Neuropsychopharmacological profiling of scoparone in mice.
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ABSTRACT:
SUBMITTER: Kowalczyk J
PROVIDER: S-EPMC8764054 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alcohol-induced liver disease (ALD) is a leading cause of non-accident-related deaths in the world. Identification of an early specific signature of ALD would aid in therapeutic intervention. Scoparone is an important constituent of Yinchenhao, and displayed bright prospects in hepatoprotective effect. However, its precise molecular mechanism has not been well explored. The present study was designed to assess the effects and possible mechanisms of scoparone against alcohol-induced liver injury. UPLC/ESI-Q-TOF/MS combined with pattern recognition approaches including PCA, and PLS-DA were integrated to get differentiating metabolites for the pathways and clarify mechanisms of disease, highlight insights into drug discovery. The results indicated four ions in the positive mode were characterized as potential differentiating metabolites which can be regulated by scoparone treatment, and suggested that therapeutic effect of scoparone could regulated the dysfunctions of citrate cycle, sphingolipid metabolism, taurine and hypotaurine.
| S-EPMC4208028 | biostudies-literature
Project description:Perturbation in sphingolipid metabolism has been regarded as a risk factor for nonalcoholic steatohepatitis (NASH) development, predisposing to inflammation, insulin resistance, and weight gain. Scoparone can regulate the level of ceramide in primary hepatocytes and effectively ameliorate hepatic inflammation, apoptosis, steatosis, and fibrogenesis in a mice model of NASH. Nevertheless, the potential effects of scoparone in sphingolipid metabolism, which is dysregulated in NASH, have not been explored so far. To uncover the impact of scoparone on sphingolipid metabolism in NASH and potential therapeutic targets for treating NASH, the liver tissue samples were collected and lipidomics analysis based on UPLC-QTRAP-MRM/MS was carried out. The collected raw data was handled with multivariate data treatment to discover the potential biomarkers in sphingolipid metabolism. Compared to the control group, 22 potential sphingolipid biomarkers were discovered in the NASH group, of which 10 were downregulated and 12 were upregulated. Orally administrated scoparone contributed to the reversal of the levels of these potential biomarkers. Ten differential metabolites showed a tendency of recovery compared to the control group and may be potential targets for scoparone to treat NASH. This study indicated that lipidomics can detect the perturbed sphingolipids to unravel the therapeutic effects of scoparone on NASH.
| S-EPMC9089391 | biostudies-literature
Project description:Lipidomics, which focuses on the global study of molecular lipids in biological systems, could provide valuable insights about disease mechanisms. In this study, we present a nontargeted lipidomics strategy to determine cellular lipid alterations after scoparone exposure in primary hepatocytes. Lipid metabolic profiles were analyzed by high-performance liquid chromatography coupled with time-of-flight mass spectrometry, and a novel imaging TransOmics tool has been developed for the analysis of high-resolution MS data, including the data pretreatment, visualization, automated identification, deconvolution and quantification of lipid species. Chemometric and statistical analyses of the obtained lipid fingerprints revealed the global lipidomic alterations and tested the therapeutic effects of scoparone. Identification of ten proposed lipids contributed to the better understanding of the effects of scoparone on lipid metabolism in hepatocytes. The most striking finding was that scoparone caused comprehensive lipid changes, as represented by significant changes of the identificated lipids. The levels of identified PG(19:1(9Z)/14:0), PE(17:1(9Z)/0:0), PE(19:1(9Z)/0:0) were found to be upregulated in ethanol-induced group, whereas the levels in scoparone group were downregulated. Lipid metabolism in primary hepatocytes was changed significantly by scoparone treatment. We believe that this novel approach could substantially broaden the applications of high mass resolution mass spectrometry for cellular lipidomics.
| S-EPMC4910084 | biostudies-literature
Project description:Scoparone, which is a major constituent of Artemisia capillaries, has been identified as an anticoagulant, hypolipidemic, vasorelaxant, anti-oxidant and anti-inflammatory drug, and it is used for the traditional treatment of neonatal jaundice. Therefore, we hypothesized that scoparone could suppress the proliferation of VSMCs by interfering with STAT3 signaling. We found that the proliferation of these cells was significantly attenuated by scoparone in a dose-dependent manner. Scoparone markedly reduced the serum-stimulated accumulation of cells in the S phase and concomitantly increased the proportion of cells in the G0/G1 phase, which was consistent with the reduced expression of cyclin D1, phosphorylated Rb and survivin in the VSMCs. Cell adhesion markers, such as MCP-1 and ICAM-1, were significantly reduced by scoparone. Interestingly, this compound attenuated the increase in cyclin D promoter activity by inhibiting the activities of both the WT and active forms of STAT3. Similarly, the expression of a cell proliferation marker induced by PDGF was decreased by scoparone with no change in the phosphorylation of JAK2 or Src. On the basis of the immunofluorescence staining results, STAT3 proteins phosphorylated by PDGF were predominantly localized to the nucleus and were markedly reduced in the scoparone-treated cells. In summary, scoparone blocks the accumulation of STAT3 transported from the cytosol to the nucleus, leading to the suppression of VSMC proliferation through G1 phase arrest and the inhibition of Rb phosphorylation. This activity occurs independent of the form of STAT3 and upstream of kinases, such as Jak and Src, which are correlated with abnormal vascular remodeling due to the presence of an excess of growth factors following vascular injury. These data provide convincing evidence that scoparone may be a new preventative agent for the treatment of cardiovascular diseases.
| S-EPMC4351406 | biostudies-literature
Project description:Scoparone (6,7-dimethoxycoumarin) is the representative ingredient of Yinchenhao (Artemisia capillaris Thunb.) which is a famous Chinese medicinal herb and shows favorable efficacy for all kinds of liver disease, specifically for the treatment of Yanghuang syndrome (YHS). The precise molecular mechanism concerning the action of scoparone on YHS is yet to be fully elucidated. The aim of the present study was to determine the mechanism of scoparone and evaluate its efficacy on metabolite levels. The differential expression of metabolites responsible for the pharmacological effects of scoparone was characterized and the protection effect of scoparone against this disease. Using multivariate statistical analysis, 33 biomarkers were identified using precise MS/MS and play an important role in the regulation of key metabolic pathways associated with liver disease. In addition, pathological results also showed consistent changes in the YHS model group and after treatment with scoparone, both the metabolic profile and histopathology resembled that of normal level, which suggesting favorable efficacy over the observed time period. The present work indicated that a metabolomics platform provided a new insight into understanding the mechanisms of action of natural medicines such as scoparone.
| S-EPMC5116618 | biostudies-literature
Project description:The activated c-Jun N-terminal kinase (JNK) specifically combined with SH3 domain-binding protein 5 (Sab) may mediate damage to the mitochondrial respiratory chain. Whether mitochondrial dysfunction induced by the JNK/Sab signaling pathway plays a pivotal role in the lipotoxic injury of nonalcoholic steatohepatitis (NASH) remains a lack of evidence. Scoparone, a natural compound from Traditional Chinese Medicine herbs, has the potential for liver protection and lipid metabolism regulation. However, the effect of scoparone on NASH induced by a high-fat diet (HFD) as well as its underlying mechanism remains to be elucidated. The HepG2 and Huh7 cells with/without Sab-knockdown induced by palmitic acid (PA) were used to determine the role of JNK/Sab signaling in mitochondrial dysfunction and cellular lipotoxic injury. To observe the effect of scoparone on the lipotoxic injured hepatocytes, different dose of scoparone together with PA was mixed into the culture medium of HepG2 and AML12 cells to incubate for 24 h. In addition, male C57BL/6J mice were fed with an HFD for 22 weeks to induce the NASH model and were treated with scoparone for another 8 weeks to investigate its effect on NASH. Molecules related to JNK/Sab signaling, mitochondrial function, and lipotoxic injury were detected in in vitro and/or in vivo experiments. The results showed that PA-induced activation of JNK/Sab signaling was blocked by Sab knockdown in hepatocytes, which improved mitochondrial damage, oxidative stress, hepatosteatosis, cell viability, and apoptosis. Scoparone demonstrated a similar effect on the PA-induced hepatocytes as Sab knockdown. For the NASH mice, treatment with scoparone also downregulated the activation of JNK/Sab signaling, improved histopathological changes of liver tissues including mitochondrial number and morphology, lipid peroxide content, hepatosteatosis and inflammation obviously, as well as decreased the serum level of lipid and transaminases. Taken together, this study confirms that activation of the JNK/Sab signaling pathway-induced mitochondrial dysfunction plays a crucial role in the development of NASH. Scoparone can improve the lipotoxic liver injury partially by suppressing this signaling pathway, making it a potential therapeutic compound for NASH.
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Project description:Scoparone, a natural compound isolated from Artemisia capillaris, has been used in Chinese herbal medicine to treat neonatal jaundice. Signal transducer and activator of transcription 3 (STAT3) contributes to the growth and survival of many human tumors. This study was undertaken to investigate the anti-tumor activity of scoparone against DU145 prostate cancer cells and to determine whether its effects are mediated by inhibition of STAT3 activity. Scoparone inhibited proliferation of DU145 cells via cell cycle arrest in G1 phase. Transient transfection assays showed that scoparone repressed both constitutive and IL-6-induced transcriptional activity of STAT3. Western blot and quantitative real-time PCR analyses demonstrated that scoparone suppressed the transcription of STAT3 target genes such as cyclin D1, c-Myc, survivin, Bcl-2, and Socs3. Consistent with this, scoparone decreased phosphorylation and nuclear accumulation of STAT3, but did not reduce phosphorylation of janus kinase 2 (JAK2) or Src, the major upstream kinases responsible for STAT3 activation. Moreover, transcriptional activity of a constitutively active mutant of STAT3 (STAT3C) was inhibited by scoparone, but not by AG490, a JAK2 inhibitor. Furthermore, scoparone treatment suppressed anchorage-independent growth in soft agar and tumor growth of DU145 xenografts in nude mice, concomitant with a reduction in STAT3 phosphorylation. Computational modeling suggested that scoparone might bind the SH2 domain of STAT3. Our findings suggest that scoparone elicits an anti-tumor effect against DU145 prostate cancer cells in part through inhibition of STAT3 activity.
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Project description:Abstract Scoparone is an active ingredient of Yinchenhao (Artemisia annua L.), a well-known Chinese medicinal plant, and has been utilized in prevention and therapy of liver damage. However, the molecular drug targets associated with the pharmacological effects of scoparone are largely unknown. In the present article, we extend the previous research on Yinchenhao through a study of its active ingredient and thus the putative targets of scoparone. We employed two-dimensional gel electrophoresis, and all proteins expressed were identified by MALDI-TOF/TOF MS and database research. Protein-interacting networks and pathways were also mapped and evaluated. The possible protein network associated with scoparone was constructed, and contribution of these proteins to the protective effect of scoparone against the carbon tetrachloride-induced acute liver injury in rats are discussed herein. Hepatoprotective effects of scoparone on liver injury in rats were associated with regulated expression of six proteins which were closely related in our protein-protein interaction network, and appear to be involved in antioxidation and signal transduction, energy production, immunity, metabolism, and chaperoning. These observations collectively provide new insights on the molecular mechanisms of scoparone action against hepatic damage in rats.
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Project description:Scoparone (SCOP), an active and efficient coumarin compound derived from Artemisia capillaris Thunb, has been used as a traditional Chinese herbal medicine. Herein, we investigated the effects of SCOP on the osteogenic processes using MC3T3-E1 pre-osteoblasts in in vitro cell systems. SCOP (C11 H10 O4 , > 99.17%) was purified and identified from A. capillaries. SCOP (0.1 to 100 μM concentrations) did not have cytotoxic effects in pre-osteoblasts; however, it promoted alkaline phosphatase (ALP) staining and activity, and mineralized nodule formation under early and late osteogenic induction. SCOP elevated osteogenic signals through the bone morphogenetic protein 2 (BMP2)-Smad1/5/8 pathway, leading to the increased expression of runt-related transcription factor 2 (RUNX2) with its target protein, matrix metallopeptidase 13 (MMP13). SCOP also induced the non-canonical BMP2-MAPKs pathway, but not the Wnt3a-β-catenin pathway. Moreover, SCOP promoted autophagy, migration and adhesion under the osteogenic induction. Overall, the findings of this study demonstrated that SCOP has osteogenic effects associated with cell differentiation, adhesion, migration, autophagy and mineralization.
| S-EPMC9357629 | biostudies-literature
Project description:Eukaryotic translation initiation factor 3 subunit A (eIF3a) is the largest subunit of the eukaryotic translation initiation factor 3 (eIF3). eIF3a plays an integral role in protein biosynthesis, hence impacting the onset, development, and treatment of tumors. The proteins regulated by eIF3a are still being explored in vivo. In this study, a Cre-loxP system was used to generate eIF3a conditional knockout mice. Tandem mass tag (TMT) labeling with LC-MS/MS analysis was used to identify differentially expressed proteins (DEPs) in fat, lungs, skin, and spleen tissue of the eIF3a knockout mice and controls. Bioinformatics analysis was then used to explore the functions and molecular signaling pathways of these protein landscapes. It was observed that eIF3a is essential for life sustenance. Abnormal tissue pathology was found in the lungs, fat, skin, spleen, and thymus. In total, 588, 210, 324, and 944 DEPs were quantified in the lungs, fat, skin, and spleen, respectively, of the eIF3a knockout mice as compared to the control. The quantified differentially expressed proteins were tissue-specific, except for eight proteins shared by the four tissues. A broad range of functions for eIF3a, including cellular signaling pathway, immune response, metabolism, defense response, phagocytes, and DNA replication, has been revealed using bioinformatics analysis. Herein, several pathways related to oxidative stress in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, including nitrogen metabolism, peroxisome, cytochrome P450 drug metabolism, pyruvate metabolism, PPAR signaling pathway, phospholipase D signaling pathway, B-cell receptor signaling pathway, ferroptosis, and focal adhesion, have been identified. Collectively, this study shows that eIF3a is an essential gene for sustaining life, and its downstream proteins are involved in diverse novel functions beyond mRNA translational regulation.
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