Search Results (1,661)

Although sorafenib (SOR) is effective for advanced hepatocellular carcinoma (HCC), significant metabolic heterogeneity limits its therapeutic effect. In this study, we employed high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) to profile the spatial lipidomic alterations in 3D HepG2 spheroids following SOR treatment. Interestingly, sphingophospholipid and glycerophospholipid metabolism played crucial roles. In an orthotopic HCC mouse model, immunohistochemical and immunofluorescence staining confirmed that SOR induced immunological and inflammatory changes. Moreover, transcriptomic and Q-PCR analyses showed increased expression of Stat1, Zbp1, Parp14, Irf1, and Tifa along with decreased Eif4e2 in the SOR treatment group compared to the tumor control group. Bio-layer interferometry and molecular docking data also indicated that ZBP1 possessed favorable binding affinities with SOR. Overall, our findings demonstrated that SOR dramatically disrupted sphingolipid metabolism in tumor cell spheroids and, in an orthotopic model, activated the NOD-like receptor signaling pathway, accompanied by altered secretion of inflammatory factors and macrophage polarization. These results suggest that SOR exerts dual effects on tumor cell lipid metabolism and the tumor immune microenvironment. These findings provide a conceptual basis for future exploration of lipid-modulating therapeutic strategies in HCC. Full article

The Hippo, as a central pathway regulating cell proliferation, apoptosis, stem cell homeostasis and organ development, is closely associated with the onset and progression of tumors, metabolic reprogramming, drug resistance and immune evasion when it is abnormally inactivated. The Hippo not only directly promotes tumor cell proliferation, maintains cancer stem cell properties, and mediates metabolic reprogramming and treatment resistance, but also reshapes the tumor microenvironment(TME) by regulating the formation, heterogeneity and function of cancer-associated fibroblasts (CAFs). Furthermore, it mediates tumor immunosuppression and immune evasion by modulating programmed death-ligand 1(PD-L1) expression, T-cell function, macrophage polarization and cytokine secretion. At the same time, inflammatory cytokines, growth factors, metabolites and physical signals within the TME can negatively regulate the activity of the Hippo, creating a pro-tumor positive feedback loop. This article provides a systematic review of the composition and regulation of the Hippo , its mechanisms of action in the biological behavior of tumor cells and interactions within the tumor microenvironment, as well as progress in the development of drugs targeting this pathway. It offers a theoretical basis for a deeper understanding of the role of the Hippo in tumors and for the development of novel anti-tumor therapeutic strategies. Full article

Trauma-induced heterotopic ossification (tHO) is characterized by aberrant ectopic bone formation in soft tissue following high-energy trauma, affecting >60% of combat-related amputees and >50% of major burn patients. Current prophylactic strategies (including NSAIDs, bisphosphonates, and low-dose radiation) lack mechanistic specificity, carry significant side effects, and surgical excision carries a 27% recurrence rate. This review reframes tHO pathogenesis through the neural–immune axis, arguing that ectopic bone formation is a downstream consequence of dysregulated neuroimmune signaling rather than a primary osteogenic event. Following trauma, nociceptor activation drives nociception-induced neural inflammation (NINI), releasing substance P (SP) and calcitonin gene-related peptide (CGRP), which disrupts the blood–nerve barrier, mobilizes neural crest-derived progenitor cells, and, alongside BMP-2/SMAD1/5/8 signaling and M1-polarized macrophage activation, establishes a permissive osteogenic microenvironment. A BMP-2/CGRP positive feedback loop sustains aberrant osteogenesis, converging on osteogenic transcription factors Runx2, SOX5/6/9, and Osterix. Dysregulated noncoding RNAs represent promising pre-radiographic biomarkers. This neural–immune framework motivates mechanism-based therapeutic strategies targeting CGRP (fremanezumab, erenumab), SP/NK1 signaling (aprepitant), and macrophage polarization (metformin, palovarotene, rapamycin), with multi-node combination approaches tailored to the temporal stages of tHO offering the most promise for precision prophylaxis. Full article

Concurrent alcohol and cannabis use (“crossfading”) is increasingly prevalent, especially among adolescents, yet its toxicological impact on pulmonary innate immunity remains largely unexplored. Alveolar macrophages (AMs) orchestrate inflammatory responses in the lung, and dysregulated macrophage polarization is a hallmark of alcohol-associated lung disease. Although alcohol and cannabinoids individually modulate immune function, the mechanisms by which their co-exposure alters macrophage activation and inflammatory signaling in the lung are largely unknown. AMs are highly sensitive to xenobiotic exposure and play a central role in regulating inflammatory and cytotoxic responses. In this study, we investigated how acute ethanol exposure, synthetic cannabinoid exposure, and their combined exposure affect macrophage viability, polarization, and the release of inflammatory mediators via cannabinoid receptor (CB1R/CB2R)-dependent pathways. Human THP-1-derived macrophages and KG-1 macrophage-like cells were exposed to ethanol, the CB1/CB2 agonist WIN 55,212-2, or both, with selective pharmacological antagonism of CB1R and CB2R. Ethanol exposure activated and polarized macrophages toward a pro-inflammatory M1 phenotype, accompanied by increased secretion of pro-inflammatory cytokines MCP-1, TGF-α, IFN-β, IL-6, and TNF-α. In contrast, WIN 55,212-2 promoted anti-inflammatory M2 polarization and increased IL-10 and IL-4 production. Notably, co-exposure to ethanol and WIN produced an antagonistic immunomodulatory response, characterized by the suppression of ethanol-induced M1 polarization and attenuation of pro-inflammatory cytokine release. Mechanistically, pharmacological CB1R blockade reduced ethanol-induced M1 polarization and cytokine secretion, whereas CB2R blockade exacerbated these effects, underscoring divergent roles for cannabinoid receptors in regulating pulmonary macrophage responses. This study provides novel findings demonstrating the mechanism by which alcohol–cannabinoid co-use reshapes macrophage immune phenotypes and identifies the endocannabinoid system as a potential therapeutic target for alcohol-related inflammatory lung disease. Full article

Micro- and nanoplastics (MNPs) have now been detected in human blood, placenta, and arterial tissue, yet the oral cavity has received strikingly little mechanistic attention despite serving as a primary portal of environmental exposure and a local site of polymer generation from dental and oral-care materials. This narrative review addresses that gap from an environmental microbiology perspective, synthesizing recent literature on periodontal disease, chronic low-grade inflammation, oral biofilms, dental materials, microbial–plastic interactions, and systemic chronic disease risk. Unlike prior reviews, we apply an explicit three-tier evidentiary framework (established, plausible, unproven) that distinguishes what is directly demonstrated from what is biologically plausible but unproven, and we situate the periodontal environment specifically as a particle-retention and inflammatory-amplification niche. The strongest direct oral evidence shows that human dental calculus harbors at least 26 microplastic types, dominated by polyamide (41.4%), polyethylene (32.7%), and polyurethane (7.0%). Polyethylene isolated from calculus induces cytotoxicity, apoptosis, impaired migration, NF-κB activation, and upregulation of IL-1β and IL-6 in human gingival fibroblasts. From a microbiological standpoint, oral organisms actively degrade methacrylate dental polymers, and the degradation products of these polymers reciprocally modulate oral bacterial virulence gene expression. Across experimental systems, MNPs activate oxidative stress, inflammasome signaling, macrophage polarization, and barrier dysfunction, pathways that overlap extensively with periodontal pathobiology. Adjacent environmental microbiology demonstrates that plastic-associated biofilms enhance extracellular polymeric substance production, quorum sensing, pathogen persistence, and antibiotic resistance gene transfer, supporting a plausible but not yet validated oral plastisphere within plaque and calculus. We argue that periodontitis should be reconceptualized as a chronically inflamed particle-processing interface that may increase local MNP retention, cellular reactivity, and systemic inflammatory spillover, with implications for cardiovascular, metabolic, and other chronic disease risk pathways. Current evidence does not yet prove that environmental MNP exposure causes human periodontitis, and that evidentiary boundary is maintained throughout. A priority research agenda is proposed, centered on contamination-controlled subgingival biomonitoring stratified by periodontal status, spatially resolved multi-species biofilm models, polymer source attribution, and longitudinal clinical studies linking oral plastic burden to inflammatory and systemic outcomes. Full article

Tumor-associated macrophages (TAMs) are pivotal in shaping the immunosuppressive tumor microenvironment (TME). Reprogramming TAMs towards an anti-tumor M1 phenotype represents a promising strategy to enhance anti-tumor immunity. While Fe₃O₄ nanoparticles (NPs) possess immunomodulatory potential, the influence of NP size on macrophage polarization and the underlying mechanisms remain unclear. This study aims to systematically investigate the size-dependent immunomodulatory effects of Fe₃O₄ NPs and elucidate their mechanisms. We synthesized a series of Fe₃O₄ NPs of controlled sizes (5 nm, 10 nm, 30 nm, and 100 nm) via the polyol method. Among these, the 10 nm NPs demonstrated superior cellular uptake efficiency in macrophages. This enhanced uptake induced a significant increase in intracellular reactive oxygen species (ROS) levels. Subsequently, the elevated ROS activated the NF-κB signaling pathway, promoting M1 macrophage polarization. This polarization was evidenced by enhanced CD86 expression, increased nitric oxide (NO) release, and elevated secretion of pro-inflammatory cytokines. This study identifies 10 nm as the optimal size for Fe₃O₄ NPs to elicit their maximal immunomodulatory effects. Our findings establish a crucial size-design principle for the rational development of nano-immunotherapeutic agents and identify 10 nm Fe₃O₄ NPs as a promising candidate for TAM-targeted cancer therapy. Full article

Inflammation is a physiological and tightly regulated component of normal pregnancy, contributing to implantation, placental development, and the initiation of parturition. The placenta functions as an active immunological hub, coordinating innate and adaptive immune responses to maintain tolerance while protecting against infection. Preeclampsia and fetal growth restriction (FGR) are major causes of maternal and perinatal morbidity worldwide and represent central manifestations of placental disease. Increasing evidence indicates that these conditions share key pathophysiological mechanisms, including placental dysfunction and maladaptive maternal immune responses. When immune regulation at the maternal–fetal interface becomes disrupted, inflammatory pathways contribute to impaired placental development and vascular maladaptation. In this context, excessive immune activation—driven by inflammasome signaling, Th1/Th17 polarization, and altered natural killer and macrophage function—can compromise placental perfusion, promote antiangiogenic imbalance, and lead to systemic endothelial dysfunction. This review, therefore, focuses on how immune dysregulation contributes to placental dysfunction in preeclampsia and FGR, synthesizing current knowledge of the maternal–fetal immune interface and exploring therapeutic strategies that link pathogenic mechanisms to targeted interventions. A deeper understanding of placental immunology and inflammatory signaling is essential to develop precision therapies. Established therapies, including low-dose aspirin, low-molecular-weight heparin, and antenatal corticosteroids, aim to mitigate inflammation and optimize fetal outcomes, while adjunctive strategies target oxidative stress, nutritional deficits, and the maternal microbiome. Emerging approaches such as cytokine-targeted biologics, inflammasome inhibitors, and mesenchymal stem cell therapies show promise but require rigorous safety and efficacy evaluation. Future research should prioritize biomarker validation, pathway-specific interventions, and equitable implementation to reduce inflammation-driven pregnancy complications. Full article

Tumor-associated macrophages (TAMs) are among the most abundant immune cell populations in breast cancer and have emerged as central regulators of tumor progression, metastatic dissemination, immune evasion, and therapeutic resistance. While TAMs were historically described using a simplified M1/M2 polarization framework, accumulating evidence indicates that TAMs in breast cancer comprise a continuum of phenotypic and functional states shaped by ontogeny (tissue-resident vs monocyte-derived), spatial localization (including hypoxic, perivascular, and invasive niches), tumor-intrinsic programs, and therapy-induced selective pressures. In breast cancer, mechanistic studies integrating lineage tracing, intravital imaging, single-cell and spatial profiling, and clinical analyses have established that TAMs actively coordinate rate-limiting steps of the metastatic cascade. These include promotion of angiogenesis and vascular permeability, orchestration of tumor cell invasion and TMEM-mediated intravasation, facilitation of metastatic seeding and niche formation, and suppression of anti-tumor immunity. TAMs also critically influence therapeutic response by modulating chemotherapy efficacy and limiting the activity of immune checkpoint blockade. Therapeutic strategies targeting TAMs in breast cancer have evolved from depletion approaches (CSF1/CSF1R blockade) to inhibition of monocyte recruitment (CCL2/CCR2 axis), functional reprogramming (CD40 agonism, PI3Kγ inhibition), and macrophage-directed checkpoint modulation (CD47–SIRPα axis). Early clinical studies demonstrate clear pharmacodynamic activity but highlight the need for context-specific and combination-based approaches. This review focuses on TAM biology in breast cancer progression and metastasis, synthesizing key mechanistic and translational evidence and proposing a framework in which spatially and functionally defined macrophage states act as rate-limiting regulators of dissemination and therapy response. We further outline principles for rational TAM-targeting strategies that integrate tumor stage, metastatic niche, and treatment context. Full article

Toxoplasma gondii, an obligate intracellular protozoan infecting approximately one-third of the global population, poses a significant yet underappreciated threat to reproductive health in both sexes. Although this parasite has long been linked to birth defects caused by infection during pregnancy, new research shows that it also reduces fertility in both sexes through different but related mechanisms. This review synthesizes knowledge on T. gondii-induced reproductive pathology across females and males, examining shared mechanistic themes while respecting tissue-specific differences, and evaluates emerging therapeutic strategies. In females, the parasite establishes persistent uterine reservoirs, triggers decidual immune dysregulation characterized by NK cell cytotoxicity, M1 macrophage polarization, Treg apoptosis, and inflammasome-mediated pyroptosis, while disrupting estrogen and progesterone signaling through both host receptor modulation and intrinsic parasite steroidogenic enzymes (TgCYP450mt, TgMAPR, Tg-HSD). In males, T. gondii breaches the blood–testis barrier, induces germ cell and Leydig cell apoptosis via ER stress and caspase pathways, impairs sperm quality parameters across acute and chronic infection, and disrupts the hypothalamic–pituitary–gonadal axis. Conserved molecular mechanisms—including NLRP3 inflammasome activation, PERK/eIF2α/ATF4/CHOP-mediated ER stress, and oxidative stress—operate in both reproductive tissues. The parasite’s intrinsic steroidogenic capability and bidirectional hormonal manipulation represent a paradigm shift in understanding host–parasite interactions. Conventional antiparasitics face limitations due to poor reproductive sanctuary penetration. Immunomodulatory approaches targeting Trem2, Tim-3, and the NLRP3 inflammasome show promise, along with natural products including Inonotus obliquus polysaccharide and ginseng polysaccharide. Nanomedicine platforms and mRNA vaccine candidates offer new directions for overcoming tissue barrier limitations. Toxoplasma gondii represents a fundamental threat to fertility and pregnancy outcomes rather than merely a risk for congenital infection. Integrated therapeutic strategies addressing direct parasitism, immunopathology, and endocrine disruption are needed. Longitudinal cohort studies, strain-specific mechanistic comparisons, and clinical trials of immunomodulatory adjuncts are urgently required. Full article

Diabetic chronic wounds (particularly diabetic foot ulcers) are difficult to heal due to factors such as high glucose levels, infection, and inflammatory imbalance. In severe cases, they can lead to tissue necrosis and amputation. Hydrogel materials, as moist wound dressings, possess high water content, biocompatibility, and tunability, making them an important platform for promoting diabetic wound healing. In recent years, novel smart hydrogels have been developed to integrate multiple functions. They respond to abnormal stimuli in the wound microenvironment—such as acidic pH, high glucose levels, or excessive reactive oxygen species—to trigger the release of drugs, delivering on-demand antimicrobial, antioxidant, and anti-inflammatory effects. Simultaneously, they modulate immune responses (promoting macrophage polarization toward the M2 type) and stimulate angiogenesis, creating a microenvironment conducive to tissue regeneration. Some hydrogels incorporate antimicrobial agents, anti-biofilm components, or photothermal/photodynamic agents to effectively eliminate drug-resistant pathogens and control infections. Others serve as carriers for delivering stem cells and their exosomes, enhancing cell survival rates and releasing growth factors to accelerate wound healing. This review systematically summarizes recent advances in hydrogel strategies for diabetic wound treatment, focusing on stimulus-responsive hydrogels, antimicrobial and immune modulation mechanisms, pro-angiogenic and oxygen-supplying therapies, smart dressings and monitoring technologies, integration of stem cells and exosomes, as well as hydrogel injection, self-healing, and adhesion properties. Based on this, we analyze challenges and prospects for clinical translation of these strategies. Collectively, functionalized hydrogels hold promise as multifunctional therapeutic platforms for diabetic non-healing wounds. They offer a multi-pronged approach to disrupt the vicious cycle of “infection–inflammation–tissue destruction” thereby achieving more efficient wound healing. Full article

The secondary immunomodulatory effects of conventional therapeutics, such as antibiotics and cytostatics, are frequently overlooked despite their significant clinical implications. Building on our previous findings that drugs like paclitaxel and doxorubicin heavily influence macrophage polarization—potentially driving metastasis or inflammation—this study systematically evaluates the secondary immune-modulating actions of standard drugs and natural adjuvants. Using patient-derived bronchoalveolar lavage (BAL) fluid (ex vivo alveolar macrophages), we developed an analytical platform using synthetic carbohydrate-functionalized fluorescent ligands targeting key receptors (CD206, CD209, CD280, CD301). Integrating ligand-binding profiles with Linear Discriminant Analysis (LDA) yielded quantitative immune-state vectors capable of differentiating favorable and unfavorable prognostic signatures and imbalanced immune states. Pro-filing samples across heterogeneous respiratory conditions revealed highly con-text-dependent responses. While some treatments synergistically corrected unfavorable imbalanced profiles, others provoked dysregulation. Notably, in pneumonia or bronchitis with an asthma-prone M2-dominant profile, specific antibiotic regimens are critical; doxycycline, for instance, may exacerbate patient deterioration by further driving M2a polarization. Crucially, we identified that natural adjuvants (e.g., curcumin, coumarins, polyphenols) exhibit potent properties capable of correcting these adverse secondary drug effects. Ultimately, this profiling platform highlights the necessity of evaluating patient-specific secondary drug effects, offering a functional blueprint for precision immunotherapy and the rational design of adjuvant-enhanced treatments. Full article

Mesenchymal stem/stromal cells (MSCs) are widely recognized as potent modulators of inflammation and immune function in bacterial and viral infections. However, their roles in fungal disease remain comparatively under-defined despite the growing clinical burden of invasive and opportunistic mycoses. This Feature Review synthesizes emerging evidence that MSCs influence antifungal outcomes through two complementary axes: (i) host-directed effects, including modulation of immune responses, particularly macrophage responses, and tissue/barrier conditioning; and (ii) fungus-directed effects (direct antifungal activity mediated by contact-dependent mechanisms and secreted antimicrobial factors). We will summarize how MSCs reshape cytokine and chemokine networks and tune innate immune effector functions, with emphasis on macrophage polarization, pattern-recognition receptor signaling, and downstream phagocytic and fungicidal pathways. In parallel, we will review data suggesting that MSCs can interact more directly with fungal pathogens through sensing, physical engagement, and secretion of antimicrobial mediators while highlighting mechanistic uncertainties and model-dependent limitations. A dedicated section will address MSC-derived secretome products (conditioned media, extracellular vesicles) as a cell-free strategy to enhance antifungal immunity. We will critically evaluate conflicting findings across studies, highlighting that outcomes depend on pathogen and host context. Clarifying these context dependencies is essential to rationally develop MSC or secretome-based interventions that are safe, reproducible, and tailored to specific fungal pathogens and patient populations. Full article

Type 2 diabetes mellitus (T2DM) is a progressive metabolic disease that necessitates individualized therapeutic strategies focusing on both glycemic control and the mitigation of comorbidities. In recent years, sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a cornerstone of modern treatment due to their unique renal mechanism of action. This review summarizes the metabolic mechanisms, pleiotropic effects, and clinical significance of SGLT2 inhibitors in the management of T2DM. This review provides an updated overview of the metabolic and systemic effects of SGLT2 inhibition. By promoting glycosuria, SGLT2 inhibitors induce a negative energy balance that contributes to modest weight loss, improved body composition, and beneficial alterations in lipid metabolism. Beyond their metabolic effects, accumulating preclinical evidence suggests that SGLT2 inhibitors exert anti-inflammatory and antifibrotic actions, partly through modulation of macrophage polarization and attenuation of oxidative stress. The clinical utility of SGLT2 inhibitors is highlighted through the review of major cardiovascular and renal outcome trials, which confirm significant benefits in reducing heart failure hospitalizations and slowing the progression of chronic kidney disease. Finally, we integrate these findings into the context of the latest international guidelines while addressing safety profiles, the rationale for combination therapies, and the transition toward a personalized, risk-based management approach in T2DM. Full article

Diabetic wounds are a common and severe complication of diabetes mellitus, characterized by delayed healing due to persistent inflammation, impaired angiogenesis, and cellular dysfunction. Conventional therapeutic approaches remain limited in efficacy. In recent years, exosomes have attracted considerable attention in wound healing and regenerative medicine because of their crucial role in intercellular communication and tissue repair. However, rapid clearance of exosomes in vivo greatly limits their therapeutic efficacy. To address this critical limitation, we engineered a decellularized extracellular matrix (dECM)-based hydrogel system functionalized with exosomes derived from skin-derived precursor cells (SKPs). This biomimetic scaffold was designed to serve as a local exosome-delivery platform at the wound site, with the aim of improving exosome utilization and augmenting their regenerative effects. Comprehensive in vitro characterization demonstrated that the exosome-loaded composite hydrogels exhibited robust pro-angiogenic activity, as evidenced by enhanced endothelial cell proliferation, migration, and tube formation. Moreover, the hydrogels displayed significant antibacterial effects against wound-relevant pathogens and potent reactive oxygen species (ROS)-scavenging capacity, thereby mitigating oxidative damage. Notably, the composite hydrogels also promoted the phenotypic polarization of macrophages toward the pro-regenerative M2 phenotype. In parallel, in vivo studies using a streptozotocin-induced diabetic rat wound model confirmed that treatment with the composite hydrogels significantly accelerated wound closure rates compared to control groups. Histological and immunohistochemical analyses revealed enhanced angiogenesis, as evidenced by increased CD31-positive microvessel density, as well as improved collagen deposition, re-epithelialization, and an attenuated local inflammatory microenvironment characterized by reduced pro-inflammatory cytokine expression and elevated M2 macrophage infiltration. Collectively, the SKPs exosome-loaded dECM based composite hydrogels developed in this study represent a potential therapeutic strategy for the treatment of diabetic wounds. Full article

Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) play a central role in tumor progression and therapeutic resistance in gynecological malignancies, including ovarian cancer (OC), cervical cancer (CC), and endometrial cancer (EC). This review systematically summarizes common regulatory mechanisms and tumor-specific variations in TAMs across these three malignancies, emphasizing the dual-origin developmental trajectories of tissue-resident macrophages and monocyte-derived macrophages, the CCL2-CCR2 and CSF1-CSF1R core signaling axes, and the regulation of TAMs’ functional polarization by hypoxia and metabolic reprogramming. Furthermore, the molecular mechanisms through which TAMs mediate immunosuppression and therapeutic resistance via physical barrier construction, metabolic competition, and antigen presentation impairment are analyzed, and the specific characteristics of the peritoneal microenvironment in OC, HPV-driven mechanisms in CC, and hormonal regulation in EC are compared. Therapeutic strategies targeting TAM recruitment, survival, and phenotypic reprogramming are discussed, along with TAM markers, and may provide a theoretical foundation and clinical indications for overcoming immune therapeutic resistance in gynecological malignancies. Full article