PMID- 37127800 OWN - NLM STAT- MEDLINE DCOM- 20230721 LR - 20230721 IS - 1573-6903 (Electronic) IS - 0364-3190 (Linking) VI - 48 IP - 9 DP - 2023 Sep TI - Protection of Oxygen Glucose Deprivation-Induced Human Brain Vascular Pericyte Injury: Beneficial Effects of Bellidifolin in Cellular Pyroptosis. PG - 2794-2807 LID - 10.1007/s11064-023-03943-7 [doi] AB - Pericytes play critical roles in the maintenance of brain vascular homeostasis. However, very little is currently known about how pericytes regulate ischemic stroke-induced brain injury. Inflammation is a key event in the pathobiology of stroke, in which the nod-like receptor protein-3 (NLRP3) inflammasome is involved in, triggering sterile inflammatory responses and pyroptosis. In the current study, an immortalized cell line derived from human brain vascular pericytes (HBVPs) was constructed, and it showed that HBVPs challenged with oxygen glucose deprivation (OGD) displays pronounced cellular excretion of LDH, IL-1beta, IL-18 and increased PI positive staining. Mechanistically, upon OGD treatment, NLRP3 forms an inflammasome with its adaptor protein apoptosis-associated speck-like protein, containing a caspase recruitment domain (ASC) and caspase-1, manifested as much more co-stainings of NLRP3, ASC and Caspase-1 in HBVPs, accompanied by the increased protein levels of NLRP3, ASC, caspase-1 as well as the pyroptosis-associated protein gasdermin D (GSDMD). Intriguingly, GSDMD-N shuttled to the mitochondrial membrane triggered by OGD exposure, which promoted massive mitochondria-derived ROS generation. Importantly, the invention value of the specific targets was evaluated by treatment with bellidifolin, a kind of ketone compound derived from Swertia chirayita in traditional Tibetan medicine. It showed that bellidifolin exerts beneficial effects and attenuates the formation of NLRP3/ASC/Caspase-1 complex, thereby impeding GSDMD-N shuttling and resultant ROS generation, protecting against OGD-induced HBVPs pyroptosis. Overall, these findings unravel the potential mechanisms of pericyte injury induced by OGD and indicate that bellidifolin may exert its beneficial effects on pyroptosis, thus providing new therapeutic insights into stroke. CI - (c) 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - An, Di AU - An D AD - Department of Emergency Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. FAU - Xu, Weixiao AU - Xu W AD - Department of Emergency Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. FAU - Ge, Yingxin AU - Ge Y AD - Key Lab of Modern Toxicology (NJMU), Ministry of Education, School of Public Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing, 211166, Jiangsu, China. FAU - Ge, Yaning AU - Ge Y AD - Key Lab of Modern Toxicology (NJMU), Ministry of Education, School of Public Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing, 211166, Jiangsu, China. FAU - Zhang, Linwei AU - Zhang L AD - Key Lab of Modern Toxicology (NJMU), Ministry of Education, School of Public Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing, 211166, Jiangsu, China. FAU - Zhu, Yi AU - Zhu Y AD - Department of Emergency Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. FAU - Zhang, Zhongman AU - Zhang Z AD - Department of Emergency Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. FAU - Fan, Junting AU - Fan J AD - Department of Pharmaceutical Analysis, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China. FAU - Gao, Rong AU - Gao R AD - Department of Hygienic Analysis and Detection, Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China. FAU - Jiang, Lei AU - Jiang L AD - Department of Emergency Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. FAU - Huang, Peipei AU - Huang P AD - Department of Emergency Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. FAU - Wang, Jun AU - Wang J AD - Key Lab of Modern Toxicology (NJMU), Ministry of Education, School of Public Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing, 211166, Jiangsu, China. wangjun@njmu.edu.cn. AD - China International Cooperation Center for Environment and Human Health, Nanjing Medical University, 818 Tianyuan East Road, Nanjing, 211166, Jiangsu, China. wangjun@njmu.edu.cn. FAU - Chen, Xufeng AU - Chen X AD - Department of Emergency Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. cxfyx@njmu.edu.cn. LA - eng GR - 82072159/National Natural Science Foundation of China/ GR - WSN-005/Six Talent Peaks Project in Jiangsu Province/ GR - LGY2019068/"333 Project" of Jiangsu Province/ PT - Journal Article DEP - 20230502 PL - United States TA - Neurochem Res JT - Neurochemical research JID - 7613461 RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - S88TT14065 (Oxygen) RN - 2798-25-6 (bellidifolin) RN - 0 (Reactive Oxygen Species) RN - IY9XDZ35W2 (Glucose) RN - EC 3.4.22.- (Caspases) RN - EC 3.4.22.36 (Caspase 1) SB - IM MH - Humans MH - *Inflammasomes/metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - Pyroptosis MH - Pericytes MH - Oxygen MH - Reactive Oxygen Species/metabolism MH - Glucose/pharmacology MH - Caspases/metabolism MH - *Stroke MH - Brain/metabolism MH - Caspase 1/metabolism OTO - NOTNLM OT - Bellidifolin OT - Human brain vascular pericytes OT - Ischemic stroke OT - Oxygen glucose deprivation OT - Pyroptosis EDAT- 2023/05/02 00:42 MHDA- 2023/07/21 06:43 CRDT- 2023/05/01 23:26 PHST- 2022/10/09 00:00 [received] PHST- 2023/04/20 00:00 [accepted] PHST- 2023/01/31 00:00 [revised] PHST- 2023/07/21 06:43 [medline] PHST- 2023/05/02 00:42 [pubmed] PHST- 2023/05/01 23:26 [entrez] AID - 10.1007/s11064-023-03943-7 [pii] AID - 10.1007/s11064-023-03943-7 [doi] PST - ppublish SO - Neurochem Res. 2023 Sep;48(9):2794-2807. doi: 10.1007/s11064-023-03943-7. Epub 2023 May 2.