Beneficial effect and mechanism of natural resourced polysaccharides on regulating bone metabolism through intestinal flora: A review.

Bone metabolism is an important biological process for maintaining bone health. Polysaccharides of natural origin exert beneficial effects on bone metabolism. Polysaccharide molecules often have difficulty passing through the intestinal cell membrane and are directly absorbed in the gastrointestinal tract. Therefore, polysaccharides may affect intestinal flora and play a role in disease treatment. We performed a comprehensive review of the relevant literature published from 2003 to 2023. We found that several polysaccharides from traditional Chinese medicines, including Astragalus, Achyranthes bidentata and Eucommia ulmoides, and the polysaccharides from several dietary fibers mainly composed of inulin, resistant starch, and dextran could enrich the intestinal microbiota group to regulate bone metabolism. The promotion of polysaccharide decomposition by regulating the Bacteroides phylum is particularly critical. Studies on the structure-activity relationship showed that molecular weight, glycosidic bonds, and monosaccharide composition may affect the ability of polysaccharides. The mechanism by which polysaccharides regulate intestinal flora to enhance bone metabolism may be related to the regulation of short-chain fatty acids, immunity, and hormones, involving some signaling pathways, such as TGF-ß, Wnt/ß-catenin, BMP/Smads, and RANKL. This paper provides a useful reference for the study of polysaccharides and suggests their potential application in the treatment of bone metabolic disorders.

Codelivery of Ponatinib and SAR302503 by Active Bone-Targeted Polymeric Micelles for the Treatment of Therapy-Resistant Chronic Myeloid Leukemia.

Point mutations in the BCR-ABL1 domain and primitive chronic myelogenous leukemia (CML) cells existing in the bone marrow environment insensitive to tyrosine kinase inhibitors (TKIs) have become two major challenges in the CML therapy. In this study, combined TKI ponatinib and JAK2 inhibitor SAR302503 short-term treatment effectively suppressed growth and promoted apoptosis of BaF3/T315I cells in cytokine-containing medium in vitro. SAR302503 prevented cytokine-dependent resistance to ponatinib via inhibition of JAK2/STAT5 phosphorylation. Codelivery of ponatinib and SAR302503 by active bone-targeted polymeric micellar formulation greatly increased the drug accumulation in medullary cavity. The therapeutic efficacy of bone-targeted formulation was demonstrated in BaF3/T315I cells inoculated murine model with no dose-limited toxicity detectable in health mice. Thus, the intravenous injectable bone-homing ponatinib and SAR302503 micellar formulation represents a promising strategy for the treatment of therapy-resistant CML.