The Type I-E CRISPR/Cas system in Salmonella enterica is increasingly hypothesized to function as a condition-dependent regulatory interface rather than exclusively as an adaptive immune module. Rooted in its evolutionary origins within mobile genetic elements such as casposons, this system reflects a functional transition toward influencing bacterial pathogenesis. A central hypothesis suggests that CRISPR components-specifically Cascade, Cas3, and Cas6-are integrated into core regulatory networks governing pathogenicity islands, biofilm formation, and oxidative stress adaptation. This regulatory control likely operates through a programmed deviation from the traditional immunity paradigm, where suboptimal PAM recognition or partial sequence complementarity allows Cascade to bind DNA without licensing Cas3 for lethal cleavage. Consequently, the machinery may facilitate transcriptional modulation through steric hindrance, acting as a natural CRISPR interference mechanism. Coordinated by global regulators like H-NS and LeuO in response to environmental cues such as pH fluctuations, this system effectively functions as a molecular rheostat. Collectively, these hypotheses offer a conceptual framework for novel translational strategies, including anti-CRISPR-based therapeutics and engineered evolutionary trap concepts.
The ability of an individual's immune system to mount a productive response against the tumor is critical for the success of immunotherapy. Clinical trials in multiple tumor types have revealed that the degree and way in which any one person's immune system mobilizes to eliminate tumor cells can vary widely, contributing to immunotherapeutic efficacy. Efforts to uncover biological factors contributing to response rates is a crucial area of ongoing research given the pressing clinical need to better stratify patients based on likelihood of response to a given therapy. While sex differences have long been observed in the field of immunobiology, the consideration of sex as a biological variable in the immunotherapeutic treatment of cancer patients has yet to be addressed or incorporated into patient care. Over the past decade, in part due to the National Institute of Health (NIH)‑mandated changes in how sex is handled as a biological variable, research has shifted markedly in how clinical and preclinical data are reported and interpreted. These changes have brought renewed attention to the ways sex shapes anti‑tumor immunity and responses to immunotherapy. In this review, we examine the expanding body of research demonstrating that male and female immune responses differ in their effectiveness against tumors and explore the implications of these differences for responses to immunotherapy.
A recent study in Nature identified the rice (Oryza sativa) nucleotide-binding site and leucine-rich repeat (NLR) receptor XA48, which recognized the ancient bacterial effector XopG and triggered immunity by promoting degradation of the negative regulators OsVOZ1/2. Population genomics revealed an asymmetric selection, with Xa48 retained in indica but lost in japonica due to a reproductive penalty. By stacking XA48-mediated effector-triggered immunity (ETI) with XA21-mediated pattern-triggered immunity (PTI) and introducing the compatible OsVOZ1S allele, broad-spectrum bacterial blight resistance from wild rice was reconstituted. This work provides a design strategy that helps break the growth-defence trade-off.
NK cells are classically defined by their rapid cytotoxicity against tumor cells and infected cells and by early inflammatory cytokine production. However, unconventional roles for NK cells as regulators of immunity and tissue homeostasis have recently been uncovered. Beyond their classical roles, NK cells can orchestrate leukocyte trafficking, curtail responses of other immune cells, remove protein aggregates, support pregnancy, and contribute to healthy tissue regeneration. We discuss the importance of these myriad functional activities of NK cells in infection, cancer, autoimmunity, atopic and allergic disease, pregnancy, tissue injury, and neurodegenerative diseases. The functional pleiotropy of NK cells provides new avenues of translational utility for these innate lymphocytes and represents an unexplored complexity in conventional clinical applications of NK cells against infection and cancer.
Vaccination is the most effective way to prevent infectious diseases and safeguard public health. Yet, most new vaccines fail in late clinical trials, and even established ones often underperform in populations apart from those in which they were initially tested. This can lead to reduced vaccine responsiveness, breakthrough infections, and prevent or delay herd immunity. While the causes of vaccine hyporesponsiveness remain difficult to identify, quantify, and therefore address, numerous reports indicate a predominant role of environmental factors. This has notably been demonstrated by a reduction in the immunogenicity and efficacy of various vaccines when transitioning from urban to rural human populations. Here, we tested whether and, if so, how the environment can cause vaccine hyporesponsiveness. We hypothesised that if the leading causes of vaccine hyporesponsiveness were environmental, then environmentally driven hyporesponsiveness would be exacerbated when individuals are under nutritional stress; specifically predicting that high-quality diet supplementation would increase vaccine responsiveness. Finally, we predicted that parasitic helminth infections, which are more common in rural populations, would degrade vaccine responsiveness, e.g., due to their ability to modulate host immunity, and that anthelmintic treatment could rescue vaccine responsiveness in infected individuals. To test these hypotheses, we coupled lab and field experiments with structural causal modelling, and quantified diphtheria toxoid-specific IgG1 optical density (OD) in paired conspecific cohorts of laboratory-reared and wild wood mice (Apodemus sylvaticus) given a single or two doses of diphtheria toxoid vaccine formulated with alum, with and without diet supplementation. We found that anti-toxoid IgG1 OD was ∼ 47 % lower in thewildwoodmice compared to the laboratory-reared population. We also demonstrated that, across both habitats (wild and lab), substantial variation in vaccine responsiveness was caused by diet. However, contrary to our predictions, this high-quality dietary supplementation resulted in lower vaccine responsiveness. Further, once the effects of habitat, diet, and sex were adjusted for, increasing helminth infection burdens negatively affected anti-toxoid IgG1 OD. Counterfactual predictions from our structural causal model suggested that targeting anthelmintic treatment at heavily infected individuals could have improved their anti-toxoid IgG1 OD responses by approximately 2 to 4-fold. Our results indicated that the wild environment and access to a high-quality diet played a dramatic role in shaping the immune system's response to immunisation. Further, we showed that laboratory settings, even when using a genetically diverse, non-traditional model, systematically yielded higher IgG1 OD than was observed in free-living conspecifics on the same protocol. We provide a causally explicit modelling approach to quantify how habitat, diet, and parasites jointly shape anti-diphtheria toxoid IgG1 levels in a focal population, and to prioritise adjunct interventions such as deworming where model assumptions hold.
Human sapovirus (HuSaV) has long occupied a peripheral position in etiological research on acute gastroenteritis. However, in the context of widespread rotavirus vaccination, the pathogen spectrum of childhood diarrhoea has been reshaped; molecular diagnostics have continued to evolve; and evidence from birth cohorts and environmental surveillance has accumulated. Together, these developments have prompted a systematic reassessment of the public health significance of HuSaV in childhood diarrhoea, outbreaks in childcare facilities and schools, asymptomatic infection, and persistent infection in immunocompromised hosts. Here, we review key advances in HuSaV research across disease burden and epidemiological patterns, genome organization and evolution, natural history and immune responses, experimental models and host interactions, complex clinical phenotypes, and surveillance-to-public-health translation. We further propose priority directions for the next 5 years, including the establishment of standardized antigen panels and reference strain repositories, integration of serological and genotyping data within longitudinal cohorts, elucidation of viral receptor recognition, cell entry and immune-evasion mechanisms, and the development of closed-loop linkages between experimental-model research and population-level surveillance systems. Overall, HuSaV has evolved from a historically underestimated pathogen associated with acute gastroenteritis in infants and young children into a key enteric viral pathogen that requires dedicated surveillance, mechanistic investigation and translational intervention strategies in the post-rotavirus vaccine era. The research paradigm is likewise shifting from descriptive epidemiology towards an integrated framework that combines disease burden, host immunity, experimental systems and transmission surveillance.
Loss of major histocompatibility complex (MHC)-I is a hallmark of prostate cancer (PCa) immune evasion and immunotherapy failure. Here, we identify ZNF263 as a transcriptional repressor that silences MHC-I by recruiting nucleosome-remodeling and deacetylase (NuRD) to the STAT1 promoter, reducing STAT1 and MHC-I expression. Hypoxia enhances this repression through two ZNF263 modifications: phosphorylation-driven phase separation that strengthens NuRD interaction and O-GlcNAcylation at S662 that aids STAT1 promoter binding. O-GlcNAcylation also promotes interaction with protein kinase, DNA‑activated catalytic subunit (PRKDC), amplifying phosphorylation. Interferon‑gamma (IFN‑γ)‑induced MHC-I induction is augmented upon ZNF263 loss. In silico docking identified Viroptic as a Krüppel‑associated box (KRAB) pocket binder disrupting ZNF263-NuRD, derepressing STAT1, and potentiating IFN-γ antitumor immunity in vivo. High ZNF263 correlates with low MHC-I, scarce CD8+ T cells, and poor survival, providing rationale for targeting ZNF263 in PCa immunotherapy.
Angiogenesis serves as a central hallmark of breast cancer progression by driving the formation of a dysfunctional vascular network that sustains tumor growth, enables metabolic adaptation, and facilitates metastasis. Hypoxia within the tumor microenvironment (TME) stabilizes hypoxia-inducible factor-1α (HIF-1α), that transcriptionally activates key pro-angiogenic mediators, including vascular endothelial growth factor (VEGF) and angiopoietins (ANGPT). Concurrently, stromal and immune constituents of the TME, particularly cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), potently augment angiogenesis through the secretion of cytokines, growth factors, and extracellular matrix-remodeling enzymes. These mediators promote endothelial cell activation, increase vascular permeability, and facilitate immune suppression. The VEGF/VEGFR signaling axis serves as a master regulator, orchestrating endothelial cell proliferation, migration, survival, and neovascularization. Although anti-angiogenic agents such as the VEGF-neutralizing monoclonal antibody bevacizumab have demonstrated clinical efficacy, responses are frequently transient owing to intrinsic and acquired resistance, intratumoral vascular heterogeneity, and compensatory activation of alternative angiogenic pathways. Consequently, contemporary therapeutic approaches prioritize rational combination regimens integrating anti-angiogenic agents with chemotherapy, immunotherapy, or radiotherapy to induce vascular normalization, enhance drug penetration, and potentiate antitumor immunity. Targeting the TME, including stromal and immune components, together with bioactive phytochemicals, possessing anti-angiogenic and immunomodulatory properties, has emerged as a promising strategy. This review integrates current knowledge on tumor-endothelial crosstalk, hypoxia- and inflammation-driven angiogenic signatures such as VEGF, miR-20a, and ANGPTL4, while evaluating emerging modalities, including microRNA-based interventions, nanoparticle delivery, and TME reprogramming to overcome resistance and enhance the precision and durability of anti-angiogenic therapies in breast cancer.
Evidence from multiple studies shows that the appendix may play a significant role in the pathogenesis of ulcerative colitis (UC). These findings have sparked interest in the possibility of appendicectomy as a potential adjunctive strategy in UC. This narrative review was conducted by synthesizing data from meta-analyses, immunological research, surgical case studies, population data reports, and prospective trials published since 2000. The evidence was appraised with a focus on appendicectomy and its clinical outcomes in UC, risks and limitations, as well as possible future directions. Observational studies show a reduced risk of colectomy and UC-related hospital admissions when appendicectomy is performed before UC diagnosis. On the other hand, appendicectomy post UC diagnosis in the presence of appendiceal inflammation has shown increased risk of colectomy. But if an appendicectomy is performed in the absence of inflammation, it might not correlate to the risk or reduce the risk of relapse and complications. Evidence also shows that patients with refractory UC may benefit from appendicectomy and may show longer periods of remission. However, some studies show appendicectomy might increase the colorectal cancer risk due to alterations in immunity and microbiota. While medical management remains the first line, appendicectomy may act as an adjunct surgical option in carefully selected cases before escalating to a colectomy. Large multicenter studies and randomized clinical trials are required to identify strategies for patient selection, potential complications, durability of response, and long-term outcomes. The appendix plays a major role in the pathogenesis of ulcerative colitis. Studies show appendicectomy could benefit selected patients with this disease and may be considered as an adjunct treatment to delay or avoid colectomy.
Endometritis is a prevalent uterine inflammatory disease that significantly compromises fertility; however, the host-microbial mechanisms governing disease susceptibility remain poorly defined. Although the gut microbiota is increasingly recognized as a central regulator of systemic and extraintestinal immunity, its role in uterine inflammation has received little attention. Here, we investigated whether gut microbiota dysbiosis modulates susceptibility to endometritis and sought to identify the microbial mediators underlying this relationship. Antibiotic-induced dysbiosis markedly exacerbated uterine inflammation and tissue injury in mice, whereas fecal microbiota transplantation (FMT) re-established microbial homeostasis and substantially ameliorated uterine pathology. 16S rRNA sequencing identified Bifidobacterium pseudolongum as a commensal species depleted during dysbiosis and restored following FMT. Monocolonization with B. pseudolongum conferred protection against dysbiosis-associated uterine inflammation, evidenced by diminished IL-1β, TNF-αand IL-10 production, reduced HMGB1 and HABP2 levels, restored epithelial tight junction protein expression-including ZO-1, Claudin-3, and Occludin, and attenuated neutrophil and macrophage infiltration. Beyond the dysbiosis model, B. pseudolongum demonstrated both prophylactic and therapeutic efficacy in murine models of Escherichia coli- and LPS-induced endometritis, suppressing inflammatory responses, limiting tissue damage, preserving epithelial barrier integrity, and reducing immune cell infiltration. In vitro assays showed that culture supernatants of B. pseudolongum inhibited E. coli growth under cell-free conditions, indicating a potential antimicrobial activity in vitro. Taken together, these findings support a gut-uterus immunological axis in which B. pseudolongum attenuates infection-driven uterine inflammation through the coordinated modulation of immune responses, epithelial barrier maintenance, and antimicrobial defense. Our study positions B. pseudolongum as a compelling microbiota-based candidate for the prevention and treatment of endometritis.
Nanozymes hold considerable promise for in vivo therapy due to their stable and versatile enzyme-mimicking activities. However, real-time tracking of their dynamics with high spatiotemporal resolution and ensuring biosafety remain challenging. Here, we report a class of single-component, metal-free autofluorescent nanozymes (AFNZs) that simultaneously exhibit ultrabright second near-infrared (NIR-II) fluorescence (FL) and potent multienzyme-like activities. By precisely controlling sulfur/nitrogen (S/N) stoichiometry during the solvothermal conversion of cyanine precursors, we developed intrinsically emissive nanozymes with high-brightness NIR-II FL (quantum yield >1.4%, maximum emission wavelength >1100 nm) among metal-free nanozyme systems, achieving a 20-fold enhancement over their precursors. The optimized AFNZs exhibit strong peroxidase (POD)-, catalase (CAT)-, and oxidase (OXD)-like activities, enabling high-contrast in vivo imaging and catalytic tumor therapy. Mechanistic studies suggest that the enhanced FL is associated with restricted intramolecular motion (RIM). These nanozymes support deep-tissue tumor imaging (∼8 mm) and high-resolution angiography (∼30 µm), substantially outperforming their precursors and the clinical contrast agent indocyanine green (ICG). Furthermore, they enable precise tumor margin identification, image-guided resection of microtumors (< 5 mm), and real-time monitoring of catalytic immunotherapy associated with autophagic flux disruption and immune activation. This work offers a stoichiometry-guided strategy for constructing intrinsically fluorescent metal-free AFNZs for image-guided catalytic therapy.
Cardiovascular medicine continues to move towards precision-based, individualised patient care, supported by novel biomarkers, refined imaging protocols, and multidisciplinary risk assessment. The studies featured in this issue of Acta Cardiologica span cardio-oncology, structural heart disease, immune and proteomic biomarkers, sepsis-related cardiac dysfunction, arrhythmia management, and vascular disease. Collectively, they underscore the growing importance of individualised diagnostic and therapeutic strategies across the cardiovascular spectrum, from cancer-related heart failure to conduction system pacing and cardiac arrest prevention.
To evaluate whether the application of cell-free adipose liquid extract (ALE) synergistically enhances the therapeutic efficacy of vascularized lymph node transfer (VLNT) by reconstructing the lymphatic-vascular network and restoring the lymph node immune niche in a rat lymphedema model. A rat hindlimb lymphedema model was established involving popliteal lymph node excision. Animals were randomized into four groups: Control, ALE only, VLNT only, and VLNT combined with ALE (VLNT + ALE). ALE was prepared using a mechanical emulsification and filtration protocol. Edema resolution was monitored by limb circumference. Lymphatic drainage function was visualized via indocyanine green (ICG) lymphography. Histological assessments included Masson's trichrome and immunofluorescence for LYVE-1 (lymphangiogenesis), CD31 (angiogenesis), and MECA-79 (high endothelial venules, HEVs) to evaluate structural and functional regeneration. The VLNT + ALE group achieved the most rapid and significant edema regression compared to VLNT or ALE alone. ICG lymphography revealed that the combined therapy orchestrated the formation of continuous, linear lymphatic channels, effectively eliminating dermal backflow. Histologically, ALE treatment significantly increased the density of both LYVE-1+ lymphatic vessels and CD31+ blood vessels, suggesting a dual-regenerative effect on the microenvironment. ALE directly promoted tube formation in human lymphatic endothelial cells (HLECs), confirming its pro-lymphangiogenic activity in vitro. Crucially, within the transplanted lymph nodes, ALE treatment restored the expression of MECA-79+ HEVs to levels comparable to healthy young nodes. This indicates that ALE not only supports graft survival but also preserves the essential lymphoid microarchitecture required for immune surveillance. Cell-free ALE synergistically enhances the therapeutic efficacy of VLNT by promoting vascular-lymphatic coupling and restoring the functional immune niche of transplanted nodes. As a readily available, safe, and cell-free biologic adjuvant, ALE represents a promising translational strategy to optimize surgical outcomes in secondary lymphedema.
This study investigates the potential of [47Sc]Sc-NOTA-trastuzumab as a novel targeted radionuclide agent in HER2 + breast cancer. Targeted radionuclide therapy offers a promising approach for enhanced delivery and internalization of radiation, minimizing off-target effects and treating advanced metastatic HER2 + breast cancers. By examining the synergistic relationship between [47Sc]Sc with trastuzumab, assessing [47Sc]Sc-NOTA-trastuzumab's impact on immune function, and monitoring its passage of a compromised blood-brain barrier for targeting HER2 + breast-to-brain metastases, this study provides a path towards synergistic and precision radiotherapy in breast cancer metastasis. The stability, specificity and reactivity of [47Sc]Sc-NOTA-trastuzumab was characterized with high performance liquid chromatography, Lindmo, and cell binding assays. In vivo localization and therapeutic efficacy were assessed with SPECT imaging, biodistribution, and tumor monitoring in models of HER2 + breast cancer. Immunostaining against M1 macrophages was assessed to determine mechanisms of enhanced anti-tumoral immune activity. [47Sc]Sc-NOTA-trastuzumab demonstrates high specificity and serum stability in HER2 + cells. SPECT shows [47Sc]Sc-NOTA-trastuzumab has high specificity for HER2 + breast cancer cells in vivo in both the primary and metastatic setting. Longitudinally, tumors treated with [47Sc]Sc-NOTA-trastuzumab show therapeutic benefit and are comparable to those treated with 16x dose of trastuzumab alone, with no significant toxicity. Exploratory results show radiopharmaceutical uptake in a model of HER2 + brain metastasis. Increased M1-like macrophages were seen in HER2 + tumors relative to HER2- tumors following treatment with [47Sc]Sc-NOTA-trastuzumab. [47Sc]Sc-NOTA-trastuzumab is serum stable and highly specific to HER2 + breast cancer. Developing and characterizing novel targeted radionuclide therapeutics has the potential to significantly improve radionuclide delivery in HER2 + metastatic disease.
People living with HIV are at higher risk of severe illness due to common respiratory pathogens. We estimated uptake of influenza, pneumococcal, and COVID-19 vaccines among people engaged in HIV care in Ontario, Canada, and identified factors associated with vaccine uptake. We conducted a cross-sectional analysis of interviewer-administered, annual questionnaires (2021-2023) linked to medical charts and laboratory data. We used modified Poisson regression to calculate adjusted prevalence ratios and 95% confidence intervals for self-reported uptake of influenza (yes vs. no, last year), pneumococcal (≥ 1 vs. 0 doses, lifetime), and COVID-19 (≥ 2 vs. 0 - 1 doses and ≥ 3 vs. 2 doses, lifetime) vaccines. Among 3,163 people with HIV (median age = 54 years; 78% men; 98% on antiviral treatment), overall uptake was 70% (95%CI = 68.5% - 72.1%) for influenza, 72.7% (95%CI = 70.8% - 74.7%) for pneumococcal, and 89% (95%CI = 88.0% - 90.3%) for ≥ 2 doses COVID-19 vaccines. Among two-dose COVID-19 vaccine recipients, uptake of ≥ 3 doses was 84.9% (95%CI = 83.4% - 86.5%). Across all three vaccines, uptake was significantly associated with older age, identifying as a sexual minority man, higher education, difficulty paying for housing costs, food insecurity, being a former or non-smoker, abstaining from alcohol or recreational drugs, having greater social support, certain comorbidities, entering HIV care earlier in time, and having well-managed HIV. Despite generally high coverage, vaccine uptake remains below national targets in people living with HIV in Ontario, particularly for those at highest risk of severe respiratory infections. Interventions that address predisposing, enabling, and need factors associated with vaccine uptake may help improve access and promote vaccine confidence in this population. Las personas que viven con VIH corren un mayor riesgo de desarrollar enfermedades graves causadas por patógenos respiratorios comunes. Estimamos la cobertura de vacunación contra la influenza, el neumococo y la COVID-19 en personas que reciben atención por VIH en Ontario, Canadá, e identificamos los factores asociados con dicha cobertura. Llevamos a cabo un análisis de corte transversal de cuestionarios anuales realizados por entrevistadores (2021–2023), vinculados con historias clínicas y datos de laboratorio. Utilizamos una regresión de Poisson modificada para calcular las tasas de prevalencia ajustadas y los intervalos de confianza del 95% para la cobertura de vacunación declarada por los entrevistados contra la influenza (sí vs. no, durante el último año), el neumococo (≥1 vs. 0 dosis, tiempo de vida) y la COVID-19 (≥2 vs. 0–1 dosis y ≥3 vs. 2 dosis, tiempo de vida). Entre 3 163 personas que viven con VIH (mediana de edad = 54 años; 78 % hombres; 98 % en tratamiento antirretroviral), la cobertura de vacunación fue del 70 % (IC95 % = 68,5 %–72,1 %) para la vacuna contra la influenza, del 72,7 % (IC95 % = 70,8 %–74,7 %) para la vacuna antineumocócica y del 89 % (IC95 % = 88,0 %–90,3 %) para ≥2 dosis de la vacuna contra la COVID-19. Entre quienes habían recibido dos dosis de la vacuna contra la COVID-19, la cobertura de ≥3 dosis fue del 84,9 % (IC95 % = 83,4 %–86,5 %). Para las tres vacunas, los siguientes factores mostraron una relación significativa con el nivel de cobertura: mayor edad, identificarse como hombre perteneciente a una minoría sexual, mayor nivel educativo, dificultad para cubrir los costos de la vivienda, inseguridad alimentaria, ser exfumador o no fumador, abstenerse del consumo de alcohol o drogas recreativas, contar con un mayor apoyo social, presencia de ciertas comorbilidades, haber ingresado más temprano al sistema de atención para el VIH y tener la infección por VIH bien controlada. A pesar de que la cobertura de vacunación fue, en general, elevada, en Ontario sigue estando por debajo de las metas nacionales entre las personas que viven con VIH, especialmente en aquellas que corren un mayor riesgo de desarrollar infecciones respiratorias graves. Las intervenciones destinadas a abordar los factores de predisposición, viabilidad y necesidades específicas asociados con la cobertura de vacunación podrían contribuir a mejorar el acceso y promover la confianza en las vacunas dentro de esta población.
Membranous nephropathy (MN), a leading cause of nephrotic syndrome, is associated with hypercoagulability and an increased risk of thromboembolic events; however, the relationship between coagulation-related alterations and the immune microenvironment remains incompletely understood. In this study, microarray datasets (GSE73953 and GSE140713) and single-cell RNA sequencing data (GSE233275) were obtained from the Gene Expression Omnibus (GEO), and a broad set of coagulation-related genes was retrieved from GeneCards. Differentially expressed coagulation-related genes (DECGs) between peripheral blood mononuclear cells (PBMCs) from MN patients and healthy controls were identified. Functional enrichment and protein-protein interaction (PPI) network analyses were performed, and candidate hub genes were prioritized using multiple topological algorithms. Single-cell RNA sequencing data were analyzed exploratorily to evaluate the cellular distribution and disease-associated expression patterns of hub genes across immune cell populations. Receiver operating characteristic (ROC) curves were used to assess the apparent discriminatory performance of hub genes between MN and healthy control PBMC samples in an exploratory manner. Immune cell infiltration was estimated using CIBERSORTx, and correlations between hub genes, immune cell subsets, and coagulation-related genes were evaluated. In addition, glomerular proteomics data from PXD054062 were independently analyzed to explore potential links between systemic PBMC alterations and the local renal microenvironment. A total of 413 DECGs were identified, and five hub genes (CCL5, CYBB, C3AR1, JUN, and TIMP1) were prioritized. Among them, C3AR1 was closely associated with monocyte-related signatures and was positively correlated with the coagulation-related gene F2R. Glomerular proteomics analysis indicated enrichment of complement- and coagulation cascade-related proteins in MN samples, suggesting that local complement-related alterations may coexist with procoagulant or thrombo-inflammatory features in the kidney. Taken together, this study proposes a hypothesis-driven model in which C3a/C3AR1-related monocyte activation and F2R/PAR-1 expression may be interrelated with procoagulant and inflammatory features in MN. This model remains exploratory and requires direct validation in patient samples and mechanistic experiments. These findings may help generate testable hypotheses for future studies on MN-associated hypercoagulability.
Biological barriers remain a primary limitation to effective cancer therapy, restricting drug delivery, distribution, and therapeutic efficacy across tumor sites. These barriers arise from a complex and dynamic interplay between tumor- and host-derived factors, including abnormal vasculature, dense extracellular matrices, immune clearance, and spatiotemporal heterogeneity within the tumor microenvironment. Increasing evidence suggests that these components operate as an integrated and adaptive network. Here, we conceptualize this network as "tumor systemic intelligence," which enables tumors to sense and respond to therapeutic and physiological perturbations by reinforcing delivery barriers and limiting drug access. Conventional nanomedicine strategies, often designed to overcome individual barriers, have shown limited success in addressing this coordinated system. To overcome these limitations, we propose "adaptive intelligence" as a design paradigm for next-generation nanocarriers. In this framework, nanocarriers are engineered as responsive systems capable of sensing microenvironmental cues and dynamically modulating their physicochemical properties to navigate multiple, evolving barriers during systemic circulation and tumor penetration. We discuss key design strategies for adaptive nanocarriers, including programmable control over size, shape, surface charge, and bioactive interfaces, enabling improved circulation stability, enhanced transvascular transport, deeper tumor penetration, and reduced immune recognition. We further examine how these systems can modulate or bypass critical barriers such as extracellular matrix density, abnormal perfusion, and cellular uptake limitations. Integration with external physical stimuli is also considered to further enhance barrier penetration and delivery efficiency. Despite promising advances, clinical translation remains limited by challenges including nanocarrier safety, immunogenicity, and the complexity of tumor-host interactions. This review highlights emerging opportunities and design principles for adaptive nanocarriers that effectively navigate biological barriers, with the goal of improving drug delivery and therapeutic outcomes in cancer treatment. Importantly, the concepts of systemic intelligence and adaptive intelligence are intended as conceptual frameworks to guide the rational design of next-generation nanomedicines rather than as formal biological classifications.
Regulatory T cells (Tregs) maintain immune tolerance through mechanisms tightly coupled to cellular metabolism. Whereas glycolysis supports Treg migration, lipid metabolism sustains their suppressive phenotype. Here, we identify the sterol regulatory element-binding protein 1c (SREBP1c) as a central regulator of Treg immunobiology. Tregs from Srebp1c-deficient mice displayed impaired suppressive function, reduced frequencies in circulation and lymphoid tissues, and diminished expression of functional markers. These defects stemmed from intrinsic metabolic rewiring rather than systemic alterations, as both ex vivo Tregs (CD4+CD25hiFoxP3+) and in vitro-derived Tregs lacking Srebp1c were shifted toward glycolysis. Integrated transcriptomic and lipidomic analyses revealed that Srebp1c-deficient Tregs exhibited defective phospholipid remodeling, with an accumulation of lysophosphatidylcholines over phosphatidylcholines, which we attributed to enhanced cytosolic phospholipase A2 (cPLA2α) activity and disruption of the Lands cycle. Altered lipid composition impaired adenosine-mediated immunosuppression by reducing CD73 expression and extracellular adenosine generation. Accordingly, pharmacological inhibition of cPLA2α restored adenosine signaling, CD73 expression, and Treg suppressive capacity. Thus, by preserving phospholipid homeostasis, SREBP1c functions as an immunometabolic checkpoint that links lipid metabolism to adenosine-dependent Treg suppression.
Bronchiectasis is increasingly recognized as a chronic inflammatory airway disease involving persistent immune dysregulation, recurrent infection, and progressive lung tissue damage. Older adults bear a particularly high burden of bronchiectasis, as age-related changes such as immunosenescence, multimorbidity, and polypharmacy complicate disease management in this population. Anti-inflammatory therapies are emerging as a central component of treatment strategies, reflecting the growing understanding of inflammation as a key driver of disease progression. However, applying these therapies to older populations requires considering altered pharmacokinetics and pharmacodynamics, increased susceptibility to adverse effects, and comorbid conditions. This review examines current and emerging anti-inflammatory treatments for bronchiectasis, focusing on their relevance, safety, and limitations in older patients. Attention is given to the roles of neutrophilic and type 2 inflammatory pathways, as well as the challenges of implementing precision medicine approaches for older people.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease whose complex etiology is increasingly linked to gut microbiota dysbiosis. While conventional pharmacological treatments often face limitations due to side effects, cost, and variable efficacy, synbiotics combinations of probiotics and prebiotics have emerged as a promising therapeutic strategy to restore intestinal homeostasis. This review synthesizes evidence from recent animal model studies to elucidate the multifaceted mechanisms and superior efficacy of synbiotic interventions in ameliorating colitis. We demonstrate that synbiotics, whether composed of traditional components like lactobacilli, bifidobacteria, inulin, and fructooligosaccharides, or novel formulations involving exopolysaccharides, engineered glucans, and specific fatty acid-producing consortia, consistently outperform their individual components. The therapeutic effects are mediated through a synergistic restoration of gut microbial diversity, enhanced production of protective metabolites (especially short-chain fatty acids and secondary bile acids), fortification of the intestinal barrier via upregulation of tight junction proteins, and modulation of key immune pathways, including NF-κB, MAPK, and AhR. Furthermore, we highlight the advanced strategy of microencapsulation using prebiotic wall materials to enhance probiotic viability and targeted colonic delivery. The collective evidence positions synbiotics not merely as nutritional supplements but as sophisticated, multi-targeted therapeutics. This review underscores the critical need for future research to focus on structure-function relationships, precision synbiotic formulations tailored to individual microbiota profiles, and robust human clinical trials to translate these compelling preclinical results into effective clinical management strategies for UC.