Senile osteoporosis (SOP) seriously disturbs the life of elder people. Inhibition of autophagy can contribute to the progression of SOP. Meanwhile, Salvianic acid A (SA) could inhibit the progression of SOP, and it could regulate the autophagy. However, the relationship between SA and autophagy in SOP remains to be further explored.
Bone marrow mesenchymal stem cells (BMSCs) were isolated from senescence-accelerated mouse propensity 6 (SAMP6) mice. Then, Alizarin red S (ARS) and alkaline phosphatase (ALP) staining were performed to analyze the osteogenesis in BMSCs. Meanwhile, protein levels were investigated using Western blot. The binding between Ariadne RBR E3 ubiquitin-protein ligase 1 (ARIH1) and Rubicon was investigated using Co-IP. ChIP and Dual-luciferase assay were used to explore the binding between bromodomain-containing protein 4 (BRD4) and ARIH1 promoter region.
The levels of BRD4, Rubicon and p62 were upregulated in BMSCs from SAMP6 mice, while ARIH1, Beclin1, ATG5 and the ratio of LC3II/LC3I were downregulated. SA could promote the osteogenesis of BMSCs through mediating the autophagy. In addition, SA dose-dependently upregulated the levels of OPN, OCN and Runx2 in BMSCs from SAMP6 mice. ARIH1 could degrade Rubicon through ubiquitination, and BRD4 could transcriptionally inhibit the expression of ARIH1. Meanwhile, SA obviously promoted the autophagy and osteogenesis in BMSCs through mediation of BRD4/ARIH1/Rubicon axis.
SA promoted osteogenic differentiation of BMSCs in senile osteoporosis through BRD4/ARIH1/Rubicon axis. Thus, our study might provide a new theoretical basis for developing the new strategies against SOP in clinic.
© 2025 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.

In gastric cancer (GC), the dissemination of neoplastic cells (NCs) in the peritoneal cavity is related to disease progression and poor prognosis. Elimination of NC through chemotherapy is needed to achieve better outcomes before conversion surgery.
The objective of this study was to evaluate the impact of NC CD44+/CD326+ levels through flow cytometry (FC) on peritoneal lavage (PL) fluid as a response indicator for conversion surgery.
Patients with GC and NCs in the peritoneal cavity with or without peritoneal carcinomatosis (PC) and ascites were evaluated via minimally invasive staging. The PLs of patients were analyzed by FC to quantify NCs. All patients were treated with repeated intraperitoneal perfusion normothermic chemotherapy (RIPPENC). Patients who had negative NCs or reduced NCs were referred for conversion surgery.
Thirty patients were enrolled in this study and divided into three groups. In the first group, 20 patients with positive cytology (C+) and/or PC with a PC index (PCI) ⩽6 were treated with RIPPENC. Otherwise, six patients with C+ and PC with a PCI >7 and four patients with C+, ascites, and a PCI ranging from 15 to 22 were treated with palliative RIPPENC. The percentage of CD44+/CD326+ cells was correlated with the number of RIPPENC cycles and resections. The median follow-up time was 14.8 months. The overall median survival since the first RIPPENC was 14.6 months among those who did not undergo resection and 22.6 months among those who underwent resection (p = 0.001). Moreover, we observed a correlation between the percentage of CD44+/CD326+ cells in the PL region and patient survival.
The use of FC to identify PL CD44+/CD326+ cell levels may be an important innovative biomarker for determining the presence of NCs, directly affecting the success of RIPPENC for conversion surgery.
© The Author(s), 2025.

Enhancer RNAs (eRNAs) are a pivotal class of enhancer-derived non-coding RNAs that drive gene expression. Here we identify the SNAI1 enhancer RNA (SNAI1e; SCREEM2) as a key activator of SNAI1 expression and a potent enforcer of transforming growth factor-β (TGF-β)/SMAD signaling in cancer cells. SNAI1e depletion impairs TGF-β-induced epithelial-mesenchymal transition (EMT), migration, in vivo extravasation, stemness, and chemotherapy resistance in breast cancer cells. SNAI1e functions as an eRNA to cis-regulate SNAI1 enhancer activity by binding to and strengthening the enrichment of the transcriptional co-activator bromodomain containing protein 4 (BRD4) at the local enhancer. SNAI1e selectively promotes the expression of SNAI1, which encodes the EMT transcription factor SNAI1. Furthermore, we reveal that SNAI1 interacts with and anchors the inhibitory SMAD7 in the nucleus, and thereby prevents TGF-β type I receptor (TβRI) polyubiquitination and proteasomal degradation. Our findings establish SNAI1e as a critical driver of SNAI1 expression and TGF-β-induced cell plasticity.
© 2025. The Author(s).

Breast cancer stem-like cells (CSCs) are enriched following treatment with chemotherapy, and posited as having a high level of plasticity and enhanced tumor-initiation capacity, which can enable cancer relapse. Here, we show that such features are shared by breast cancer (BCA) cells that express receptor tyrosine kinase-like orphan receptor (ROR2), which is expressed primarily during embryogenesis and by various cancers. We find that Wnt5a can induce ROR2 homooligomerization to activate noncanonical Wnt signaling and enhance tumor-initiation capacity of BCA cells. Molecular analysis reveals that the cysteine-rich domain and transmembrane domain are required for ROR2 homooligomerization to activate ROR2. Treatment with a newly generated monoclonal antibody (mAb) specific for ROR2 can block Wnt5a-induced ROR2 homooligomerization, ROR2-dependent noncanonical Wnt signaling, and impair the capacity of BCA patient-derived xenografts to initiate tumor in immune-deficient mice. Collectively, these results indicate that targeting ROR2 (e.g., using mAb) suppresses BCA stemness and, thereby, may prevent BCA relapse.
© 2024 The Authors.

This study aims to investigate the regulatory effects of quercetin extracellular vesicles (EVs)-mediated expression of vascular endothelial growth factor receptor 2 (VEGFR2) in hepatocellular carcinoma (HCC)-derived circulating tumor cells (CTCs) and the underlying mechanisms. CTCs were isolated from patients with pathologically diagnosed HCC, with VEGFR2 expression visualized by fluorescence in situ hybridization (FISH). The human HCC cell line Huh-7 and SK-HEP-1 were used for in vitro studies to assess EVs uptake, VEGFR2 mRNA transfer, invasion, migration, cancer stem cell (CSC) properties, and VEGF secretion. Results showed that VEGFR2 mRNA was commonly expressed in HCC-CTCs, with a higher incidence in biphenotypic CTCs. Its expression was limited in HCC cell lines, but present in certain liver cells. In vitro experiments confirmed that VEGFR2 mRNA could be transferred to HCC cells via EVs from primary tumor endothelial cells (PTECs), which was impaired by quercetin treatment. Quercetin significantly reduced VEGFR2 mRNA and protein expression in HCC cells, weakened their invasive and metastatic capacities, and diminished VEGFR2-mediated CSC properties. In vivo, quercetin reduced VEGF secretion, impaired angiogenesis, slowed tumor growth, and decreased the number and proportion of VEGFR2-positive CTCs. In summary, VEGFR2 mRNA is present in HCC-CTCs, potentially sourced from PTECs-derived EVs. Quercetin effectively inhibits VEGFR2 expression, impacting HCC cell invasion, metastasis, and CSC characteristics. Besides, it reduces VEGFR2-positive CTCs in vivo. These effects support its therapeutic potential in HCC treatment by targeting the angiogenesis and tumor dissemination pathway.
© 2024 Wiley Periodicals LLC.