Stem Cell Research & Therapy•2024•DOI: 10.1186/s13287-024-03908-9
Background The formation of stem cell clones enables close contact of stem cells inside. The gap junctions in such clone spheres establish a microenvironment that allows frequent intercellular communication to maintain self-renewal and functions of stem cells. Nevertheless, the essential gap junction protein for molecular signaling in clones is poorly known. Methods Primary human airway basal cells (hBCs) were isolated from brushing samples through bronchoscopy and then cultured. A tightly focused femtosecond laser was used to excite the local Ca2+ in an individual cell to initiate an internal Ca2+ wave in a clone to screen gap junction proteins. Immunoflourescence staining and clonogenicity assay were used to evaluate self-renewal and functions. RNA and protein levels were assessed by PCR and Western blot. Air–liquid interface assay was conducted to evaluate the differentiation potential. A Naphthalene injury mouse model was used to assess the regeneration potential. Results Herein, we identify Connexin 25 (Cx25) dominates intercellular Ca2+ communications in clones of hBCs in vitro to maintain the self-renewal and pluripotency of them. The self-renewal and in vitro differentiation functions and in vivo regeneration potential of hBCs in an airway damage model are both regulated by Cx25. The abnormal expression of Cx25 is validated in several diseases including IPF, Covid-19 and bronchiectasis. Conclusion Cx25 is essential for hBC clones in maintaining self-renewal and functions of hBCs via gap junctions.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025076
EGFR-tyrosine kinase inhibitor (TKI) therapy is the most effective targeted therapy for non-small cell lung cancer (NSCLC). However, drug resistance remains a significant factor in the failure of lung cancer therapy. In the present study, we utilize network pharmacology, molecular docking, in vitro and in vivo experiments to explore the targets and biological mechanisms of CP, a novel curcumin-piperlongumine hybrid molecule, in EGFR-TKI-resistant NSCLC cells. The results reveal that CP exhibits enhanced biological activity compared to its parent compounds. CP can effectively inhibit cell proliferation by arresting cell cycle in the G2/M phase and inducing apoptosis. Mechanistically, CP-induced apoptosis is partially mediated by PI3K/AKT signaling pathway. These findings highlight the potential of CP as a promising therapeutic agent for EGFR-TKI-resistant lung cancer therapy.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2025147
CD47, a cell surface transmembrane glycoprotein, is an innate immune checkpoint that suppresses phagocytic clearance. Emerging evidence suggests that CD47 has noncanonical functions. However, its involvement in chemotherapy resistance is not well understood. Our study reveals that cisplatin treatment upregulates CD47 expression across multiple cancer cell lines. Cisplatin induces the expression of CD47 through the ATM/NF-κB signaling pathway. Genetic ablation of CD47 dramatically sensitizes cancer cells to cisplatin. Mechanistically, CD47 depletion potentiates cisplatin-induced DNA damage, as demonstrated by elevated γH2AX formation and ATM phosphorylation. Knockdown of CD47 inhibits the expression of DNA repair genes ERCC1, FANCA, and BRCA2 through the ATM/NF-κB pathway. Remarkably, CD47 blockade with neutralizing antibodies recapitulates these effects, synergistically potentiating cisplatin’s DNA-damaging capacity while suppressing DNA repair capacity. CD47 blockade also potentiates cisplatin’s tumor inhibitory effect in vivo. These findings establish a novel mechanism whereby CD47 promotes cisplatin resistance through transcriptional regulation of DNA repair pathway, providing rationale for combining CD47-targeted therapies with conventional chemotherapy. This dual approach could simultaneously overcome immune evasion while enhancing treatment efficacy.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21283
BACKGROUND: High cumulative remnant cholesterol levels are associated with the risk of various metabolic diseases, but their impact on bone quality remains to be explored. OBJECTIVE: To investigate the effects of high cumulative remnant cholesterol levels on bone mass, microstructure, and biomechanical properties in high-fat diet treated mice. METHODS: Ten healthy male SPF-grade C57BL6 mice were randomly allocated into normal control group and high-fat diet group. The normal control group was fed a normal diet for 20 weeks, while the high-fat diet group was fed a high-fat, high-cholesterol diet for 20 weeks. Mouse body mass was detected every week. After 20 weeks of feeding, serum levels of total cholesterol, remnant cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, type I collagen carboxy-terminal cross-linked telopeptide, and type I procollagen amino-terminal propeptide were measured. Micro-CT was used to assess the microstructure of femoral cancellous and cortical bone. Three-point bending test was performed to measure the elastic modulus and maximum stress of the femur. RT-qPCR was used to detect the mRNA expression of RUNT-related transcription factor 2, type I collagen, osteocalcin, alkaline phosphatase, osteoprotegerin, receptor activator of nuclear factor-κB ligand, nuclear factor of activated T cells 1, and cathepsin K in the tibia. Pearson correlation analysis was used to analyze the correlation between remnant cholesterol, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels and bone mineral density, as well as the correlation between remnant cholesterol levels and bone volume fraction, trabecular number, structure model index, and trabecular separation. RESULTS AND CONCLUSION: (1) From the 6th week of feeding, the body mass of mice in the high-fat diet group was higher than that in the control group (P < 0.05). The serum levels of total cholesterol, remnant cholesterol, and type I collagen carboxy-terminal cross-linked telopeptide in the high-fat diet group were higher than those in the control group (P < 0.05). (2) Micro-CT detection showed that compared with the control group, the bone microstructure of mice in the high-fat diet group underwent obvious degeneration, specifically manifested as significantly decreased bone mineral density, bone volume fraction, trabecular connectivity density, and trabecular number in cancellous bone, and significantly increased trabecular separation, structure model index, and trabecular pattern factor (P < 0.05). There were no significant changes in cortical bone thickness, volume, and area (P > 0.05). There was no significant difference in elastic modulus and maximum stress of the femur between the two groups (P > 0.05). (3) RT-qPCR detection showed that the mRNA expression of RUNT-related transcription factor 2, type I collagen, osteocalcin, alkaline phosphatase, and osteoprotegerin in the high-fat diet group was lower than that in the control group (P < 0.05), while the mRNA expression of nuclear factor of activated T cells 1 and cathepsin K was higher than that in the control group (P < 0.05). (4) Pearson analysis showed that remnant cholesterol and total cholesterol levels were significantly negatively correlated with bone mineral density (P < 0.05), and remnant cholesterol was significantly negatively correlated with bone volume fraction and trabecular number (P < 0.05), and significantly positively correlated with structure model index and trabecular separation (P < 0.05). These results indicate that remnant cholesterol may reduce bone quality by affecting the balance of bone turnover.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21489
BACKGROUND: The pathological process of Alzheimer's disease is closely related to β-amyloid/Tau deposition and cerebrovascular dysfunction, and existing therapies are difficult to effectively intervene. In recent years, research on glucagon-like peptide-1 receptor agonists for the treatment of Alzheimer's disease has gained increasing popularity. As a novel dual agonist of the glucagon-like peptide-1 receptor and glucagon receptor, the therapeutic mechanism of Mazdutide in Alzheimer’s disease remains to be elucidated.
OBJECTIVE: To systematically explore the mechanism by which Mazdutide improves cognitive function in Alzheimer's disease using network pharmacology and experimental validation, and to identify potential core molecular targets, providing a theoretical basis for new therapeutic strategies.
METHODS: A multi-omics integration strategy was employed. Co-localization targets of Alzheimer's disease and Mazdutide were screened using DisGeNET and SEA databases. A protein-protein interaction network was constructed via STRING, and hub genes were identified by Cytoscape topological analysis. In APP/PS1/Tau triple transgenic Alzheimer's disease mice, Mazdutide (30 nmol/kg) was administered intraperitoneally. Cognitive function was assessed using Morris water maze, novel object recognition, and Y maze tests. Western blot was used to detect hippocampal β-amyloid (6E10), p-Tau181, and endothelin receptor A expression.
RESULTS AND CONCLUSION: ① Fifty-two co-localized targets were identified, with endothelin receptor A (EDNRA) as the top hub gene. ② Mazdutide significantly improved cognition in 3xTg mice: shortened spatial memory latency, increased novel object recognition index, increased spontaneous alternation in Y maze, and reduced hippocampal pathological burden, with decreased p-Tau181 and EDNRA overexpression. ③ Gene Ontology and KEGG enrichment revealed core pathways: biological processes included blood pressure regulation, amine transport regulation, and amine transport; cellular components included symmetric synapses, sperm head, and pseudopodia; molecular functions included G protein-coupled peptide receptor activity, peptide receptor activity, and neuropeptide receptor activity. KEGG pathways included neuroactive ligand-receptor interaction, calcium signaling, and hormone signaling. ④ This study confirms that Mazdutide may improve cognitive deficits in Alzheimer's disease by targeting and inhibiting EDNRA overexpression, reducing neuronal pathological damage, and acting through multiple dimensions. The discovery of EDNRA provides a novel therapeutic target for Alzheimer's disease.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025076
Acquired resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs) such as osimertinib (AZD9291) remains an unresolved clinical bottleneck in non-small cell lung cancer (NSCLC), with median progression-free survival plateauing at 18.9 months. This study evaluates CP, a novel curcumin-piperlongumine hybrid molecule, against AZD9291-resistant NSCLC using network pharmacology, molecular docking, and in vitro/in vivo validation. PPI network analysis of intersecting targets identified EGFR, SRC, PIK3R, PIK3CA, KDR, MET, GRB2, PIK3CB, HSP90AA1, and ITGB1 as core nodes, with KEGG enrichment converging on the PI3K/AKT signaling axis. Molecular docking confirmed hydrogen-bond-mediated binding between CP and these targets. Western blot analysis demonstrated that CP markedly suppressed phosphorylation of EGFR, PI3K, AKT, and GSK-3β. Functionally, CP arrested the cell cycle at G2/M and induced apoptosis in drug-resistant NSCLC cells, with enhanced potency relative to parent compounds curcumin and piperlongumine. In vivo xenograft experiments corroborated growth inhibition. The data position CP as a dual-pathway inhibitor targeting both EGFR and PI3K/AKT cascades, providing a mechanistic rationale for its development as a therapeutic candidate in EGFR-TKI-resistant advanced NSCLC. The unresolved question of whether GSK-3β inhibition operates independently of EGFR-AKT signaling warrants further investigation.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025201
Colorectal cancer (CRC) remains the third most common malignancy and second leading cause of cancer mortality worldwide, with 608,000 new cases and 202,000 deaths annually in China. The Warburg effect, characterized by elevated glucose consumption and lactate production under normoxia, sustains CRC proliferation, migration, chemoresistance, and stemness. Prior work established that SUN5, a nuclear membrane protein, promotes CRC proliferation and migration, but its role in glycolysis remained undefined. Here, SUN5 overexpression increased glucose uptake and lactate production, whereas SUN5 knockdown produced reciprocal reductions. Mechanistically, SUN5 activates NF-κB signaling, an effect abolished by the IKK inhibitor BAY11-7082. SUN5 interacts with TRIM28 to enhance IκBα ubiquitination, driving nuclear translocation of phosphorylated P65 and transcriptional upregulation of GLUT1 and LDHA. Xenograft transplantation confirmed that SUN5 knockdown suppresses glycolysis and tumorigenesis in vivo. These findings position the SUN5–TRIM28–IκBα–NF-κB axis as a tractable target for CRC diagnosis and therapy.