58-F, a flavanone from Ophiopogon japonicus, prevents hepatocyte death by decreasing lysosomal membrane permeability

Yan, Xiaofeng; Ye, Tingjie; Hu, Xudong; Zhao, Pei; Wang, Xiaoling

doi:10.1038/srep27875

Cited by 11 publications

(5 citation statements)

References 40 publications

(47 reference statements)

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“…Confirming these observations, the ultrastructure of infected Rab20 KO BMM more often showed multiple p62-labeled host-derived membranes and vesicles in close proximity to Mtb compared with WT BMM ( Figure 4 D). To monitor phagosome integrity dynamics in macrophages, we used LysoTracker as a probe that, after irreversible protonation, gets trapped into the lumen of acidic compartments ( Yan et al., 2016 ). We observed that Mtb phagosomes became leaky for LysoTracker at different stages in WT BMM and fusion with endosomes restored LysoTracker levels within phagosomes ( Figures 4 E–4G; Movie S3 ).…”

Section: Resultsmentioning

confidence: 99%

A Rab20-Dependent Membrane Trafficking Pathway Controls M. tuberculosis Replication by Regulating Phagosome Spaciousness and Integrity

Schnettger

Rodgers

Repnik

et al. 2017

Cell Host & Microbe

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SummaryThe intracellular pathogen Mycobacterium tuberculosis (Mtb) lives within phagosomes and also disrupts these organelles to access the cytosol. The host pathways and mechanisms that contribute to maintaining Mtb phagosome integrity have not been investigated. Here, we examined the spatiotemporal dynamics of Mtb-containing phagosomes and identified an interferon-gamma-stimulated and Rab20-dependent membrane trafficking pathway in macrophages that maintains Mtb in spacious proteolytic phagolysosomes. This pathway functions to promote endosomal membrane influx in infected macrophages, and is required to preserve Mtb phagosome integrity and control Mtb replication. Rab20 is specifically and significantly upregulated in the sputum of human patients with active tuberculosis. Altogether, we uncover an immune-regulated cellular pathway of defense that promotes maintenance of Mtb within intact membrane-bound compartments for efficient elimination.

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Section: Resultsmentioning

confidence: 99%

A Rab20-Dependent Membrane Trafficking Pathway Controls M. tuberculosis Replication by Regulating Phagosome Spaciousness and Integrity

Schnettger

Rodgers

Repnik

et al. 2017

Cell Host & Microbe

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“…4G,H). Recently, a flavanone, 5,8-dimethoxy-6-methyl-7-hydroxy-3-3(2-hydroxy-4-methoxybenzyl) chroman-4-one (58-F), extracted from Ophiopogon japonicas has been reported to play a similar role (Yan et al, 2016). This flavonoid protects the H 2 O 2 -induced damage in hepatocytes by decreasing the calcium concentration and suppressing the PLCγ1-IP 3 R-SOC pathway, leading to reduced HMGB1 release.…”

Section: Discussionmentioning

confidence: 99%

A small bioactive glycoside inhibits epsilon toxin and prevents cell death

Shivappagowdar

Pati

Narayana

et al. 2019

Disease Models &Amp; Mechanisms

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Clostridium perfringens epsilon toxin (Etx) is categorized as the third most lethal bioterrorism agent by the Centers for Disease Control and Prevention (CDC), with no therapeutic counter measures available for humans. Here, we have developed a high-affinity inhibitory compound by synthesizing and evaluating the structure activity relationship (SAR) of a library of diverse glycosides (numbered 1-12). SAR of glycoside-Etx heptamers revealed exceptionally strong H-bond interactions of glycoside-4 with a druggable pocket in the oligomerization and β-hairpin region of Etx. Analysis of its structure suggested that glycoside-4 might self-aggregate to form a robust micelle-like supra-molecular complex due to its linear side-chain architecture, which was authenticated by fluorescence spectroscopy. Further, this micelle hinders the Etx monomer-monomer interaction required for oligomerization, validated by both surface plasmon resonance (SPR) and immunoblotting. This phenomenon in turn leads to blockage of pore formation. Downstream evaluation revealed that glycoside-4 effectively blocked cell death of Etx-treated cultured primary cells and maintained cellular homeostasis via disrupting oligomerization, blocking pore formation, restoring calcium homeostasis, stabilizing the mitochondrial membrane and impairing high mobility group box 1 (HMGB1) translocation from nucleus to cytoplasm. Furthermore, a single dosage of glycoside-4 protected the Etx-challenged mice and restored normal function to multiple organs. This work reports for the first time a potent, nontoxic glycoside with strong ability to occlude toxin lethality, representing it as a bio-arm therapeutic against Etx-based biological threat.

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“…The suspension was incubated with Annexin V-kFluor488 and stained with PI (Kaiji Biology Corp., China) at room temperature for 20 minutes and then analyzed on flow cytometer (Cyto Flexz, Beckman, USA). The annexin V-positive/PI-negative cells indicated apoptotic cells at the early period, and the annexin V-positive/PI-positive cells showed those at the later period [ 36 ]. The ratio of apoptosis or apoptosis index (AI) was calculated using the following equation: …”

Section: Methodsmentioning

confidence: 99%

Differential induction of apoptosis and autophagy by pyrrolizidine alkaloid clivorine in human hepatoma Huh-7.5 cells and its toxic implication

Liu

Zhou

et al. 2017

PLoS ONE

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Growing evidence suggests that the pyrrolizidine alkaloids (PAs)-induced hepatotoxicity is mediated by multiple cell death/defence modalities. However, the detailed mechanisms are still lacking. In this study, the hepatotoxic effects of four PAs including three retronecine-type ones (senecionine, seneciphylline and monocrotaline) and one otonecine-type (clivorine) on the proliferation of Huh-7.5 cells and the possible mechanisms were investigated. The results showed that all the PAs could inhibit cell proliferation and induce apoptosis in a concentration-dependent manner. Among them clivorine was the most significant one. In addition to its effect on apoptosis, clivorine treatment could promote autophagy in Huh-7.5 cells, as evidenced by the accumulation of autophagosomes, the enhancement of LC3B expression at the concentrations close to its IC0 value, and the increased conversion of LC3B-I to LC3B-II in the presence of lysosomal inhibitor (chloroquine) and decreased formation of green fluorescent protein (GFP)-LC3 positive puncta in the presence of autophagic sequestration inhibitor (3-methyladenine). Among the other tested PAs, senecionine and seneciphylline also activated autophagy at the same concentrations used for clivorine but monocrotaline did not. Furthermore, our study demonstrated that suppression or enhancement of autophagy resulted in the remarkable enhancement or suppression of senecionine, seneciphylline and clivorine-induced apoptosis at the concentration close to the IC10 for clivorine, respectively, indicating a protective role of autophagy against the PA-induced apoptosis at the low level of exposure. Collectively, our data suggest that PAs in different structures may exert different toxic disturbances on the liver cells. Apoptosis may be one of the most common models of the PA-induced cytotoxicity, while autophagy may be a structure-dependent defence model in the early stage of PA intoxication. Differential induction of apoptosis and autophagy probably depending on the concentration is essential for the cytotoxic potency of clivorine.

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58-F, a flavanone from Ophiopogon japonicus, prevents hepatocyte death by decreasing lysosomal membrane permeability

Cited by 11 publications

References 40 publications

A Rab20-Dependent Membrane Trafficking Pathway Controls M. tuberculosis Replication by Regulating Phagosome Spaciousness and Integrity

A Rab20-Dependent Membrane Trafficking Pathway Controls M. tuberculosis Replication by Regulating Phagosome Spaciousness and Integrity

A small bioactive glycoside inhibits epsilon toxin and prevents cell death

Differential induction of apoptosis and autophagy by pyrrolizidine alkaloid clivorine in human hepatoma Huh-7.5 cells and its toxic implication

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