1.Inhibitory activities of Lignum Sappan extractives on growth and growth-related signaling of tumor cells.
Qing ZHANG ; Jing-Li LIU ; Xiao-Man QI ; Chun-Ting QI ; Qiang YU
Chinese Journal of Natural Medicines (English Ed.) 2014;12(8):607-612
AIM:
To investigate the active constituents of Lignum Sappan (Caesalpinia sappan L.) on growth-related signaling and cell mitosis.
METHOD:
The influence of the ethyl acetate (EtOAc) extract of Lignum Sappan and its constituents on growth-related signaling were evaluated by a luciferase assay in cells stably-transfected with NF-κB, STAT1, or STAT3 responsive luciferase reporter plasmid. The inhibitory effect on the cell cycle was determined by flow cytometric analysis. The anti-tumor activities were assessed in vitro and in vivo.
RESULTS:
The EtOAc extract of Lignum Sappan had inhibitory activities on growth-related signaling and cell mitosis. Three major active compounds were sappanchalcone, brazilin, and butein. Sappanchalcone blocked cell cycle progression in the G2/M phase, brazilin inhibited TNFα/NF-κB signaling, while butein inhibited IL-6/STAT3 signaling, as well as TNFα/NF-κB signaling. The three compounds all demonstrated cytotoxic activities against human tumor cells in vitro. In a S180 tumor cell-bearing mice model, the anti-tumor efficacy of the EtOAc extract was better than the individual compounds acting alone.
CONCLUSION
These results indicate that Lignum Sappan contains multiple active compounds with different antitumor activities, which act synergistically to enhance their anti-tumor effects. The EtOAc extract of Lignum Sappan may be better than individual active constituent as a novel medicine for the treatment of cancer.
Animals
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Antineoplastic Agents, Phytogenic
;
pharmacology
;
therapeutic use
;
Benzopyrans
;
pharmacology
;
therapeutic use
;
Caesalpinia
;
Cell Cycle Checkpoints
;
drug effects
;
Chalcones
;
pharmacology
;
therapeutic use
;
Hep G2 Cells
;
Humans
;
Interleukin-6
;
metabolism
;
Male
;
Mice, Inbred BALB C
;
Mitosis
;
drug effects
;
NF-kappa B
;
metabolism
;
Phytotherapy
;
Plant Extracts
;
pharmacology
;
therapeutic use
;
STAT3 Transcription Factor
;
metabolism
;
Sarcoma
;
drug therapy
;
metabolism
;
Signal Transduction
;
Tumor Necrosis Factor-alpha
;
metabolism
2.Involvement of the mitochondrion-dependent and the endoplasmic reticulum stress-signaling pathways in isoliquiritigenin-induced apoptosis of HeLa cell.
Xuan YUAN ; Bo ZHANG ; Lu GAN ; Zhen Hua WANG ; Ba Cui YU ; Liang Liang LIU ; Qiu Sheng ZHENG ; Zhi Ping WANG
Biomedical and Environmental Sciences 2013;26(4):268-276
OBJECTIVEIsoliquiritigenin (ISL), a licorice chalconoid, is considered to be a bioactive agent with chemopreventive potential. This study investigates the mechanisms involved in ISL-induced apoptosis in human cervical carcinoma HeLa cells.
METHODSCell viability was evaluated using a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay. Apoptosis was determined by flow cytometry using an Annexin V-FITC Apoptosis Detection Kit. The intracellular ROS levels were assessed using a 2, 7-dichlorofluorescein probe assay. The mitochondrial membrane potential was measured with the dual-emission potential-sensitive probe 5, 5', 6, 6'-tetra-chloro-1, 1', 3, 3'-tetraethyl-imidacarbocyanine iodide (JC-1). The degradation of poly-ADP-ribose polymerase (PARP) protein, the phosphorylation of PKR-like ER kinase (PERK), the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2α), the expression of the 78 kD glucose-regulated protein (GRP 78), and the activation of caspase-12 were analyzed via western blot analysis.
RESULTSISL significantly inhibited the proliferation, the increase in ROS levels and apoptotic rates of HeLa cells in a concentration-dependent manner. Moreover, ISL induced mitochondrial dysfunction, caspase activation, and PARP cleavage, which displayed features of mitochondria dependent on apoptotic signals. Besides, exposure of HeLa cells to ISL triggered endoplasmic reticulum (ER) stress, as indicated by the increase in p-eIF2α and GRP78 expression, ER stress-dependent apoptosis is caused by the activation of ER-specific caspase-12.
CONCLUSIONThe findings from our study suggest that ISL-induced oxidative stress causes HeLa cell apoptosis via the mitochondrion-dependent and the ER stress-triggered signaling pathways.
Aldehyde Reductase ; antagonists & inhibitors ; Apoptosis ; drug effects ; Cell Survival ; drug effects ; Chalcones ; pharmacology ; therapeutic use ; Chemoprevention ; Drug Screening Assays, Antitumor ; Endoplasmic Reticulum Stress ; drug effects ; HeLa Cells ; Humans ; Mitochondria ; drug effects ; Neoplasms ; prevention & control ; Reactive Oxygen Species ; metabolism
3.Preventive and therapeutic effect of bioactive component of licorice on antidepressant-induced liver injury.
Wen-Qing MU ; Guang XU ; Jia ZHAO ; Yuan-Yuan CHEN ; Zhao-Fang BAI ; Xiao-He XIAO
China Journal of Chinese Materia Medica 2022;47(22):6146-6154
Since exploding rates of modern mental diseases, application of antidepressants has increased. Worryingly, the antidepressant-induced liver injury has gradually become a serious health burden. Furthermore, since most of the knowledge about antidepressant hepatotoxicity are from pharmacovigilance and clinical case reports and lack of observational studies, the underlying mechanisms are poorly understood and there is a lack of efficient treatment strategies. In this study, antidepressant paroxetine directly triggered inflammasome activation evidenced by caspase-1 activation and downstream effector cytokines interleukin(IL)-1β secretion. The pretreatment of echinatin, a bioactive component of licorice, completely blocked the activation. This study also found that echinatin effectively inhibited the production of inflammasome-independent tumor necrosis factor α(TNF)-α induced by paroxetine. Mechanistically, the accumulation of mitochondrial reactive oxygen species(mtROS) was a key upstream event of paroxetine-induced inflammasome activation, which was dramatically inhibited by echinatin. In the lipopolysaccharide(LPS)-mediated idiosyncratic drug-induced liver injury(IDILI) model, the combination of LPS and paroxetine triggered aberrant activation of the inflammasome to induce idiosyncratic hepatotoxicity, which was reversed by echinatin pretreatment. Notably, this study also found that various bioactive components of licorice had an inhibitory effect on paroxetine-triggered inflammasome activation. Meanwhile, multiple antidepressant-induced aberrant activation of the inflammasome could be completely blocked by echinatin pretreatment. In conclusion, this study provides a novel insight for mechanism of antidepressant-induced liver injury and a new strategy for the treatment of antidepressant-induced hepatotoxicity.
Animals
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Humans
;
Mice
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Antidepressive Agents/adverse effects*
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Chemical and Drug Induced Liver Injury, Chronic/prevention & control*
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Glycyrrhiza/chemistry*
;
Inflammasomes/drug effects*
;
Interleukin-1beta/metabolism*
;
Lipopolysaccharides/toxicity*
;
Mice, Inbred C57BL
;
NLR Family, Pyrin Domain-Containing 3 Protein
;
Paroxetine/adverse effects*
;
Tumor Necrosis Factor-alpha
;
Chalcones/therapeutic use*