Macrophage polarization is critically involved in the initiation and progression of ulcerative colitis (UC); however, whether microvesicles (MVs) released from macrophages with distinct polarization states exert different effects on the intestinal epithelial barrier and endoplasmic reticulum (ER) stress remains unclear. Here, MVs were isolated from M0, M1, and M2 macrophages and evaluated in a dextran sulfate sodium (DSS)-induced mouse colitis model and an inflammatory cytokine-stimulated NCM460 epithelial cell model. M2 macrophage-derived MVs (M2-MVs) mitigated body-weight loss, disease activity, colon shortening, and histopathological injury and partially restored Claudin-1, Occludin, ZO-1, and MUC2 expression. In contrast, M1 macrophage-derived MVs (M1-MVs) tended to aggravate inflammation and barrier disruption. Mechanistically, M2-MVs reduced IL-1β, TNF-α, and IL-6, increased IL-10, and inhibited GRP78, PERK/eIF2α phosphorylation, CHOP, and cleaved caspase-3. Consistent effects were observed in vitro, where M2-MVs restored barrier proteins and reduced ER stress and apoptosis. Moreover, the ER-stress inhibitor 4-phenylbutyric acid attenuated the detrimental effects of M1-MVs, supporting ER stress as an important downstream mechanism. By systematically comparing MVs from M0, M1, and M2 macrophages in parallel, this study reveals a polarization-dependent, bidirectional pattern of macrophage-epithelial communication in experimental colitis and provides preclinical evidence supporting M2-MVs as candidate cell-free effectors for intestinal mucosal repair.

Bladder cancer (BLCA) is a urinary system malignant tumor with high morbidity and mortality worldwide. There is an urgent need for new biomarkers and therapeutic targets. By integrating single-cell RNA sequencing, MitoCarta database and the Cancer Genome Atlas data, this study found that mitochondrial ribosomal protein L37 (MRPL37) was significantly up-regulated in BLCA, and its expression level was related to disease progression and poor prognosis. Functional experiments in vitro and in vivo confirmed that knockdown of MRPL37 could inhibit the proliferation, invasion, migration, metabolism and cisplatin resistance of BLCA cells by cell experiments, mouse subcutaneous tumor model, mouse orthotopic bladder cancer model and patient-derived organoid (PDO) model. A novel MRPL37-LRPPRC-ROS-AKT signaling axis was identified: loss of MRPL37 leads to the disorder of branched-chain amino acid metabolism, down-regulates the key mitochondrial protein LRPPRC, and then causes mitochondrial membrane potential damage and reactive oxygen species accumulation, which ultimately exert anti-cancer effect by inhibiting the AKT pathway. This study not only advances the understanding of the mechanism by which mitochondrial translation defects drive tumorigenesis, but also highlights the potential of MRPL37 as a target in BLCA prognosis and targeted therapy.

Sepsis, particularly septic shock, is a life-threatening condition driven by a dysregulated inflammatory response. Mitochondria are vital for orchestrating the LPS (lipopolysaccharide)-induced innate immune response. At the core of mitochondrial functionality lies mitochondrial RNA Polymerase (POLRMT). This study delineates POLRMT's functional role and underlying mechanisms in LPS-induced pro-inflammatory responses across various macrophage models and in vivo. Through multiple genetic strategies, including stable shRNA-mediated knockdown and CRISPR/Cas9-mediated ablation, we demonstrated that POLRMT deficiency in THP-1 human macrophages, peripheral blood mononuclear cells (PBMCs), and murine bone marrow-derived macrophages (BMDMs) consistently attenuated LPS-induced transcriptional upregulation and secretion of key pro-inflammatory cytokines (IL-1β, TNF-α, IL-6). Conversely, POLRMT overexpression in THP-1 cells augmented these inflammatory responses. LPS-induced enhancements in mitochondrial Complex I activity and ATP content, alongside NFκB activation, were dependent on POLRMT expression. Genetic perturbation of POLRMT directly correlated with altered mitochondrial function and NFκB activity. Pharmacological inhibition of POLRMT with a specific inhibitor IMT1 also suppressed LPS-induced cytokine production, mitochondrial activation, and NFκB activity in vitro. The in vivo studies revealed that knockdown of POLRMT in CD68-expressing cells protected mice from LPS-induced septic shock, reducing mortality and systemic cytokine levels. Oral administration of IMT1 similarly conferred protection against septic shock, correlating with diminished circulating pro-inflammatory cytokines and reduced NFκB activity in murine PBMCs. Collectively, these findings establish POLRMT as a mediator of LPS-induced inflammatory responses in macrophages/monocytes.

Alkali burn is one of the main causes of corneal injury. Corneal neovascularization caused by alkali burns aggravates corneal damage, resulting in aberrant vascular proliferation and consequent visual impairment. The present study investigated the role of enhancer of zeste homolog 2 (EZH2) in alkali burn‑induced corneal neovascularization. Through integrated bioinformatics and experimental approaches, we identified S100B, S100A4 and PI3K/AKT pathway activation as key drivers of alkali-induced corneal injury. In corneal alkali burn mice, knockdown of S100B or S100A4 attenuated corneal neovascularization and suppressed PI3K/AKT/FoxO3a pathway. EZH2 was upregulated in alkali-burn models and transcriptionally activated S100B and S100A4 via direct promoter binding. The deubiquitinase ZRANB1 was identified to stabilize EZH2 protein through deubiquitination, thereby amplifying its transcriptional activity. In alkali-injured human corneal epithelial cells, EZH2 overexpression enhanced cell viability, angiogenic capacity, migration and invasion ability, which was reversed by S100B or S100A4 knockdown. In vivo, EZH2 overexpression exacerbated PI3K/AKT/FoxO3a pathway activation and corneal neovascularization via regulating S100B or S100A4. Collectively, this study demonstrated that ZRANB1-mediated stabilization of EZH2 drove pathological corneal angiogenesis in corneal alkali burns by activating S100B/S100A4-PI3K/AKT/FoxO3a axis. These findings provided novel therapeutic targets for corneal alkali burns.

Reactive oxygen species (ROS) are key mediators of cellular signalling and play a vital role in regulating both physiological and pathological processes. In urologically relevant tissues, particularly the prostate, bladder and kidneys, redox processes influence vascular function, immune responses, cell proliferation, metabolic adaptations and programmed cell death. A disruption of redox homeostasis contributes significantly to the development and progression of urological diseases, including prostate cancer, urothelial carcinoma of the bladder and renal cell carcinoma. This review article examines the mechanisms underlying the transition from physiological redox regulation to pathological dysregulation, as well as their significance for tumourigenesis, the tumour microenvironment, therapeutic resistance and disease progression. Finally, diagnostic and therapeutic perspectives of redox-based strategies, including innovative approaches such as medical gas plasma, are discussed.

Restoring endangered ecosystems has become a pressing issue as the effects of global warming continue to harm existing communities. During the last decade, several studies have suggested the use of synthetic biology as a tool to protect these biodiverse communities by increasing their functionality. A critical example concerns soil microbiome communities in drylands, where increasing water retention by some of the constituent species could effectively protect the ecosystem from abrupt degradation. However, how to effectively deploy a functional synthetic construct that can scale its impact to the community level remains an open question. Recent experimental research has designed recombinant gene plasmids with the capacity to horizontally transfer across soil microbial communities. Here, we explore the impacts of synthetic horizontal gene transfer in models of ecological consortia. We define a consumer-resource model in which species can share an engineered plasmid that reduces resource loss, effectively coupling multispecies dynamics and gene spreading. By doing so, we identify a wide range of parameters and the optimal gene transfer conditions for which the intervention promotes biodiversity and biomass gains, while regulating gene propagation and the spread of engineered organisms. Our work provides a first step toward understanding the mechanisms and opportunities of engineered plasmid transfer in multispecies ecological communities.