The Protective Effect of Chronic Intermittent Hypobaric Hypoxia on Preventing the Destruction of CD34+ Haematopoietic Stem Cells in Aplastic Anaemia by Modulating the Th1/Th2 Balance.

Aplastic anaemia (AA) is a haematopoietic disorder caused by immune-mediated attack on haematopoietic stem cells (HSCs). Stem cell transplantation and immunosuppressive therapy remain the major treatment choice for AA patients but have limited benefits and undesired side effects. The aim of our study was to clarify the protective role of immunity of chronic intermittent hypobaric hypoxia (CIHH) and the underlying mechanism in AA. Our integrative analysis demonstrated that CIHH pre-treatment significantly improved haematopoiesis and survival in an AA rat model. We further confirmed that CIHH pre-treatment was closely associated with the Th1/Th2 balance and a large number of negative regulatory haematopoietic factors, such as TNF-α and IFN-γ, produced by hyperactive Th1 lymphocytes released in AA rats, which induced the death program in a large number of CD34+ HSCs by activating the Fas/FasL apoptosis pathway, while CIHH pre-treatment effectively downregulated the expression of TNF-α and IFN-γ, resulting in a reduction in Fas antigen expression in CD34+ HSCs. In summary, this study provides evidence that CIHH has good protective effect against AA by modulating immune balance in Th1/Th2 cells and may provide a new therapeutic strategy.

MiRNA Delivery System Based on Stimuli-Responsive Gold Nanoparticle Aggregates for Multimodal Tumor Therapy.

In this work, a composite of microRNA-124-5p mimics (miR-124-5p) and gold nanoparticle (AuNP) aggregates was fabricated to combine the gene therapy and photothermal therapy for effective tumor medicine. The AuNP aggregates cross-linked by cystamine not only serve as photothermal therapeutic agents but are able to condense miR-124-5p as nanocarrier for gene delivery because of the coulomb interaction. The release of miR-124-5p could be initiated by the cleavage of cystamine when the nanocarrier enter the cytoplasm of tumor cells through endocytosis, where contains high concentration of glutathione (GSH). Moreover, the size of the AuNP aggregates did not change after the GSH-triggered miR-124-5p release because of the coinstantaneous disruption of disulfide bond and reformation of the thiol-gold bond, resulting in sustained photothermal property of the nanocarrier for tumor therapy. In vitro experiments showed that the miRNA@AuNAs (miR-124-5p) composite under near-infrared radiation performed great cytotoxicity to tumor cells, which is two and three times higher than the group of pure AuNP aggregates under near-infrared radiation and miRNA@AuNAs composite without near-infrared radiation, respectively. All experiment statistics show that the miRNA@AuNAs composite with combination of photothermal therapy and gene therapy has great potential for effective tumor treatment.