Aims: Two unmet therapeutic strategies for diabetes treatment are prevention of beta‐cell death and stimulation of beta‐cell replication. Our aim was to characterize the role of neuropeptide Y receptors in the control of beta‐cell mass. Materials and Methods: We used endogenous and selective agonists of the NPY receptor system to explore its role in the prevention of beta‐cell apoptosis and proliferation in islets isolated from both mouse and human donors. We further explored the intra‐cellular signalling cascades involved, using chemical inhibitors of key signalling pathways. As proof of principle we designed a long‐acting analogue of [Leu ³¹ Pro ³⁴ ]‐NPY, an agonist of the islet‐expressed Y receptors, to determine if targeting this system could preserve beta‐cell mass in vivo. Results: Our data reveal that NPY Y1, 4 and 5 receptor activation engages a generalized and powerful anti‐apoptotic pathway that protects mouse and human islets from damage. These anti‐apoptotic effects were dependent on stimulating a Gαi‐PLC‐PKC signalling cascade, which prevented cytokine‐induced NFkB signalling. NPY receptor activation functionally protected islets by restoring glucose responsiveness following chemically induced injury in both species. NPY receptor activation attenuated beta‐cell apoptosis, preserved functional beta‐cell mass and attenuated the hyperglycaemic phenotype in a low‐dose streptozotocin model of diabetes. Conclusion: Taken together, our observations identify the islet Y receptors as promising targets for the preservation of beta‐cell mass. As such, targeting these receptors could help to maintain beta‐cell mass in both type 1 and type 2 diabetes, and may also be useful for improving islet transplantation outcomes.

Many human diseases, such as malignant tumors and neurological diseases, have a complex pathophysiological etiology, often accompanied by aberrant epigenetic changes including various histone modifications. Plant homologous domain finger protein 8 (PHF8), also known as lysine-specific demethylase 7B (KDM7B), is a critical histone lysine demethylase (KDM) playing an important role in epigenetic modification. Characterized by the zinc finger plant homology domain (PHD) and the Jumonji C (JmjC) domain, PHF8 preferentially binds to H3K4me3 and erases repressive methyl marks, including H3K9me1/2, H3K27me1, and H4K20me1. PHF8 is indispensable for developmental processes and the loss of PHF8 enzyme activity is linked to neurodevelopmental disorders. Moreover, increasing evidence shows that PHF8 is highly expressed in multiple tumors as an oncogenic factor. These findings indicate that studying the role of PHF8 will facilitate the development of novel therapeutic agents by the manipulation of PHF8 demethylation activity. Herein, we summarize the current knowledge of PHF8 about its structure and demethylation activity and its involvement in development and human diseases, with an emphasis on nervous system disorders and cancer. This review will update our understanding of PHF8 and promote the clinical transformation of its predictive and therapeutic value.

Whether protein samples should be pretreated to remove nonspecific binding proteins in co-immunoprecipitation (CO-IP) is controversial. In this work, nonspecific binding of proteins to agarose bead... METHOD SUMMARY Co-immunoprecipitation is a common method for investigation of protein–protein interactions. However, according to published protocols, it is unclear whether the protein samples shou...

Objective Efferocytosis, a process of apoptotic cell clearance, is implicated in the initiation and progression of breast cancer. This study aims to construct an efferocytosis-related genetic risk model to evaluate its prognostic value and its association with immune infiltration in breast cancer. Methods The expression patterns of efferocytosis-related genes in breast cancer were analyzed, followed by clustering analysis to explore their relationship with tumor immune infiltration across different subtypes. A risk model based on efferocytosis-related genes was developed to predict breast cancer prognosis and assess its correlation with immune infiltration. Using this model, the association between ALOX15B expression and breast cancer survival was evaluated. In Vitro Functional Assays, the biological role of ALOX15B in breast cancer progression was investigated using the following approaches: Cellular Proliferation: MTT assay, EdU incorporation assay, and colony formation assay were performed to assess proliferation in MCF7 and MDA-MB-231 cells. Transwell was used to quantify migratory and invasive. Flow cytometry was conducted to evaluate cell cycle distribution. Western blotting was performed to assess Epithelial-Mesenchymal Transition marker expression. Results Clustering analysis of the expression of efferocytosis-related genes in breast cancer, Cluster A had a good prognosis and was closely associated with immune cell infiltration. Functional enrichment analysis of the activation and adaptation of immune response in Cluster A clustering may be an important factor in improving breast cancer prognosis. In addition, an immune-related gene risk model was constructed, which was found to be a valid predictor of breast cancer prognosis. Finally, it was highlighted that the expression of ALOX15B inhibited the proliferation, movement, invasion, and DNA replication capability of breast cancer cells. The growth of breast cancer cells was also impeded by ALOX15B, which hindered cell division during the G1 phase. The expression of ALOX15B is associated with the sensitivity of a variety of chemotherapeutic agents. Conclusion Efferocytosis-related models can be used for the assessment of breast cancer prognosis, while the efferocytosis-related gene ALOX15B can affect the migration and invasive ability of breast cells.