocompatibility complex (MHC)-unrestricted cytotoxicity, phagocytosis, trogocytosis, cytokine secretion, and cross-talk with adaptive immunity. Early-phase clinical studies (e.g., CT-0508) demonstrate feasibility and TME remodeling with CAR-MΦ. However, persistent challenges remain, including transient in vivo survival, manufacturing complexity, and risks of off-target inflammation. Emerging combinatorial strategies, such as dual-effector regimens (CAR-NK⁺ CAR-MΦ), cytokine-modulated cross-support, and bispecific or logic-gated CARs, may overcome these barriers and provide more durable, tumor-selective responses. Taken together, CAR-NK and CAR-MΦ platforms are poised to expand the reach of engineered cell therapy into the solid tumor domain. Full article

Avian pathogenic Escherichia coli (APEC) is highly infective in poultry, causing significant economic losses to the poultry industry. As an extraintestinal pathogenic strain, adherence is a critical step in the infection. The functions of several adhesins, including type I, P, and Curli fimbriae, have been extensively studied. However, the roles of other adhesins, like Sfm, remain largely unexplored. Sfm is widely present in E. coli. Although the Sfm cluster is an ortholog of the fim gene cluster of Salmonella type I fimbriae, the biological function of Sfm in APEC has not yet been elucidated. To investigate whether Sfm in APEC CE129 plays a role in virulence, in this study, we constructed recombinant strains by expressing Sfm in the fimbriae-deficient strain SE5000. Additionally, a CE129 sfmA mutant strain was constructed. The resulting changes in adherence, biofilm formation, resistance to macrophage phagocytosis, and resistance to serum bactericidal ability were observed. The adherence ability of CE129ΔsfmA was reduced by 41%. HD-11 cells demonstrated a 30% increase in the phagocytosis of CE129ΔsfmA, and a 50% reduction in SE5000 (pBR322-sfm). The sfm deletion mutant showed a 23.9% reduction in the resistance to serum bactericidal ability, while SE5000 (pBR322-sfm) displayed a 32% increase. SE5000 (pBR322-sfm) exhibited a 34% increase in biofilm formation, and CE129ΔsfmA demonstrated a 21% decrease. Real-time PCR was employed to examine the impact of Sfm deletion on the transcription level of key virulence factors (fimA, fliC, papC, tsh, ompA, and iss). The results indicated that Sfm in CE129 is closely associated with bacterial adherence and survivability, contributing to biofilm formation and influencing the expression of key virulence factors. This study yields initial insight into the functional roles of Sfm in APEC and provides a foundation for the effective control of E. coli in the poultry industry. Full article

Ovarian cancer, the most lethal form of gynecological cancer worldwide with a poor prognosis, is largely driven by an immunosuppressive tumor microenvironment. In this study, we investigated the anticancer effects of hydnocarpin, a natural flavonolignan derived from the flowers of Pueraria lobata, focusing on its effects on ovarian cancer and tumor-associated immune cells, including ovarian cancer-stimulated macrophages (MQs) and T cells. Hydnocarpin exhibited potent cytotoxicity against multiple ovarian cancer cell lines but only minimal toxicity against normal ovarian surface epithelial cells. Mechanistically, hydnocarpin triggered caspase-dependent apoptosis, as evidenced by the activation of caspase-9 and -3, with limited involvement of caspase-8, indicating the activation of the intrinsic apoptotic pathway. Experimental data implicated reactive oxygen species generation as a key mediator of hydnocarpin cytotoxicity, and reactive oxygen species inhibition significantly inhibited this cytotoxicity. In addition to its direct tumoricidal effects, hydnocarpin reprogrammed the tumor-associated immune cells, ovarian cancer-stimulated macrophages and T cells, by downregulating the levels of M2 MQ markers and pro-tumoral factors (matrix metalloproteinase-2/9, C–C motif chemokine ligand 5, transforming growth factor-β, and vascular endothelial growth factor) and enhancing MQ phagocytosis. Additionally, hydnocarpin promoted T-cell activation (interferon-γ and interleukin-2) and reduced the expression levels of immune evasion markers (CD80, CD86, and VISTA). Overall, this study demonstrated the dual anti-tumor effects of hydnocarpin on both ovarian cancer cells and immunosuppressive immune components in the tumor microenvironment, highlighting its potential as a novel therapeutic candidate for ovarian cancer. Full article

This study aimed to optimize the enzyme-assisted extraction of polysaccharides (RTFPs) from Rosa roxburghii fruit using response surface methodology. Under the optimal extraction conditions, the yield of RTFPs reached 14.02%, which was close to the predicted value of 13.96%. The primary structural characteristics and the antioxidative and immunomodulatory activities of RTFPs were also examined. Structural characterization revealed that RTFPs comprise 36.38% neutral sugar, 48.83% uronic acid, and 7.29% protein. Their heteropolysaccharide structure features two distinct molecular weight fractions (1.87 × 10⁵ Da and 4.75 × 10³ Da) and a monosaccharide composition dominated by glucose (38.93%), arabinose (20.66%), galactose (20.58%), galacturonic acid (10.94%), and xylose (6.52%). Antioxidant assays demonstrated potent radical scavenging activity, with IC₅₀ values of 11 μg/mL (DPPH) and 150 μg/mL (ABTS), comparable to conventional antioxidants. Immunomodulatory studies on RAW264.7 macrophages revealed that RTFPs (100–400 μg/mL) significantly enhanced phagocytosis by 12.61–76.63% and stimulated the secretion of nitric oxide (NO) and tumor necrosis factor-α (TNF-α). These bioactivities are attributed to RTFPs’ high uronic acid content, moderate molecular weight distribution, unique monosaccharide profile, and highly branched conformation. Full article

Glioblastoma is a highly aggressive brain tumor with an overall poor prognosis due to its immunosuppressive tumor microenvironment (TME). Microglia and tumor-associated macrophages (TAMs) with pro-tumorigenic properties are dominant populations of immune cells in the glioblastoma TME. To date, several studies targeting TAMs to fight tumor progression in different tumor entities have been initiated. However, the impact of standard therapy schemes of glioblastoma cells on macrophage polarization, activation, and phagocytosis remains controversial. The same applies to the relevance of PD-1/PD-L1 blockade in the interaction between macrophages and tumor cells. Our study, therefore, investigated patient-oriented treatment of GLIOBLASTOMA by examining the phagocytic capacity of polarized M1- and M2-like macrophages using GL261-luc2 tumor cells as a preclinical model system. Additionally, we analyzed the expression of activation and immune checkpoint markers on these macrophage subtypes following contact with tumor cells and their microenvironment. These factors were also determined after PD-1 blockade was initiated. The analyses revealed that the immunoregulatory M2-like macrophages generally exhibited a higher phagocytosis rate than the pro-inflammatory M1-like macrophages; however, this was not influenced by the pretreatment of glioblastoma cells with chemo- or radiotherapy. This could not be improved by blocking the PD-1 receptor. Furthermore, there were no modulations in the expression of differentiation, activation, or immune checkpoint molecules of M1- and M2-like macrophages after cell-to-cell contact with glioblastoma cells. But the medium conditioned by tumor cells strongly altered M1-like macrophages toward a more activated state, whereas M2-like cells were only mildly influenced. This was further enhanced by tumor cell treatment, with the most prominent effect after irradiation. These results suggest that conventional GLIOBLASTOMA tumor cell treatment affects the immunogenic status of macrophage subtypes, which is relevant for enhancing the anti-tumor immune response in brain tumors. Full article

Paracoccidioides brasiliensis is a thermally dimorphic fungal pathogen and the main etiological agent of paracoccidioidomycosis (PCM), a neglected systemic mycosis endemic in Latin America. The virulence of P. brasiliensis is closely associated with its capacity to survive under hostile host conditions, including acidic environments. In this study, we demonstrate that acidic pH induces melanization in P. brasiliensis, modulates its cell wall composition, and alters the interaction with macrophages. Cultivation at acidic pH resulted in reduced fungal growth without compromising viability and triggered increased production of melanin-like pigments, as confirmed by enhanced laccase activity and upregulation of genes in the DHN-melanin biosynthetic pathway. Additionally, growth under acidic pH induced significant remodeling of the fungal cell wall, leading to increased chitin on the cell wall surface and reduced mannan content, while β-glucan levels remained unchanged. These modifications correlated with decreased viability to Congo Red, suggesting altered cell wall stability. Importantly, P. brasiliensis grown under acidic conditions exhibited reduced phagocytosis by RAW 264.7 macrophages, along with changes in nitric oxide and cytokine production, indicating potential mechanisms of immune evasion. Collectively, our findings suggest that environmental acidification promotes fungal adaptations that enhance survival and modulate host–pathogen interactions, contributing to P. brasiliensis virulence. Understanding how acidic pH regulates these processes provides new insights into the pathobiology of PCM and may contribute to understanding the mechanisms of fungal immune evasion. Full article

Klebsiella pneumoniae, a zoonotic pathogen of global concern, poses significant threats to both veterinary and public health. Here, a comparative study characterized 14 clinical isolates (7 avian-derived, 7 human-derived) from Jiangsu, China, through integrated genomic and phenotypic analyses. Firstly, multilocus sequence typing (MLST) revealed distinct epidemiological patterns: the same ST type in avian isolates was circulating between different species and different regions, whereas it was not found in human isolates. In addition, hypervirulent Klebsiella pneumoniae (hvKP) phenotypes confirmed by string test were exclusive to two human isolates (KP15, KP20). Secondly, biofilm detection demonstrated 78.6% (11/14) of isolates possessed biofilm-forming capacity, with cellulose but not curli as the predominant matrix component. Human-derived KP15 and KP20 had the strongest biofilm formation ability in all isolates. Antimicrobial susceptibility profiling identified serious multidrug resistance in both avian and human isolates. Virulence gene analysis revealed striking disparities, with human isolates harboring 10–20 virulence factors (median 15) versus 6–7 (median 6.5) in avian counterparts. Finally, functional pathogenesis assessments demonstrated human-derived strains exhibited stronger epithelial cell adhesion (2-fold higher) and invasion (1.97-fold higher) in Calu-3 cell models and paradoxically showed reduced macrophage phagocytosis (2.85-fold lower at 2 h) for immune escape. In vivo models confirmed dose-dependent mortality, with human isolates demonstrating higher lethality in both Galleria mellonella and mice. Virulence gene burden positively correlated with mortality outcomes. These findings delineate critical host adaptation differences in Klebsiella pneumoniae populations and provide empirical evidence for pathogen transmission dynamics at the human-animal interface. Full article

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells are a promising platform for off-the-shelf immunotherapy due to their safety advantages over CAR-T cells, including lower risk of graft-versus-host disease, cytokine release syndrome, and neurotoxicity. However, their persistence and efficacy are limited by immunological challenges such as host T-cell-mediated rejection, NK cell fratricide, and macrophage-mediated clearance. This review summarizes gene editing strategies to overcome these barriers, including β2-microglobulin (B2M) knockout and HLA-E overexpression to evade T and NK cell attacks, CD47 overexpression to inhibit phagocytosis, and TIGIT deletion to enhance cytotoxicity. In addition, we discuss functional enhancements such as IL-15 pathway activation, KIR modulation, and transcriptional reprogramming (e.g., FOXO1 knockout) to improve persistence and antitumor activity. We also highlight the role of induced pluripotent stem cell (iPSC)-derived NK platforms, enabling standardized, scalable, and multiplex gene-edited products. Finally, we explore artificial intelligence (AI) applications in immunogenomic profiling and predictive editing to tailor NK cell therapies to patient-specific HLA/KIR/SIRPα contexts. By integrating immune evasion, functional reinforcement, and computational design, we propose a unified roadmap for next-generation CAR-NK development, supporting durable and broadly applicable cell-based therapies. Full article

Macrophages are multifunctional immune cells distributed throughout the whole body, and they have functions in antigen presentation, phagocytosis, killing, and immune regulation. As the most widely studied molecule in the netrin family, netrin-1 plays a key role in neuronal navigation, angiogenesis, and cell survival. Macrophage-derived netrin-1 not only regulates neurovascular regeneration through ligand–receptor binding but also influences macrophage phenotypes by modulating polarization, thereby achieving the purpose of promoting or repairing disease damage. In this review, we will summarize the recent research advances on the role of macrophage-derived netrin-1 and its receptors in a variety of inflammatory diseases and cancers. Full article

Regulating the innate immune response against infections, particularly drug-resistant bacteria, is a key focus in anti-infection therapy. Cathelicidins, found in vertebrates, are crucial for pathogen resistance. Few studies have explored gecko cathelicidins’ anti-infection properties. Recently, five new cathelicidins (Gj-CATH1-5) were identified in Gekko japonicus. The peptide Gj-CATH5, from G. japonicus, shows promise against Pseudomonas aeruginosa through various mechanisms. This study examined Gj-CATH5’s protective effects using in vitro and in vivo models, finding that it significantly reduced bacterial load in a mouse infection model when administered before or shortly after infection. Flow cytometry and the plate counting method showed that Gj-CATH5 boosts neutrophil and macrophage activity, enhancing chemotaxis, phagocytosis, and bactericidal functions. Gj-CATH5 increases ROS production, MPO activity, and NET formation, aiding pathogen clearance. Its amphipathic α-helical structure supports broad-spectrum bactericidal activity (MBC: 4–8 μg/mL) against Gram-negative and antibiotic-resistant bacteria. Gj-CATH5 is minimally cytotoxic (<8% hemolysis at 200 μg/mL) and preserves cell viability at therapeutic levels. These results highlight Gj-CATH5’s dual role in pathogen elimination and immune modulation, offering a promising approach to combat multidrug-resistant infections while reducing inflammation. This study enhances the understanding of reptilian cathelicidins and lays the groundwork for peptide-based immune therapies against difficult bacterial infections. Full article

Bile acids (BAs), essential for lipid metabolism and fat-soluble vitamin absorption, also act as signaling molecules that regulate immune homeostasis. This review focuses on the roles of four key BA-activated receptors, farnesoid X receptor (FXR), G protein-coupled bile acid receptor 1 (GPBAR1), liver X receptors (LXRs), and vitamin D receptor (VDR), in modulating the functions of monocytes-macrophages, and dendritic cells (DCs). The biological synthesis, transport, and metabolism of BAs were discussed and highlighted the feedback mechanisms regulating the synthesis and enterohepatic circulation of BAs. Each receptor’s role in shaping immune responses is detailed, including their function in inflammation, apoptosis, phagocytosis, and pathogen clearance. FXR and GPBAR1 activation generally exhibits anti-inflammatory effects, while LXR and VDR modulate a more nuanced interplay between immune responses and lipid homeostasis. We also explored the cross-talk between BA-activated receptors and Toll-like receptors, providing a comprehensive understanding of the complex interplay between BA signaling and innate immunity. This review culminates by highlighting the therapeutic potential of targeting these receptors for the treatment of inflammatory and autoimmune diseases. Full article

Background/Objectives: Oats and oat bran are rich in dietary fiber, polyphenols and other phytochemicals. Methods: In this study, we evaluated the phytochemical content and established LPS-induced RAW 264.7 macrophage inflammation and DSS-induced Caco-2 cell inflammation models to investigate the anti-inflammatory activities of oat and oat bran polyphenols and their molecular mechanisms. Results: The results showed that oat and oat bran polyphenols (free and bound polyphenols) enhanced phagocytosis, decreased the expression of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), reduced the production of NO and ROS, increased the mitochondrial membrane potential, and reduced the inflammatory cytokines (TNF-α, IL-1β, and IL-6) at the gene level in the RAW 264.7 macrophage inflammation model induced by LPS expression, thus demonstrating strong anti-inflammatory activity. In Caco-2 cells, oat and oat bran polyphenols pretreatment attenuated the DSS-induced decrease in trans-epithelial electron resistance value, increased tight junction protein expression, and reduced cell permeability in Caco-2 cell monolayers, which in turn reduced inflammatory damage in the organism. Conclusions: In summary, the present study not only reveals the mechanism by which oat and oat bran polyphenols inhibit macrophage inflammation and impairment of intestinal barrier function at defined concentration in vitro, but also highlights potential for oat bran as a functional food. Full article

The immunological barrier is among the most significant barriers in vivo. Macrophages and dendritic cells play a crucial role in immune responses, involving phagocytosis, antigen presentation, and triggering adaptive responses. Nanoscale drug-delivery vehicles, such as polymer-encapsulated lipid-bilayer nanodiscs, are of particular interest in the development of new therapeutic approaches, but require well-characterized human in vitro cell models. To this end, the present study differentiated human monocytes into two distinct states, resting macrophages and immature dendritic-like cells (iDCs). These cells served as model systems to assess the efficacy of lipid-bilayer nanodiscs encapsulated by anionic glyco-DIBMA (diisobutylene–maleic acid) or electroneutral sulfo-DIBMA polymers. Nanodisc–cell interaction studies—including cell viability, reactive oxygen species production, cytokine release, particle uptake, and activation marker expression—demonstrated that immune responses depend sensitively on the cell type and polymer and thus on the surface charge of the nanodiscs. Sulfo-DIBMA nanodiscs induced minimal immune cell activation, accompanied by cytokine release and reduced uptake of the nanodiscs by immune cells. In contrast, glyco-DIBMA nanodiscs exhibited increased interactions with cells, elicited pro-inflammatory immune responses, and promoted iDC maturation. This involved co-stimulatory and antigen-presenting molecules, potentially leading to T-cell activation. These findings underscore the potential of glyco-DIBMA nanodiscs to modulate immune responses through receptor-specific interactions, paving the way for immunotherapeutic strategies. Full article