Stem Cell Research & Therapy•2024•DOI: 10.1186/s13287-024-03898-8
Background Hepatic progenitor cells serve not only as the origin of combined hepatocellular cholangiocarcinoma (cHCC-CCA) but are also responsible for malignancy recurrence after surgical resection. Nucleophosmin 1 (NPM1) has been implicated in cancer metastasis and poor prognosis. This study aimed to determine the expression of NPM1 by hepatic progenitor cells in cHCC-CCA and the effects of targeting NPM1 on hepatic progenitor cells and BEL-7402 cells with characteristics of both progenitor cells and cHCC-CCA. Methods First, NPM1 was detected by RT‒PCR, western blotting, and double-immunofluorescence staining in cHCC-CCA tissues. NPM1 expression was subsequently analysed in rat hepatic progenitor cells cultured in vitro and in interleukin 6 (IL6)-treated cells. The effects and mechanism of NPM1 on hepatic progenitor cells were determined by knocking down NPM1 and performing RNA sequencing analysis. Finally, NSC348884, a small-molecule inhibitor that disrupts NPM1 dimer formation, was used to confirm the function of NPM1 in BEL-7402 cells. Results Both human hepatic progenitor cells in cHCC-CCA tissues and rat in vitro cultured hepatic progenitor cells highly expressed NPM1. IL6, a cytokine involved in the malignant transformation of hepatic progenitor cells, dose-dependently increased NPM1 and PCNA expression. Knocking down NPM1 reduced IL6R transcription (P < 0.0001) and inhibited the proliferation (P = 0.0065) of hepatic progenitor cells by suppressing the mTOR signalling pathway and activating the apoptosis pathway. Furthermore, knocking down NPM1 in hepatic progenitor cells resulted in more apoptotic cells (7.33 ± 0.09% vs. 3.76 ± 0.13%, P < 0.0001) but fewer apoptotic cells in the presence of NSC348884 (47.57 ± 0.49% vs. 63.40 ± 0.05%, P = 0.0008) than in the control cells, suggesting that low-NPM1-expressing cells are more resistant to NSC348884. In addition, NSC348884 induced the apoptosis of BEL-7402 cells with an IC50 of 2.77 μmol/L via the downregulation of the IL-6R and mTOR signalling pathways and inhibited the growth of BEL-7402 cells in a subcutaneous xenograft tumour model (P = 0.0457). Conclusions Targeting NPM1 inhibits proliferation and induces apoptosis in hepatic progenitor cells and BEL-7402 cells, thus serving as a potential therapy for cHCC-CCA.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025002
Intervertebral disc degeneration (IDD) is a major cause of low back pain (LBP), and effective therapies are still lacking. Reactive oxygen species (ROS) stress induces NLRP3 inflammasome activation, and this, along with extracellular matrix metabolism (ECM) degradation in nucleus pulposus cells (NPCs), plays a crucial role in the progression of IDD. Daphnetin (DAP) is a biologically active phytochemical extracted from plants of the Genus Daphne, which possesses various bioactivities, including antioxidant properties. In the present study, we demonstrate that DAP significantly attenuates tert-butyl hydroperoxide (TBHP)-induced ECM degradation, oxidative stress and NLRP3 inflammasome activation in NPCs. Furthermore, DAP could facilitate mitophagy to increase the removal of damaged mitochondria, consequently reducing mitochondrial ROS accumulation and alleviating NLRP3 inflammasome activation. Mechanistically, we unveil that DAP activates mitophagy by stimulating the Nrf2/PINK1 signaling pathway in TBHP-induced NPCs. In vivo experiments further corroborate the protective effect of DAP against IDD progression in a rat model induced by disc puncture. Accordingly, our findings reveal that DAP could be a promising therapeutic candidate for the treatment of IDD.
Acta Biochimica et Biophysica Sinica•2024•DOI: 10.3724/abbs.2024087
The aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of neointima formation in vascular restenosis. This study aims to explore the function of the long noncoding RNA H19 in neointima formation. A mouse carotid ligation model was established, and human vascular smooth muscle cells (VSMCs) were used as a cell model. lncRNA H19 overexpression promoted VSMC proliferation and migration. Moreover, miR-125a-3p potentially bound to lncRNA H19, and Fms-like tyrosine kinase-1 (FLT1) might be a direct target of miR-125a-3p in VSMCs. Upregulation of miR-125a-3p alleviated lncRNA H19-enhanced VSMC proliferation and migration. Furthermore, rescue experiments showed that enhanced expression of miR-125a-3p attenuated lncRNA H19-induced FLT1 expression in VSMCs. In addition, the overexpression of lncRNA H19 significantly exacerbated neointima formation in a mouse carotid ligation model. In summary, lncRNA H19 stimulates VSMC proliferation and migration by acting as a competing endogenous RNA (ceRNA) of miR-125a-3p. lncRNA H19 may be a therapeutic target for restenosis.
Chinese Traditional and Herbal Drugs•2026•DOI: 10.7501/j.issn.0253-2670.2026.16.20261609
Puerarin, a principal isoflavone from Pueraria lobata, exhibits anti-migraine activity but suffers from poor oral bioavailability and limited blood-brain barrier penetration. This study reports a puerarin-loaded chitosan-modified β-cyclodextrin supramolecular gel (Pur@CS-β-CD Gel) for intranasal delivery. Formulation optimization employed single-factor experiments and Box-Behnken design-response surface methodology (BBD-RSM). The optimal formulation comprised CS-β-CD and sodium carboxymethylcellulose at a mass ratio of 1:9, total polymer concentration 2.6%, and puerarin 40 mg. The resulting gel displayed a three-dimensional porous architecture, pH 6.5, favorable stability, and a biphasic in vitro release profile: 82.75% cumulative release within 4 h followed by sustained release. No nasal mucosal irritation was observed. In a chronic migraine rat model induced by nitroglycerin, Pur@CS-β-CD Gel significantly ameliorated behavioral deficits, reduced brain levels of calcitonin gene-related peptide (CGRP) and interleukin-1β (IL-1β), and elevated 5-hydroxytryptamine (5-HT). These pharmacodynamic outcomes are consistent with interruption of trigeminovascular CGRP release, modulation of serotonergic neurotransmission, and attenuation of IL-1β-mediated nociceptive sensitization. The study acknowledges limitations: the animal model only partially recapitulates clinical migraine heterogeneity; long-term safety and immunogenicity of repeated dosing remain unassessed; and direct quantification of brain puerarin concentration was not performed, leaving brain-targeting efficiency unproven. Nonetheless, the optimized gel offers a feasible, non-invasive nasal delivery platform with preliminary anti-migraine efficacy, warranting further pharmacokinetic and mechanistic validation.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21284
BACKGROUND: Spinal cord injury triggers a cascade of neuro-muscular system damage, involving central pattern generator dysfunction and peripheral muscle molecular network disruptions. Exercise can regulate key genes and promote the recovery of spinal cord injury. OBJECTIVE: To identify exercise-regulated key genes through bioinformatics analysis and explore the mechanisms by which exercise intervention facilitates the recovery of spinal cord injury. METHODS: The GSE45550 dataset based on the GPL1355 platform was obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes regulated by acute and short-term exercise interventions during the subacute phase of spinal cord injury in rats were identified. Gene Ontology functional enrichment analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and Gene Set Enrichment Analysis were performed on these differentially expressed genes, and a protein-protein interaction network was constructed. RESULTS AND CONCLUSION: (1) After acute exercise intervention in the subacute phase of spinal cord injury, 106 genes were upregulated and 97 genes were downregulated in the gastrocnemius muscle, whereas short-term exercise intervention resulted in 138 upregulated and 105 downregulated genes. (2) Gene Ontology analysis showed that acute exercise mainly enriched genes related to chromosome segregation, while short-term exercise mainly promoted signal transduction processes. (3) KEGG analysis indicated that acute exercise was mainly associated with gastric acid secretion and upregulation of motor protein pathways, whereas short-term exercise mainly involved upregulation of neuroactive ligand-receptor interaction and downregulation of some inflammatory signaling pathways. (4) GSEA analysis revealed that acute exercise mainly upregulated cell cycle and DNA separation, while short-term exercise mainly downregulated interleukin-17 signaling and tumor necrosis factor signaling pathways. (5) Protein-protein interaction network showed that acute and short-term exercise interventions formed 2 and 3 central modules, respectively. In summary, acute exercise intervention significantly activates cell proliferation-related pathways (such as cell cycle and mitosis), upregulating pro-proliferative genes like Top2a and Sele; whereas short-term intervention exerts anti-inflammatory effects by downregulating inflammatory pathways such as interleukin-17 and tumor necrosis factor, and downregulating factors like COMP. These findings provide a reference for the molecular mechanism research of spinal cord injury rehabilitation.