Vitamin D plays a crucial role in modulating the innate immune response by interacting with its intracellular receptor, VDR. In this review, we address vitamin D/VDR signaling and how it contributes to the regulation of intestinal and respiratory microbiota. We additionally review some components of the innate immune system, such as the barrier function of the pulmonary and intestinal epithelial membranes and secretion of mucus, with their respective modulation by vitamin D. We also explore the mechanisms by which this vitamin D/VDR signaling mounts an antimicrobial response through the transduction of microbial signals and the production of antimicrobial peptides that constitute one of the body’s first lines of defense against pathogens. Additionally, we highlight the role of vitamin D in clinical diseases, namely inflammatory bowel disease and acute respiratory distress syndrome, where excessive inflammatory responses and dysbiosis are hallmarks. Increasing evidence suggests that vitamin D supplementation may have potentially beneficial effects on those diseases.

Antimicrobial resistance (AMR) due to the prevalence of multidrug-resistant (MDR) pathogens is rapidly increasing worldwide, and the identification of new antimicrobial agents with innovative mechanisms of action is urgently required. Medicinal plants that have been utilised for centuries with minor side effects may hold great promise as sources of effective antimicrobial products. The free-living nematode Caenorhabditis elegans (C. elegans) is an excellent live infection model for the discovery and development of new antimicrobial compounds. However, while C. elegans has widely been utilised to explore the effectiveness and toxicity of synthetic antibiotics, it has not been used to a comparable extent for the analysis of natural products. By screening the PubMed database, we identified articles reporting the use of the C. elegans model for the identification of natural products endowed with antibacterial and antifungal potential, and we critically analysed their results. The studies discussed here provide important information regarding “in vivo” antimicrobial effectiveness and toxicity of natural products, as evaluated prior to testing in conventional vertebrate models, thereby supporting the relevance of C. elegans as a highly proficient model for their identification and functional assessment. However, their critical evaluation also underlines that the characterisation of active phytochemicals and of their chemical structure, and the unravelling of their mechanisms of action represent decisive challenges for future research in this area.

Bone metastases are a prevalent complication in advanced cancers, particularly in breast, prostate, and lung cancers, and are associated with severe skeletal-related events (SREs), including fractures, spinal cord compression, and debilitating pain. Conventional bone-targeted treatments like bisphosphonates and RANKL inhibitors (denosumab) reduce osteoclast-mediated bone resorption but do not directly impact tumor progression within the bone. This review focuses on examining the growing potential of immunotherapy in targeting the unique challenges posed by bone metastases. Even though immune checkpoint inhibitors (ICIs) have significantly changed cancer treatment, their impact on bone metastases appears limited because of the bone microenvironment’s immunosuppressive traits, which include high levels of transforming growth factor-beta (TGFβ) and the immune-suppressing cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). This review underscores the investigation of combined therapeutic approaches that might ease these difficulties, such as the synergy of immune checkpoint inhibitors with agents aimed at bones (denosumab, bisphosphonates), chemotherapy, and radiotherapy, as well as the combination of immune checkpoint inhibitors with different immunotherapeutic methods, including CAR T-cell therapy. This review provides a comprehensive analysis of preclinical studies and clinical trials that show the synergistic potential of these combination approaches, which aim to both enhance immune responses and mitigate bone destruction. By offering an in-depth exploration of how these strategies can be tailored to the bone microenvironment, this review underscores the need for personalized treatment approaches. The findings emphasize the urgent need for further research into overcoming immune evasion in bone metastases, with the goal of improving patient survival and quality of life.

Background/Objectives: We aimed to identify the molecular signatures of primitive CD34⁺ and CD34⁻ hematopoietic stem/progenitor cell (HSC/HPC) subsets in cord blood and bone marrow samples. Methods: CD34⁺ and CD34⁻ HSC/HPC subsets from cord blood and bone marrow were characterized using flow cytometry, real-time PCR, and proteomic analysis to evaluate their phenotypic and molecular profiles. Results: Our findings revealed a significantly higher percentage of Lin⁻CD34⁻CD38^Low/− (−/−) cells than of Lin⁻CD34⁺CD38^Low/− (+/−) cells in cord blood. Aldehyde dehydrogenase levels were significantly lower in (−/−) than in (+/−) cells. Clonogenic ability was lower in (−/−) than in (+/−) cells. However, CD34⁻ cells exhibited potent megakaryocyte/erythrocyte differentiation ability. Importantly, the HSC/HPC subsets expressed pluripotency or stemness genes (SOX2, Nanog, and OCT4); however, OCT4 expression significantly increased in (−/−) compared with (+/−) cells. We identified 304 proteins in the HSC/HPC subsets—85.6% had similar expression patterns in the two subsets; only 14.4% were differentially expressed between (−/−) and (+/−) cells. This implies their comparability at the protein level. Certain proteins were implicated in cellular-development-, gene-expression-, and embryonic-development-related signaling networks. Conclusions: Distinct biological and functional characteristics were observed between (−/−) and (+/−) HSC/HPC subsets. Some of the identified proteins may be novel HSC/HPC subsets markers for clinical applications after validation.

Objectiv e While the role of CD4⁺ regulatory T cells in the resolution of lung inflammation is well documented, their potential contribution to the onset of the inflammatory response has been largely neglected. Herein, we assessed the impact of germline CD4 deficiency on the alveolar macrophage (AMΦ)-neutrophil (PMN) axis in initiating the LPS-induced lung inflammation. Methods In vivo, The levels of AMΦ and PMN in bronchoalveolar lavage fluid (BALF) and tissue histopathology were compared in wild type (WT) and CD4-deficient (CD4^−/−) mice at 4 hours after local LPS challenge (2–3 µg/g: intranasally). CD4 expression (flow cytometry) and representative functions of AMΦ (phagocytosis, cytokine secretion) and PMN (migration) of WT and CD4^−/− mice were compared ex vivo. Results LPS increased PMN infiltration of alveoli in WT mice; a response severely blunted in CD4^−/− mice. AMΦ isolated from WT mice captured more microbeads, but secreted less tumor necrosis factor-α, than AMΦ from CD4^−/− mice. Notably, as compared to PMN of WT mice, PMN of CD4^−/− mice had a diminished motility response to a relevant chemotactic stimulus (cell-free BALF). PMN expressed CD4 while AMΦ did not. Conclusions The motility defect of PMN derived from CD4^−/− mice is most likely due to an intrinsic loss of CD4, whereas the quantitative and qualitative shift of the AMΦ pool of CD4^−/− mice cannot.

Bone metastasis develops within a specialized marrow ecosystem where hematopoiesis, immune regulation, vascular trafficking, and skeletal remodeling intersect. Neutrophil-lineage cells occupy a unique position in this setting because they are generated, retained, mobilized, aged, and reprogrammed within the same bone marrow niches that disseminated tumor cells exploit for homing and survival. This review examines how neutrophils, tumor-associated neutrophils, immature neutrophils, low-density neutrophils, and PMN-MDSCs shape skeletal colonization. We discuss tumor-to-marrow signaling, CXCR2-dependent recruitment, CXCR4/CXCL12-mediated marrow retention, neutrophil–circulating tumor cell interactions, vascular arrest, dormancy escape, NET-mediated matrix remodeling, immune suppression, and effects on osteoclast–osteoblast coupling. Evidence is strongest in breast and prostate cancer models, where pathways such as CXCL5/CXCR2, CTNND1–CXCR4/CXCL12, PR3–RAGE, and DKK1–CKAP4–STAT6–CHI3L3 link neutrophil-lineage cells to skeletal progression and immunotherapy resistance. However, several mechanisms, including CTC–neutrophil clustering and NET-driven dormancy awakening, remain partly extrapolated from non-skeletal models. We therefore emphasize evidence hierarchy, methodological limitations, and therapeutic opportunities, arguing that selective reprogramming or functional inhibition of pro-metastatic neutrophil states may be more promising than indiscriminate neutrophil depletion in metastatic bone disease. A clearer understanding of these context-dependent neutrophil programs may help refine biomarker development and guide combination therapies for patients with skeletal metastases.