RESUMEN
BACKGROUND: Up to 80 % of chemotherapeutic drugs induce myelosuppression in patients. Chemotherapy not only impairs of hematopoietic stem cells (HSCs) but also damages bone marrow niches (vascular and endosteal). Current treatments for myelosuppression overlook these chemotherapy-induced damages to bone marrow niches and the critical role of niche restoration on hematopoietic regeneration. Ginsenoside protopanaxatriol (PPT) protects vascular endothelium from injury, while icariin (ICA) promotes osteogenic differentiation. The combination of PPT and ICA aims to restore damaged vascular and endosteal niches, thus rejuvenating HSCs for treating myelosuppression. PURPOSE: This study aims to develop effective, bone marrow niche-directed PPT/ICA therapies for treating chemotherapy-induced myelosuppression. METHODS: 3D cell spheroids were used to investigate the effects of PPT/ICA on cell-cell interactions in vascular niches, osteogenesis, and extracellular matrix (ECM) secretion in endosteal niches. In vitro mimic niche models were designed to access the drug combination's efficacy in rejuvenating and mobilizing in HSCs within bone marrow niches. The delivery capability of PPT/ICA to key niche cell types (mesenchymal stromal cells (MSCs), endothelial cells (ECs), and osteoblasts (OBs)) via nanocarriers has been determined. DSS6 peptide-modified nanoparticles (DSS6-NPs) were prepared for specific co-delivery of PPT/ICA into key niche cell populations in vivo. RESULTS: PPT can prevent vascular niche injury by restoring vascular EC cell-cell adhesion and the intercellular interactions between ECs and MSCs in 5-fluorouracil (5-FU)-damaged cell spheroids. ICA repaired 5-FU-damaged endosteal niches by promoting osteogenesis and ECM secretion. The combination of PPT and ICA restores key HSC niche factor gene expressions, normalizing HSC differentiation and mobilization. The in vitro cellular uptake efficiency of nanocarriers in a mimic niche is positively correlated with their in vivo delivery into bone marrow niche cells. DSS6-NPs greatly enhance the delivery of PPT/ICA into MSCs and OBs within bone marrow niches. Co-loading of PPT/ICA into DSS6-NPs effectively repairs damaged bone marrow niches and promotes HSC rejuvenation in vivo. CONCLUSION: The combination of PPT and ICA effectively prevents injury to the vascular and endosteal niches, thereby promoting hematopoietic regeneration in the bone marrow. This study provides novel niche-directed PPT/ICA therapies for managing chemotherapy-induced myelosuppression.
RESUMEN
Idebenone, an antioxidant used in treating oxidative damage-related diseases, has unclear neuroprotective mechanisms. Oxidative stress affects cell and mitochondrial membranes, altering Adp-ribosyl cyclase (CD38) and Silent message regulator 3 (SIRT3) protein expression and possibly impacting SIRT3's ability to deacetylate Tumor protein p53 (P53). This study explores the relationship between CD38, SIRT3, and P53 in H2O2-injured HT22 cells treated with Idebenone. Apoptosis was detected using flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining after determining appropriate H2O2 and Idebenone concentrations.In this study, Idebenone was found to reduce apoptosis and decrease P53 and Caspase3 expression in H2O2-injured HT22 cells by detecting apoptosis-related protein expression. Through bioinformatics methods, CD38 was identified as the target of Idebenone, and it further demonstrated that Idebenone decreased the expression of CD38 and increased the level of SIRT3. An increased NAD+/NADH ratio was detected, suggesting Idebenone induces SIRT3 expression and protects HT22 cells by decreasing apoptosis-related proteins. Knocking down SIRT3 downregulated acetylated P53 (P53Ac), indicating SIRT3's importance in P53 deacetylation.These results supported that CD38 was used as a target of Idebenone to up-regulate SIRT3 to deacetylate activated P53, thereby protecting HT22 cells from oxidative stress injury. Thus, Idebenone is a drug that may show great potential in protecting against reactive oxygen species (ROS) induced diseases such as Parkinson's disease, and Alzheimer's disease. And it might be able to compensate for some of the defects associated with CD38-related diseases.