Cells

The purpose of our study is to explore the potential of a transcription factor-based strategy for directly converting mouse fibroblasts into photoreceptor-like cells. The mouse cDNAs of Ascl, Crx, Ngn1, Nrl, and Otx2 were cloned into a modified commercial adenoviral vector. Mouse embryonic fibroblasts (MEFs) were isolated from E13.5 embryos, and mouse postnatal fibroblasts (MPFs) were isolated from three-day-old mice. A pool of adenoviruses containing five genes was prepared to infect MEFs or MPFs once daily for two days. The MEFs or MPFs were incubated in a specific medium supplemented with forskolin and were changed every two days. After 7 or 14 days, the photoreceptor-like cells were assayed via immunofluorescence or polymerase chain reaction with reverse transcription (RT–PCR). The photoreceptor-like cells were then transplanted into adult C57BL/6 mouse retinas and were assessed by immunofluorescence 14 days following transplantation. Screening from a pool of five candidate genes, we reported that a combination of only three factors—Crx, Nrl, and Otx2—was sufficient to convert mouse embryonic and postnatal fibroblasts into photoreceptor-like cells. The induced photoreceptor-like cells expressed photoreceptor-specific proteins such as Recoverin, Rhodopsin, and Opsin and integrated into the outer nuclear layer of the retina following transplantation. This exploratory study provides preliminary evidence that fibroblasts can be directly converted into photoreceptor-like cells, suggesting a cellular model and potential source for future transplantation strategies aimed at retinal repair.

Breast cancer (BC) is a prevalent malignancy worldwide among women. HER2 overexpression in a subset of BC (HER2+ BC) serves as a critical oncogenic driver and contributes to immune evasion. The Raf Kinase Inhibitor Protein (RKIP), a metastasis suppressor and an immune enhancer, is underexpressed in HER2+ BC. The treatment of HER2+ BC with anti-HER2 mAbs or chemical inhibitors has resulted in significant clinical responses in a subset of patients; however, unresponsiveness in a larger subset was due to acquired and induced resistance. These findings highlight the need for the development of new effective therapies. By analyzing the signaling pathways mediated by both RKIP and HER2 in HER2+ BC, we have found that RKIP and HER2 downstream signaling and inductions showed an inverse relationship. These suggested the presence of a dysregulated RKIP-HER2 axis in HER2+ BC mediating immune evasion. These findings were corroborated by bioinformatic analyses. The immune evasion induced by the overexpression of HER2 was due, in part, to its regulation of the expression of PD-L1, the polarization of TAMs, the infiltration of suppressor cells (Tregs, MDSCs), and the inhibition of anti-tumor CD8+ T cells, resulting in an overall immunosuppressive TME. In contrast, RKIP expression inhibits critical signaling pathways that regulate HER2 expression, including the Raf-MEK-ERK, NF-kB, and PI3K/Akt pathways, thereby aborting HER2-mediated mechanisms of immune evasion. Overall, we analyzed the cross-talk signaling pathways between RKIP and HER2, established a novel dysregulated axis in HER2+ BC, and delineated the various mechanisms involved in the regulation of immune evasion by RKIP and HER2. Hence, we present various therapeutic strategies aimed at targeting the RKIP-HER2 axis in HER2+ BC to circumvent unresponsiveness to therapeutics and immune evasion.

Skeletal muscle is increasingly recognized as a dynamic endocrine and paracrine organ that communicates with distal tissues through a diverse secretome of peptides, proteins, metabolites, and extracellular vesicles (EVs), collectively referred to as myokines and exerkines. Beyond cataloging individual factors, emerging evidence suggests that muscle-derived signals can convey information through an integrated, context-dependent “endocrine code”—a pattern defined by secretion kinetics, co-released signal combinations, delivery modalities, and target-tissue receptor landscapes. This review synthesizes current evidence on (i) conceptual and experimental criteria for defining bona fide myokines, (ii) mechanisms governing myokine expression, processing, and release across exercise modes and physiological states, and (iii) major muscle–organ axes that connect physical activity to systemic metabolic homeostasis, immune remodeling, tissue regeneration, and neurocognitive adaptation. We further discuss non-protein mediators such as lactate, succinate, and β-aminoisobutyric acid, and highlight EVs as a multiplexed delivery modality whose interpretation requires stringent isolation, contamination controls, and functional validation. Finally, we evaluate translational opportunities—including biomarker panels, therapeutic targeting of the myostatin/activin, fibroblast growth factor 21 (FGF21), and growth differentiation factor 15 (GDF15) pathways, and precision exercise prescriptions informed by multi-omics and artificial intelligence—while emphasizing analytical standardization, causal validation, and transparent reporting as prerequisites for clinical impact.