Background: Interleukin-24 (IL-24) is a cytokine that belongs to the IL-10 family. It can selectively induce cancer cell apoptosis which has been utilized as a cancer gene therapy strategy. Methods: A recombinant type five adenovirus containing IL-24 gene (designated CNHK600-IL24) was constructed, whose replication is activated only in tumor cells. The replication of CNHK600-IL24 in breast tumor cells and fibroblasts were assessed by TCID50 and MTT assay; the secretion of IL-24 was measured by ELISA and western blotting. The in vivo anti-tumor effect of CNHK600-IL24 was investigated in nude mice carrying orthotopic or metastatic breast tumor. Results: We observed that CNHK600-IL24 could replicate efficiently and resulted in high level IL-24 expression and massive cell death in human breast cancer cell MDA-MB-231 but not in normal fibroblast cell MRC-5. In addition, orthotopic breast tumor growth in the nude mice model was significantly suppressed when CNHK600-IL24 was administered. In the metastatic model generated by tail vein injection, CNHK600-IL24 virotherapy significantly improved survival compared with the same virus expressing EGFP (median survival CNHK600-IL24, 55 days vs. CNHK600-EGFP, 41 day, p < 0.05 Mantal-Cox test). A similar phenomenon was observed in the metastatic model achieved by left ventricular injection as suggested by in vivo luminescence imaging of tumor growth. Conclusion: The oncolytic adenovirus armed with IL-24, which exhibited enhanced anti-tumor activity and improved survival, is a promising candidate for virotherapy of breast cancer.

Acute Stanford type A aortic dissection (ATAAD) is characterized by intimal tearing and false lumen formation containing large amounts of erythrocytes with heme. Heme oxygenase 1 (HO-1) is the key enzyme to degrade heme for iron accumulation and further ferroptosis. The current study aimed at investigating the role of HO-1 in the dissection progression of ATAAD. Bioinformatic analyses and experimental validation were performed to reveal ferroptosis and HO-1 expression in ATAAD. Human aortic vascular smooth muscle cell (HA-VSMC) was used to explore underlying molecular mechanisms and the role of HO-1 overexpression in ATAAD. Ferroptosis was identified as a critical manner of regulated cell death in ATAAD. HO-1 was screened as a key signature of ferroptosis in ATAAD, which was closely associated with oxidative stress. Single cell/nucleus transcriptomic analysis and histological staining revealed that HO-1 and HIF-1α were upregulated in vascular smooth muscle cell (VSMC) of ATAAD. Further in vitro experiments showed that H₂O₂-induced oxidative stress increased VSMC ferroptosis with the overexpression of HO-1, which could be suppressed by HIF-1α inhibitor PX-478. HIF-1α could transcriptionally regulate the expression of HO-1 through binding to its promoter region. Pharmacological inhibition of HO-1 by zinc protoporphyrin (ZnPP) did not reduce H₂O₂-induced HA-VSMC damage without heme co-incubation. However, H₂O₂-induced HA-VSMC damage was worsened when heme was added into the medium, and ZnPP could reduce HA-VSMC damage in this condition. HO-1 is a key signature of VSMC ferroptosis in ATAAD. HIF-1α/HO-1 mediated ferroptosis might participate in oxidative stress induced VSMC damage.

Background: Hydrogen sulfide (H₂S) has shown promising therapeutic benefits in reversing a variety of pathophysiological processes in cardiovascular system, including myocardial ischemia–reperfusion (IR) injury. However, the achievement of controlled and sustained release of H₂S has been a technical bottleneck that limits the clinical application of the gas molecule. Methods: The current study describes the development of mesoporous iron oxide nanoparticles (MIONs) which were loaded with diallyl trisulfide (DATS), a H₂S donor compound, and calibrated by stimulated Raman scattering/transient absorption. Results: The synthesized MIONs were characterized with excellent mesoporosity and a narrow size distribution, which enabled them to slow down the release of H₂S to a suitable rate and prolong the plateau period. The controlled-release feature of DATS-MIONs resulted in little adverse effect both in vitro and in vivo, and their protective effect on the heart tissue that underwent IR injury was observed in the mouse model of myocardial ischemia. The rapid biodegradation of DATS-MIONs was induced by Kupffer cells, which were specialized macrophages located in the liver and caused limited hepatic metabolic burden. Conclusion: The sustained-release pattern and excellent biocompatibility make DATS-MIONs a promising H₂S donor for research and medical purposes.

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising cancer therapeutic target due to its selective apoptosis-inducing effect in cancer cells. To efficiently deliver TRAIL to the tumor cells, an oncolytic adenovirus (p55-hTERT-HRE-TRAIL) carrying the TRAIL coding sequence was constructed. In the present study, we aimed to investigate the effect of p55-hTERT-HRE-TRAIL on the growth and metastasis of triple-negative breast cancer (TNBC). We observed that infection of the recombinant adenovirus resulted in expression of TRAIL and massive cell death in a TNBC cell line MDA-MB-231. This effect is much weaker in MCF-10A, which is a normal breast cell line. Administration of P55-HTERT-HRE-TRAIL significantly reduced orthotopic breast tumor growth and extended survival in a metastatic model. Our results suggest the oncolytic adenovirus armed with P55-HTERT-HRE-TRAIL, which exhibited enhanced anti-tumor activity and improved survival, is a promising candidate for virotherapy of TNBC.

The bicuspid aortic valve (BAV) is a congenital malformation of the aortic valve with a variety of structural features. The current research on BAV mainly focuses on the systolic phase, while ignoring the diastolic hemodynamic characteristics and valve mechanics. The purpose of this study is to compare the differences in hemodynamics and mechanical properties of BAV with different phenotypes throughout the cardiac cycle by means of numerical simulation. Based on physiological anatomy, we established an idealized tricuspid aortic valve (TAV) model and six phenotypes of BAV models (including Type 0 a–p, Type 0 lat, Type 1 L–R, Type 1 N-L, Type 1 R-N, and Type 2), and simulated the dynamic changes of the aortic valve during the cardiac cycle using the fluid–structure interaction method. The morphology of the leaflets, hemodynamic parameters, flow patterns, and strain were analyzed. Compared with TAV, the cardiac output and effective orifice area of different BAV phenotypes decreased certain degree, along with the peak velocity and mean pressure difference increased both. Among all BAV models, Type 2 exhibited the worst hemodynamic performance. During the systole, obvious asymmetric flow field was observed in BAV aorta, which was related to the orientation of BAV. Higher strain was generated in diastole for BAV models. The findings of this study suggests specific differences in the hemodynamic characteristics and valve mechanics of different BAV phenotypes, including different severity of stenosis, flow patterns, and leaflet strain, which may be critical for prediction of other subsequent aortic diseases and differential treatment strategy for certain BAV phenotype.