Background and Purpose Intravenous infusion of chemotherapy drugs can cause severe chemotherapy‐induced phlebitis (CIP) in patients. However, the underlying mechanism of CIP development remains unclear. Experimental Approach RNA‐sequencing analysis was used to identify potential disease targets in CIP. Guanylate binding protein‐5 (GBP5) genetic deletion approaches also were used to investigate the role of GBP5 in NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in lipopolysaccharide (LPS) primed murine bone‐marrow‐derived macrophages (BMDMs) induced by vinorelbine (VIN) in vitro and in mouse models of VIN‐induced CIP in vivo. The anti‐CIP effect of aescin was evaluated, both in vivo and in vivo. Key Results Here, we show that the expression of GBP5 was upregulated in human peripheral blood mononuclear cells from CIP patients. Genetic ablation of GBP5 in murine macrophages significantly alleviated VIN‐induced CIP in the experimental mouse model. Mechanistically, GBP5 contributed to the inflammatory responses through activating NLRP3 inflammasome and driving the production of the inflammatory cytokine IL‐1β. Moreover, aescin, a mixture of triterpene saponins extracted from horse chestnut seed, can alleviate CIP by inhibiting the GBP5/NLRP3 axis. Conclusion and Implications These findings suggest that GBP5 is an important regulator of NLRP3 inflammasome in CIP mouse model. Our work further reveals that aescin may serve as a promising candidate in the clinical treatment of CIP.
Aesculus L. (buckeye and horse chestnut) are woody plant species with important horticultural and medicinal values. Aesculus seeds are widely used as biomedicine and cosmetic ingredients due to their saponins. We report a chromosomal-scale genome of Aesculus wilsonii. Sequences amounting to a total of 579.01 Mb were assembled into 20 chromosomes. More than half of the genome (54.46%) were annotated as repetitive sequences, and 46,914 protein-coding genes were predicted. In addition to the widespread gamma event with core eudicots, a unique whole-genome duplication (WGD) event (17.69 Mya) occurred in Aesculus after buckeye differentiated from longan. Due to WGD events and tandem duplications, the related synthetic genes of triterpene saponins unique to Aesculus increased significantly. Combined with transcriptome characterization, the study preliminarily resolved the biosynthetic pathway of triterpenoid saponins like aescin in A. wilsonii genome. Analyses of the resequencing of 104 buckeye accessions revealed clear relationship between the geographic distribution and genetic differentiation of buckeye trees in China. We found that the buckeye species found in southern Shaanxi is A. wilsonii rather than A. chinensis. Population dynamics analysis further suggests that the population size and evolution of existing buckeye species have been influenced by climate fluctuations during the Pleistocene and recent domestication events. The genome of A. wilsonii and population genomics of Aesculus provide a resource for future research on Hippocastanaceae. These findings will contribute to the utilization and diversity protection of Aesculus.
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