Bile acid metabolomics identifies chenodeoxycholic acid as a therapeutic agent for pancreatic necrosis

Zhu, Qingtian; Yuan, Chenchen; Dong, Xiaowu; Wang, Yaodong; Li, Baiqiang; Tu, Bo; Chen, Weiwei; Xu, Xingmeng; Gong, Weijuan; Xiao, Weiming; Ding, Yanbing; Hu, Lianghao; Li, Weiqin; Lu, Guotao

doi:10.1016/j.xcrm.2023.101304

Cited by 1 publication

(1 citation statement)

References 35 publications

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“…The mouse was anesthetized and then positioned on a constant-temperature operating table (approximately 37 ± 1 °C) (Beijing Zhongshi Dichuang Technology Development Co., Ltd.) to allow laparotomy (with a 1 cm longitudinal incision in the midline abdomen). The mice were then given a retrograde intraductal injection of 3.5% TLCS (w/v) at a speed of 100 μL·min –1 , while microarterial clamps were used to block the common bile duct and the opening site of the pancreatic duct during injection to prevent reflux to the liver and duodenum . The abdomen of the mouse was closed, sutured, and sterilized again after removing the artery clamp and syringe.…”

Section: Methodsmentioning

confidence: 99%

Biomimetic Trypsin-Responsive Structure-Bridged Mesoporous Organosilica Nanomedicine for Precise Treatment of Acute Pancreatitis

Wang,

Qian,

Wang

et al. 2024

ACS Nano

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Developing strategies to target injured pancreatic acinar cells (PACs) in conjunction with primary pathophysiology-specific pharmacological therapy presents a challenge in the management of acute pancreatitis (AP). We designed and synthesized a trypsin-cleavable organosilica precursor bridged by arginine-based amide bonds, leveraging trypsin's ability to selectively identify guanidino groups on arginine via Asp189 at the active S1 pocket and cleave the carboxy-terminal (C-terminal) amide bond via catalytic triads. The precursors were incorporated into the framework of mesoporous silica nanoparticles (MSNs) for encapsulating the membrane-permeable Ca 2+ chelator BAPTA-AM with a high loading content (∼43.9%). Mesenchymal stem cell membrane coating and surface modification with PAC-targeting ligands endow MSNs with inflammation recruitment and precise PAC-targeting abilities, resulting in the highest distribution at 3 h in the pancreas with 4.7-fold more accumulation than that of naked MSNs. The outcomes transpired as follows: After bioinspired MSNs' skeleton biodegradation by prematurely and massively activated trypsin, BAPTA-AM was on-demand released in injured PACs, thereby effectively eliminating intracellular calcium overload (reduced Ca 2+ level by 81.3%), restoring cellular redox status, blocking inflammatory cascades, and inhibiting cell necrosis by impeding the IκBα/NF-κB/TNF-α/IL-6 and CaMK-II/p-RIP3/p-MLKL/caspase-8,9 signaling pathways. In AP mice, a single dose of the formulation significantly restored pancreatic function (lipase and amylase reduced more by 60%) and improved the survival rate from 50 to 91.6%. The formulation offers a potentially effective strategy for clinical translation in AP treatment.

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Section: Methodsmentioning

confidence: 99%