A new perspective of triptolide-associated hepatotoxicity: Liver hypersensitivity upon LPS stimulation

Yuan, Ziqiao; Zhang, Haoran; Hasnat, Muhammad; Ding, Jiaxin; Chen, Xi; Liang, Peishi; Sun, Lixin; Zhang, Luyong; Jiang, Zhenzhou

doi:10.1016/j.tox.2019.01.005

Cited by 43 publications

(38 citation statements)

References 55 publications

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“…In hepatitis cells, reduced GSH levels can slow the disulfide reduction and disassembly of GdNPs-Gal. The high r 1 relaxivity and prolonged retention of GdNPs-Gal compared to its reduced small-molecule products generate higher MR contrast in inflammatory liver cells, enabling noninvasive visualization of LPS-induced liver inflammation [ 40 , 41 ] via high-resolution MRI. Responsive molecular probes for noninvasive MRI of GSH levels in liver can be further applied for real-time monitoring of the anti-inflammation efficacy of dexamethasone (DEX) [ 42 , 43 ] in living mice.…”

Section: Introductionmentioning

confidence: 99%

Responsive Trimodal Probes for In Vivo Imaging of Liver Inflammation by Coassembly and GSH-Driven Disassembly

Wang

Wen

et al. 2020

Research

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Noninvasive in vivo imaging of hepatic glutathione (GSH) levels is essential to early diagnosis and prognosis of acute hepatitis. Although GSH-responsive fluorescence imaging probes have been reported for evaluation of hepatitis conditions, the low penetration depth of light in liver tissue has impeded reliable GSH visualization in the human liver. We present a liver-targeted and GSH-responsive trimodal probe (GdNPs-Gal) for rapid evaluation of lipopolysaccharide- (LPS-) induced acute liver inflammation via noninvasive, real-time in vivo imaging of hepatic GSH depletion. GdNPs-Gal are formed by molecular coassembly of a GSH-responsive Gd(III)-based MRI probe (1-Gd) and a liver-targeted probe (1-Gal) at a mole ratio of 5/1 (1-Gd/1-Gal), which shows high r1 relaxivity with low fluorescence and fluorine magnetic resonance spectroscopic (19F-MRS) signals. Upon interaction with GSH, 1-Gd and 1-Gal are cleaved and GdNPs-Gal rapidly disassemble into small molecules 2-Gd, 2-Gal, and 3, producing a substantial decline in r1 relaxivity with compensatory enhancements in fluorescence and 19F-MRS. By combining in vivo magnetic resonance imaging (1H-MRI) with ex vivo fluorescence imaging and 19F-MRS analysis, GdNPs-Gal efficiently detect hepatic GSH using three independent modalities. We noninvasively visualized LPS-induced liver inflammation and longitudinally monitored its remediation in mice after treatment with an anti-inflammatory drug, dexamethasone (DEX). Findings highlight the potential of GdNPs-Gal for in vivo imaging of liver inflammation by integrating molecular coassembly with GSH-driven disassembly, which can be applied to other responsive molecular probes for improved in vivo imaging.

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Section: Introductionmentioning

confidence: 99%

Responsive Trimodal Probes for In Vivo Imaging of Liver Inflammation by Coassembly and GSH-Driven Disassembly

Wang

Wen

et al. 2020

Research

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“…The mechanism of TP-induced liver damage has been largely linked to oxidative stress via the instigation of over generation of reactive oxygen species (ROS), anionic peroxides, liver apoptosis, autophagy, depletion, and inhibition of antioxidant enzymes activities [ 5 – 7 ]. The high levels of ROS and reactive nitrogen species (RNS) inhibit ATPase, sodium, and calcium pump activity of cell membrane leading to decrease in the mitochondrial membrane potentials (MMP) and the release of apoptosis factor caspase-3 to damage liver cells [ 8 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

Arctiin Antagonizes Triptolide-Induced Hepatotoxicity via Activation of Nrf2 Pathway

Zhou

Yao

et al. 2020

BioMed Research International

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Triptolide (TP) is the most effective ingredient found in the traditional Chinese herbal Tripterygium wilfordii Hook F, and it is widely used in therapies of autoimmune and inflammatory disorders. However, the hepatotoxicity induced by TP has restricted its use in clinical trials. Arctiin is known as a protective agent against oxidative stress, and it exerts liver-protecting effect. This study was aimed at investigating the protective role of arctiin against TP-induced hepatotoxicity using in vitro and in vivo models. The results indicated that TP not only obviously induced liver injury in mice but also significantly inhibited the growth of HepG2 cells and increased the level of intracellular reactive oxygen. Furthermore, TP obviously decreased the expressions of proteins of Nrf2 pathway including HO-1, NQO1, and Nrf2 associated with oxidative stress pathway. However, the above experimental indexes were reversed by the treatment of arctiin. Our results suggested that arctiin could alleviate TP-induced hepatotoxicity, and the molecular mechanism is likely related to its capacity against oxidative stress.

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“…The mechanisms of TP‐induced hepatotoxicity are varied. Many reports have shown the role of apoptosis and autophagy in TP‐induced liver injury (J. Wang et al, ; Yuan et al, ; Zhuang et al, ). It has been reported that the expression of cytochrome c , cleaved caspase3 and Bax were increased after TP exposure in the rat.…”

Section: Introductionmentioning

confidence: 99%

Triptolide‐induced hepatotoxicity via apoptosis and autophagy in zebrafish

Huo

Zhang

et al. 2019

J of Applied Toxicology

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Previous research about the development of triptolide (TP) as a natural active compound has often focused on hepatotoxicity. Among its various mechanisms, autophagy and apoptosis are two important signaling pathways. In this study, we used zebrafish to establish a TP‐induced hepatotoxicity model, and investigated the roles of autophagy and apoptosis in the progress of liver injury. Zebrafish exposed to TP showed increased mortality and malformation because of the increased drug dose and duration of exposure. Meanwhile, we found that TP induced liver injury in a time‐ and dose‐dependent manner, which was observed as a reduction in liver area, slow yolk absorption, upregulation of transaminase and local neurosis. With the application of the high‐content imaging system (HCIS) technique in liver 3D imaging in vivo, clear imaging of the zebrafish liver was achieved. The results showed a decrease in volume and location of necrosis in the liver after TP exposure. Increased expression of inflammatory cytokines genes tumor necrosis factor (Tnf)α, Il1β and Il6 were shown, particularly Tnfα. The Fas‐Caspase8 signaling pathway was activated. The apoptosis‐related gene Bcl‐2 was increased, and Bax, Caspase9 and Caspase3 were increased. However, autophagy related genes Beclin1, Atg5, Atg3 and Lc3 were increased more significantly, and the changes of Beclin1 and Atg5 were the most severe. This study successfully established a TP‐induced zebrafish hepatotoxicity model and applied the HCIS technique in a zebrafish hepatotoxicity study. The result indicated Fas might be the main target of TP‐induced hepatotoxicity. Autophagy played a more important role than apoptosis and was characterized by the overexpression of Beclin1 and Atg5.

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A new perspective of triptolide-associated hepatotoxicity: Liver hypersensitivity upon LPS stimulation

Cited by 43 publications

References 55 publications

Responsive Trimodal Probes for In Vivo Imaging of Liver Inflammation by Coassembly and GSH-Driven Disassembly

Responsive Trimodal Probes for In Vivo Imaging of Liver Inflammation by Coassembly and GSH-Driven Disassembly

Arctiin Antagonizes Triptolide-Induced Hepatotoxicity via Activation of Nrf2 Pathway

Triptolide‐induced hepatotoxicity via apoptosis and autophagy in zebrafish

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