- 1. Tanshinone I Activates the Nrf2-Dependent Antioxidant Response and Protects Against As(III)-Induced Lung Inflammation In Vitro and In Vivo.
Abstract Aims: The NF-E2 p45-related factor 2 (Nrf2) signaling pathway regulates the cellular antioxidant response and activation of Nrf2 has recently been shown to limit tissue damage from exposure to environmental toxicants, including As(III). In an attempt to identify improved molecular agents for systemic protection against environmental insults, we have focused on the identification of novel medicinal plant-derived Nrf2 activators. Results: Tanshinones [tanshinone I (T-I), tanshinone IIA, dihydrotanshinone, cryptotanshinone], phenanthrenequinone-based redox therapeutics derived from the medicinal herb Salvia miltiorrhiza, have been tested as experimental therapeutics for Nrf2-dependent cytoprotection. Using a dual luciferase reporter assay overexpressing wild-type or mutant Kelch-like ECH-associated protein-1 (Keap1), we demonstrate that T-I is a potent Keap1-C151-dependent Nrf2 activator that stabilizes Nrf2 by hindering its ubiquitination. In human bronchial epithelial cells exposed to As(III), T-I displays pronounced cytoprotective activity with upregulation of Nrf2-orchestrated gene expression. In Nrf2 wild-type mice, systemic administration of T-I attenuates As(III) induced inflammatory lung damage, a protective effect not observed in Nrf2 knockout mice. Innovation: Tanshinones have been identified as a novel class of Nrf2-inducers for antioxidant tissue protection in an in vivo As(III) inhalation model, that is relevant to low doses of environmental exposure. Conclusion: T-I represents a prototype Nrf2-activator that displays cytoprotective activity upon systemic administration targeting lung damage originating from environmental insults. T-I based Nrf2-directed systemic intervention may provide therapeutic benefit in protecting other organs against environmental insults. Antioxid. Redox Signal. 00, 000-000....(more)
Tao S, et al. Antioxid Redox Signal 2013 Mar 21.
Related Products: Tanshinone I
- 2. Tanshinones Inhibit Amyloid Aggregation by Amyloid-β Peptide, Disaggregate Amyloid Fibrils, and Protect Cultured Cells.
The misfolding and aggregation of amyloid-β (Aβ) peptides into amyloid fibrils is regarded as one of the causative events in the pathogenesis of Alzheimer's disease (AD). Tanshinones extracted from Chinese herb Danshen (Salvia Miltiorrhiza Bunge) were traditionally used as anti-inflammation and cerebrovascular drugs due to their antioxidation and antiacetylcholinesterase effects. A number of studies have suggested that tanshinones could protect neuronal cells. In this work, we examine the inhibitory activity of tanshinone I (TS1) and tanshinone IIA (TS2), the two major components in the Danshen herb, on the aggregation and toxicity of Aβ1-42 using atomic force microscopy (AFM), thioflavin-T (ThT) fluorescence assay, cell viability assay, and molecular dynamics (MD) simulations. AFM and ThT results show that both TS1 and TS2 exhibit different inhibitory abilities to prevent unseeded amyloid fibril formation and to disaggregate preformed amyloid fibrils, in which TS1 shows better inhibitory potency than TS2. Live/dead assay further confirms that introduction of a very small amount of tanshinones enables protection of cultured SH-SY5Y cells against Aβ-induced cell toxicity. Comparative MD simulation results reveal a general tanshinone binding mode to prevent Aβ peptide association, showing that both TS1 and TS2 preferentially bind to a hydrophobic β-sheet groove formed by the C-terminal residues of I31-M35 and M35-V39 and several aromatic residues. Meanwhile, the differences in binding distribution, residues, sites, population, and affinity between TS1-Aβ and TS2-Aβ systems also interpret different inhibitory effects on Aβ aggregation as observed by in vitro experiments. More importantly, due to nonspecific binding mode of tanshinones, it is expected that tanshinones would have a general inhibitory efficacy of a wide range of amyloid peptides. These findings suggest that tanshinones, particularly TS1 compound, offer promising lead compounds with dual protective role in anti-inflammation and antiaggregation for further development of Aβ inhibitors to prevent and disaggregate amyloid formation....(more)
Wang Q, et al. ACS Chem Neurosci 2013 Mar 29.
Related Products: Tanshinone I
- 3. Conical coils counter-current chromatography for preparative isolation and purification of tanshinones from Salvia miltiorrhiza Bunge.
Modern counter-current chromatography (CCC) originated from the helical coil planet centrifuge. Recently, spiral coils were found to possess higher separation efficiency in both the retention of stationary phase and solutes resolution than other CCC coils like the helical and toroidal coils used on type-J CCC and cross-axis CCC. In this work, we built a novel conical coil CCC for the preparative isolation and purification of tanshinones from Salvia miltiorrhiza Bunge. The conical coils were wound on three identical upright tapered holders in head-to-tail and left-handed direction and connected in series. Compared with helical and spiral coil CCC, conical coil CCC not only placed CCC column in a two-dimensional centrifugal field, but also provided a potential centrifugal force gradient both in axial and radial directions. The extra centrifugal gradient made mobile phase move faster and enabled CCC much higher retention of stationary phase and better resolution. As a result, higher efficiency has been obtained with the solvent system of hexane-ethyl acetate-methanol-water (HEMWat) with the volume ratio of 5:5:7:3 by using conical coil CCC apparatus. Four tanshinones, including cryptotanshinone (1), tanshinone I (2), 1,2-dihydrotanshinquinone (3) and tanshinone IIA (4), were well resolved from 500mg to 1g crude samples with high purity. Furthermore, the conical coil CCC can make a much higher solid phase retention, which makes it to be a powerful separation tool with high throughput. This is the first report about conical coil CCC for separation of tanshinones and it may also be an important advancement for natural products isolation....(more)
Liang J, et al. J Chromatogr A 2013 May 3;1288:35-9.
Related Products: Tanshinone I
- 4. PF2401-SF, standardized fraction of Salvia miltiorrhiza shows anti-inflammatory activity in macrophages and acute arthritis in vivo.
Standardization of processing methods for herbs is as important as authentication to maintain their quality and ensure their safe use. We had previously prepared a standardized and purified Salvia miltiorrhiza Bunge extract, PF2401-SF, and showed that it protects against liver injury in vivo, at a greater potency than an ethanol extract. PF2401-SF was enriched with tanshinone I (11.5%), tanshinone IIA (41.0%), and cryptotanshinone (19.1%). In this study, we investigated potential anti-inflammatory effects of PF2401-SF in vitro and in vivo. We demonstrated that PF2401-SF shows anti-inflammatory potency on lipopolysaccharide (LPS)-induced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells. A mechanistic study indicated that PF2401-SF induced heme oxygenase (HO)-1 expression through extracellular signal-regulated kinases (ERK1/2) phosphorylation. Moreover, we also evaluated that PF2401-SF significantly reduced inflammation on carrageenan- or dextran-induced acute arthritis in rats. Our results suggest that PF2401-SF may be a potential candidate for the treatment of various inflammatory diseases....(more)
Jiang WY, et al. Int Immunopharmacol 2013 Apr 10.
Related Products: Tanshinone I
- 5. Bioassay-guided isolation of fatty acid synthase inhibitory diterpenoids from the roots of Salvia miltiorrhiza Bunge.
Fatty acid synthase (FAS) is considered as a novel drug target for the development of anticancer and anti-obesity agents. Bioassay-guided fractionation of a n-hexane-soluble extract prepared from the roots of Salvia miltiorrhiza Bunge (Labiatae), using an in vitro enzyme assay, led to the isolation of five abietane diterpenoids: 15,16-dihydrotanshinone I (1), cryptotanshinone (2), tanshinone I (3), tanshinone IIA (4), and dansenspiroketallactone (5). Compounds 1-5 were tested for their in vitro FAS inhibitory activity and, except for compound 5 (IC(50) > 100 μM), compounds 1-4 inhibited the enzyme activity with IC(50) values ranging from 12.0 to 30.3 μM. Our findings may be partially related to the anticancer activity of abietane diterpenoids from the plant, suggesting a further study on the anticancer potential of tanshinone derivatives....(more)
Jang TS, et al. Arch Pharm Res 2012 Mar;35(3):481-6.
Related Products: Tanshinone I
- 6. Tanshinones inhibit the growth of breast cancer cells through epigenetic modification of Aurora A expression and function.
The objectives of this study were to evaluate the effects of tanshinones from a Chinese herb Salvia Miltiorrhiza on the growth of breast cancer cells, and to elucidate cellular and molecular mechanisms of action. Tanshinones showed the dose-dependent effect on the growth inhibition of breast cancer cells in vitro, with tanshinone I (T1) the most potent agent. T1 was also the only tanshinone to have potent activity in inhibiting the growth of the triple-negative breast cancer cell line MDA-MB231. T1 caused cell cycle arrests of both estrogen-dependent and estrogen-independent cell lines associated with alterations of cyclinD, CDK4 and cyclinB, and induced breast cancer cell apoptosis associated with upregulation of c-PARP and downregulation of survivin and Aurora A. Among these associated biomarkers, Aurora A showed the most consistent pattern with the anti-growth activity of tanshinones. Overexpression of Aurora A was also verified in breast tumors. The gene function assay showed that knockdown of Aurora A by siRNA dramatically reduced the growth-inhibition and apoptosis-induction activities of T1, suggesting Aurora A as an important functional target of T1 action. On the other hand, tanshinones had much less adverse effects on normal mammary epithelial cells. Epigenetic mechanism studies showed that overexpression of Aurora A gene in breast cancer cells was not regulated by gene promoter DNA methylation, but by histone acetylation. T1 treatment significantly reduced acetylation levels of histone H3 associated with Aurora A gene. Our results supported the potent activity of T1 in inhibiting the growth of breast cancer cells in vitro in part by downregulation of Aurora A gene function. Our previous studies also demonstrated that T1 had potent anti-angiogenesis activity and minimal side effects in vivo. Altogether, this study warrants further investigation to develop T1 as an effective and safe agent for the therapy and prevention of breast cancer....(more)
Gong Y, et al. PLoS One 2012;7(4):e33656.
Related Products: Tanshinone I
- 7. Growth-inhibitory and apoptosis-inducing effects of tanshinones on hematological malignancy cells and their structure-activity relationship.
This study has investigated the growth-inhibitory and apoptosis-inducing effects of dihydrotanshinone, tanshinone I, tanshinone IIA, and cryptotanshinone on hematological malignancy cell lines, aiming to explore their structure-activity relationship. The growth-inhibitory effects of the tanshinones on K562 and Raji cells were assessed using a modified MTT assay; the apoptosis-inducing effects were assessed by fluorescence microscopy and flow cytometry analysis. The changes in cellular morphology were observed using an inverted phase-contrast microscope. MTT results revealed that these tanshinones inhibited cell proliferation in a concentration-dependent and time-dependent manner. The IC50 values of dihydrotanshinone, tanshinone I, tanshinone IIA, and cryptotanshinone for K562 cells were 3.50, 13.52, 19.32, and 47.52 μmol/l at 24 h; 1.36, 4.70, 5.67, and 22.72 μmol/l at 48 h; and 1.15, 1.59, 2.82, and 19.53 μmol/l at 72 h, and the values for Raji cells were 3.30, 4.37, 12.92, and 52.36 μmol/l at 24 h; 1.55, 1.71, 6.54, and 25.45 μmol/l at 48 h; and 1.07, 1.38, 1.89, and 18.47 μmol/l at 72 h. The flow cytometry analysis demonstrated that these tanshinones induced apoptosis of K562 cells in a concentration-dependent manner, and dihydrotanshinone as well as tanshinone I were more potent than tanshinone IIA and cryptotanshinone. Some noticeable apoptotic morphologies could be observed by fluorescence microscopy on tanshinones-treated Raji cells. Collectively, these tanshinones caused growth inhibition and apoptosis in hematological malignancy cell lines, with dihydrotanshinone being the most potent, followed by tanshinone I, tanshinone IIA, and cryptotanshinone. These results suggested that the structure of aromatic ring A enhanced the cytotoxicity and the structure of ring C may have contributed to the cytotoxicity, but the mechanisms need to be further investigated....(more)
Li H, et al. Anticancer Drugs 2012 Sep;23(8):846-55.
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- 8. Molecular docking and enzyme kinetic studies of dihydrotanshinone on metabolism of a model CYP2D6 probe substrate in human liver microsomes.
The effects of Danshen and its active components (tanshinone I, tanshinone IIA, dihydrotanshinone and cryptotanshinone) on CYP2D6 activity was investigated by measuring the metabolism of a model CYP2D6 probe substrate, dextromethorphan to dextrorphan in human pooled liver microsomes. The ethanolic extract of crude Danshen (6.25-100 μg/ml) decreased dextromethorphan O-demethylation in vitro (IC(50)=23.3 μg/ml) and the water extract of crude Danshen (0.0625-1 mg/ml) showed no inhibition. A commercially available Danshen pill (31.25-500 μg/ml) also decreased CYP2D6 activity (IC(50)=265.8 μg/ml). Among the tanshinones, only dihydrotanshinone significantly inhibited CYP2D6 activity (IC(50)=35.4 μM), compared to quinidine, a specific CYP2D6 inhibitor (IC(50)=0.9 μM). Crytotanshinone, tanshinone I and tanshinone IIA produced weak inhibition, with IC(20) of 40.8 μM, 16.5 μM and 61.4 μM, respectively. Water soluble components such as salvianolic acid B and danshensu did not affect CYP2D6-mediated metabolism. Enzyme kinetics studies showed that inhibition of CYP2D6 activity by the ethanolic extract of crude Danshen and dihydrotanshinone was concentration-dependent, with K(i) values of 4.23 μg/ml and 2.53 μM, respectively, compared to quinidine, K(i)=0.41 μM. Molecular docking study confirmed that dihydrotanshinone and tanshinone I interacted with the Phe120 amino acid residue in the active cavity of CYP2D6 through Pi-Pi interaction, but did not interact with Glu216 and Asp301, the key residues for substrate binding. The logarithm of free binding energy of dihydrotanshinone (-7.6 kcal/mol) to Phe120 was comparable to quinidine (-7.0 kcal/mol) but greater than tanshinone I (-5.4 kcal/mol), indicating dihydrotanshinone has similar affinity to quinidine in binding to the catalytic site on CYP2D6....(more)
Zhou X, et al. Phytomedicine 2012 May 15;19(7):648-57.
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- 9. Activation of c-Jun N-terminal kinase mediates tanshinone IIA-induced apoptosis in KBM-5 chronic myeloid leukemia cells.
Aim of this study was to identify the molecular mechanisms of tanshinone IIA-induced apoptosis in chronic myelogenous leukemia (CML) cells. Cytotoxicity of tanshinone IIA was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Our data demonstrate that tanshinone IIA induced apoptosis by increasing the sub-G1 DNA contents and DNA fragmentation in KBM-5 CML cell line. In addition, tanshinone IIA significantly reduced mitochondrial membrane potential (MMP), mediated cytochrome c release from mitochondria and activated caspase-3 and 9, indicating mitochondria-dependent apoptosis by tanshinone IIA. Tanshinone IIA attenuated expression of several apoptosis-related proteins such as c-inhibitor of apoptosis protein (IAP) 2, Mcl-1(L) and Bcl-2. Interestingly, although tanshinone IIA notably enhanced the phosphorylation of both c-Jun N-terminal protein kinase (JNK) and p38, JNK inhibitor, but not p38 inhibitor, reversed tanshinone IIA-induced apoptosis. Our findings suggest that tanshinone IIA induces mitochondria-dependent apoptosis via activation of JNK in KBM 5 cells as a potent anti-cancer agent for CML therapy....(more)
Yun SM, et al. Biol Pharm Bull 2013;36(2):208-14.
Related Products: Tanshinone IIA
- 10. Tanshinone I Activates the Nrf2-Dependent Antioxidant Response and Protects Against As(III)-Induced Lung Inflammation In Vitro and In Vivo.
Abstract Aims: The NF-E2 p45-related factor 2 (Nrf2) signaling pathway regulates the cellular antioxidant response and activation of Nrf2 has recently been shown to limit tissue damage from exposure to environmental toxicants, including As(III). In an attempt to identify improved molecular agents for systemic protection against environmental insults, we have focused on the identification of novel medicinal plant-derived Nrf2 activators. Results: Tanshinones [tanshinone I (T-I), tanshinone IIA, dihydrotanshinone, cryptotanshinone], phenanthrenequinone-based redox therapeutics derived from the medicinal herb Salvia miltiorrhiza, have been tested as experimental therapeutics for Nrf2-dependent cytoprotection. Using a dual luciferase reporter assay overexpressing wild-type or mutant Kelch-like ECH-associated protein-1 (Keap1), we demonstrate that T-I is a potent Keap1-C151-dependent Nrf2 activator that stabilizes Nrf2 by hindering its ubiquitination. In human bronchial epithelial cells exposed to As(III), T-I displays pronounced cytoprotective activity with upregulation of Nrf2-orchestrated gene expression. In Nrf2 wild-type mice, systemic administration of T-I attenuates As(III) induced inflammatory lung damage, a protective effect not observed in Nrf2 knockout mice. Innovation: Tanshinones have been identified as a novel class of Nrf2-inducers for antioxidant tissue protection in an in vivo As(III) inhalation model, that is relevant to low doses of environmental exposure. Conclusion: T-I represents a prototype Nrf2-activator that displays cytoprotective activity upon systemic administration targeting lung damage originating from environmental insults. T-I based Nrf2-directed systemic intervention may provide therapeutic benefit in protecting other organs against environmental insults. Antioxid. Redox Signal. 00, 000-000....(more)
Tao S, et al. Antioxid Redox Signal 2013 Mar 21.
Related Products: Tanshinone IIA
- 11. Tanshinone IIA inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via Akt/Skp2/p27-associated pathway.
We previously showed that tanshinone IIA ameliorated the hypoxia-induced pulmonary hypertension (HPH) partially by attenuating pulmonary artery remodeling. The hypoxia-induced proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the major causes for pulmonary arterial remodeling, therefore the present study was performed to explore the effects and underlying mechanism of tanshinone IIA on the hypoxia-induced PASMCs proliferation. PASMCs were isolated from male Sprague-Dawley rats and cultured in normoxic (21%) or hypoxic (3%) condition. Cell proliferation was measured with 3 - (4, 5 - dimethylthiazal - 2 - yl) - 2, 5 - diphenyltetrazoliumbromide assay and cell counting. Cell cycle was measured with flow cytometry. The expression of of p27, Skp-2 and the phosphorylation of Akt were measured using western blot and/or RT-PCR respectively. The results showed that tanshinone IIA significantly inhibited the hypoxia-induced PASMCs proliferation in a concentration-dependent manner and arrested the cells in G1/G0-phase. Tanshinone IIA reversed the hypoxia-induced reduction of p27 protein, a cyclin-dependent kinase inhibitor, in PASMCs by slowing down its degradation. Knockdown of p27 with specific siRNA abolished the anti-proliferation of tanshinone IIA. Moreover, tanshinone IIA inhibited the hypoxia-induced increase of S-phase kinase-associated protein 2 (Skp2) and the phosphorylation of Akt, both of which are involved in the degradation of p27 protein. In vivo tanshinone IIA significantly upregulated the hypoxia-induced p27 protein reduction and downregulated the hypoxia-induced Skp2 increase in pulmonary arteries in HPH rats. Therefore, we propose that the inhibition of tanshinone IIA on hypoxia-induce PASMCs proliferation may be due to arresting the cells in G1/G0-phase by slowing down the hypoxia-induced degradation of p27 via Akt/Skp2-associated pathway. The novel information partially explained the anti-remodeling property of tanshinone IIA on pulmonary artery in HPH....(more)
Luo Y, et al. PLoS One 2013;8(2):e56774.
Related Products: Tanshinone IIA
- 12. IL-1β promotes corneal epithelial cell migration by increasing MMP-9 expression through NF-κB- and AP-1-dependent pathways.
Interleukin-1β (IL-1β) plays a critical mediator in the pathogenesis of eye diseases. The implication of IL-1β in inflammatory responses has been shown to be mediated through up-regulation of inflammatory genes, including matrix metalloproteinase-9 (MMP-9). However, the detailed mechanisms of IL-1β-induced MMP-9 expression in Statens Seruminstitut Rabbit Corneal Cells (SIRCs) are largely unclear. Here, we demonstrated that in SIRCs, IL-1β induced MMP-9 promoter activity and mRNA expression associated with an increase in the secretion of pro-MMP-9. IL-1β-induced pro-MMP-9 expression and MMP-9 mRNA levels were attenuated by pretreatment with the inhibitor of MEK1/2 (U0126), JNK1/2 (SP600125), NF-κB (Bay11-7082), or AP-1 (Tanshinone IIA) and transfection with siRNA of p42 or JNK2. Moreover, IL-1β markedly stimulated p42/p44 MAPK and JNK1/2 phosphorylation in SIRCs. In addition, IL-1β also enhanced p42/p44 MAPK translocation from the cytosol into the nucleus. On the other hand, IL-1β induced c-Jun and c-Fos mRNA expression, c-Jun phosphorylation, and AP-1 promoter activity. NF-κB translocation, IκBα degradation, and NF-κB promoter activity were also enhanced by IL-1β. Pretreatment with U0126 or SP600125 inhibited IL-1β-induced AP-1 and NF-κB promoter activity, but not NF-κB translocation from the cytosol into the nucleus. Finally, we established that IL-1β could stimulate SIRCs migration via p42/p44 MAPK-, JNK1/2-, AP-1-, and NF-κB-dependent MMP-9 induction. These results suggested that NF-κB and AP-1 activated by JNK1/2 and p42/p44 MAPK cascade are involved in IL-1β-induced MMP-9 expression in SIRCs....(more)
Tseng HC, et al. PLoS One 2013;8(3):e57955.
Related Products: Tanshinone IIA
- 13. Tanshinones Inhibit Amyloid Aggregation by Amyloid-β Peptide, Disaggregate Amyloid Fibrils, and Protect Cultured Cells.
The misfolding and aggregation of amyloid-β (Aβ) peptides into amyloid fibrils is regarded as one of the causative events in the pathogenesis of Alzheimer's disease (AD). Tanshinones extracted from Chinese herb Danshen (Salvia Miltiorrhiza Bunge) were traditionally used as anti-inflammation and cerebrovascular drugs due to their antioxidation and antiacetylcholinesterase effects. A number of studies have suggested that tanshinones could protect neuronal cells. In this work, we examine the inhibitory activity of tanshinone I (TS1) and tanshinone IIA (TS2), the two major components in the Danshen herb, on the aggregation and toxicity of Aβ1-42 using atomic force microscopy (AFM), thioflavin-T (ThT) fluorescence assay, cell viability assay, and molecular dynamics (MD) simulations. AFM and ThT results show that both TS1 and TS2 exhibit different inhibitory abilities to prevent unseeded amyloid fibril formation and to disaggregate preformed amyloid fibrils, in which TS1 shows better inhibitory potency than TS2. Live/dead assay further confirms that introduction of a very small amount of tanshinones enables protection of cultured SH-SY5Y cells against Aβ-induced cell toxicity. Comparative MD simulation results reveal a general tanshinone binding mode to prevent Aβ peptide association, showing that both TS1 and TS2 preferentially bind to a hydrophobic β-sheet groove formed by the C-terminal residues of I31-M35 and M35-V39 and several aromatic residues. Meanwhile, the differences in binding distribution, residues, sites, population, and affinity between TS1-Aβ and TS2-Aβ systems also interpret different inhibitory effects on Aβ aggregation as observed by in vitro experiments. More importantly, due to nonspecific binding mode of tanshinones, it is expected that tanshinones would have a general inhibitory efficacy of a wide range of amyloid peptides. These findings suggest that tanshinones, particularly TS1 compound, offer promising lead compounds with dual protective role in anti-inflammation and antiaggregation for further development of Aβ inhibitors to prevent and disaggregate amyloid formation....(more)
Wang Q, et al. ACS Chem Neurosci 2013 Mar 29.
Related Products: Tanshinone IIA
- 14. Akt mediates sodium tanshinone IIA silate inhibition of oxygen-glucose deprivation/reperfusion-induced myocardial cell apoptosis via suppression of the NF-κB/TNF-α pathway.
BACKGROUND AND PURPOSE:
Inhibition of apoptosis may attenuate irreversible injury associated with reperfusion. In the current study, we focused on the cardioprotective effects and the underlying mechanism of sodium tanshinone IIA silate (STS) against oxygen-glucose deprivation/reperfusion (OGD/R) damage in H9c2 cardiomyocytes and the underlying mechanisms.
EXPERIMENTAL APPROACH:
We investigated the cardioprotective effects of STS in a cellular oxygen glucose deprivation/recovery (OGD/R) model of ischemia/reperfusion. Apoptosis of cells was observed using Hoechst 33342-based fluorescence microscopy, and Annexin V-FITC based flow cytometry. Caspase-3 and caspase-8 activities and mitochondrial membrane potential (MMP) were assessed using commercial kits. TNF-α in the supernatant fractions were measured with sandwich ELISA, and protein levels assayed using Western blot.
KEY RESULTS:
STS inhibited OGD/R-induced apoptosis significantly by suppressing JNK mediated NF-κB activation, TNF-α expression, caspase-3 and caspase-8 activation; and the Bax/Bcl-2 ratio. Additionally, positive feedback between NF-κB and TNF-α and amplification of TNF-α were inhibited, suggesting that STS plays a protective role against apoptosis in cardiomyocytes, even upon activation of pro-inflammatory cytokines. Interestingly, the cardioprotective effects of STS on OGD/R-induced apoptosis and promotion of cell survival were attenuated upon inhibition of PI3K.
CONCLUSION AND IMPLICATIONS:
The inhibitory effects of STS on TNF-α and positive feedback signaling of the NF-κB/TNF-α pathways may play important roles in myocardial protection against ischemia/reperfusion. These protective effects of STS are mediated by suppressing JNK activity through activation of the PI3K-Akt pathway.
© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society....(more)
Wu WY, et al. Br J Pharmacol 2013 Mar 20.
Related Products: Tanshinone IIA
- 15. Qualitative and quantitative analysis of the major constituents in Chinese medicinal preparation Dan-Lou tablet by ultra high performance liquid chromatography/diode-array detector/quadrupole time-of-flight tandem mass spectrometry.
A rapid ultra high performance liquid chromatography/diode-array detector/quadrupole time-of-flight tandem mass spectrometry (UPLC-DAD-QTOF) method and a ultra high performance liquid chromatography coupled with diode-array detector (UPLC-DAD) method were developed for qualitative and quantitative analyses of the major chemical constituents in Dan-Lou tablet. Sixty-eight compounds including flavonoids, phenolic acids, tanshinones, protostane triterpenoids, lactones, and paeoniflorins were unambiguously or tentatively identified by comparing their retention times and accurate mass measurement in 40min with references or literature data. Among them, 19 compounds: gallic acid, danshensu, 5-hydroxymethyl-2-furaldehyde, 3'-hydroxy puerarin, puerarin, 3'-methoxy puerarin, mirificin, daidzin, paeoniflorin, calycosin-7-O-β-D-glucoside, naringin, genistin, rosmarinic acid, salvianolic acid B, salvianolic acid A, formononetin, calycosin, cryptotanshinone and tanshinone IIA were further quantified in 30min as marker substances. It was found that the calibration curves for all analytes showed good linearity (R(2)>0.9997) within the test ranges. The overall limits of detection (LODs) and limits of quantification (LOQs) were 0.0073-0.34μg/mL and 0.022-1.04μg/mL, respectively. The relative standard deviations (RSDs) for intra- and inter-day precisions were below 1.90% and 2.85%, respectively. The results of repeatability were less than 2.74%. The sample was stable for at least 48h. The mean recovery rates ranged from 95.5% to 105% with the relative standard deviations (RSDs) less than 2.96%. The results showed that the developed quantitative method was linear, sensitive, and precise for quality control of Dan-Lou tablet....(more)
Dong J, et al. J Pharm Biomed Anal 2013 Jun;80:50-62.
Related Products: Tanshinone IIA
- 16. Impurities preparation of sodium tanshinone IIA sulfonate by high-speed counter-current chromatography and identification by liquid chromatography/multistage tandem mass spectrometry.
Sodium Tanshinone IIA Sulfonate, the chemical modification product of Tanshinon IIA (STIIAS) is widely used in clinical treatment of angiocardiopathy, and the preparation of reference compounds of related substances for quality control is necessary. A method for separating three related substances from the bulk drug of STIIAS with high-speed counter-current chromatography (HSCCC) was developed. A solvent system composed of chloroform-n-butanol-methanol-water (17:0.3:14:9) was used and 0.5% saturated ammonium acetate aqueous solution was added to depress the emulsification in order to enhance sample loading capacity. Twelve related substances were identified in the bulk drug by HPLC-DAD and liquid chromatography/multistage tandem mass spectrometry (LC-MS(n)). Among them, three compounds were prepared and confirmed with (1)H NMR, one was identified without pretreatment, and seven components were identified after HSCCC enrichment since the contents of them were too low to be detected through direct LC-MS(n) injection. This research successfully broadened the application of HSCCC and introduced it to the field of impurities preparation of chemical medicine....(more)
Chen S, et al. J Chromatogr A 2013 May 3;1288:28-34.
Related Products: Tanshinone IIA
- 17. Tanshinone IIA and Cryptotanshinone Prevent Mitochondrial Dysfunction in Hypoxia-Induced H9c2 Cells: Association to Mitochondrial ROS, Intracellular Nitric Oxide, and Calcium Levels.
The protective actions of tanshinones on hypoxia-induced cell damages have been reported, although the mechanisms have not been fully elucidated. Given the importance of nitric oxide (NO) and reactive oxygen species (ROS) in regulation of cell functions, the present study investigated the effects of two major tanshinones, Tanshinone IIA (TIIA) and cryptotanshinone (CT), on hypoxia-induced myocardial cell injury and its relationships with intracellular NO and ROS, calcium, and ATP levels in H9c2 cells. Chronic hypoxia significantly reduced cell viability which accompanied with LDH release, increase in mitochondrial ROS, intracellular NO and calcium levels, decrease in superoxide dismutase (SOD) activity, and cellular ATP contents. TIIA and CT significantly prevented cell injury by increasing cell viability and decreasing LDH release. The protective effects of tanshinones were associated with reduced mitochondrial superoxide production and enhanced mitochondrial SOD activity. Tanshinones significantly reduced intracellular NO and Ca(2+) levels. ATP levels were also restored by TIIA. These findings suggest that the cytoprotective actions of tanshinones may involve regulation of intracellular NO, Ca(2+), ATP productions, mitochondrial superoxide production, and SOD activity, which contribute to their actions against hypoxia injuries....(more)
Jin HJ, et al. Evid Based Complement Alternat Med 2013;2013:610694.
Related Products: Tanshinone IIA
- 18. Tanshinone IIA reverses the malignant phenotype of SGC7901 gastric cancer cells.
BACKGROUNDS:
Tanshinone IIA (TIIA), a phenanthrenequinone derivative extracted from Salvia miltiorrhiza BUNGE, has been reported to be a natural anti-cancer agent in a variety of tumor cells. However, the effect of TIIA on gastric cancer cells remains unknown. In the present study, we investigated the influence of TIIA on the malignant phenotype of SGC7901 gastric cancer cells.
METHODS:
Cells cultured in vitro were treated with TIIA (0, 1, 5, 10 μg/ml) and after incubation for different periods, cell proliferation was measured by MTT method and cell apoptosis and cell cycling were assessed by flow cytometry (FCM). The sensitivity of SGC7901 gastric cancer cells to anticancer chemotherapy was investigated with the MTT method, while cell migration and invasion were examined by wound-healing and transwell assays, respectively.
RESULTS:
TIIA (1, 5, 10 μg/ml) exerted powerful inhibitory effects on cell proliferation (P < 0.05, and P < 0.01), and this effect was time- and dose-dependent. FCM results showed that TIIA induced apoptosis of SGC7901 cells, reduced the number of cells in S phase and increased those in G0/G1 phase. TIIA also significantly increased the sensitivity of SGC7901 gastric cancer cells to ADR and Fu. Moreover, wound-healing and transwell assays showed that TIIA markedly decreased migratory and invasive abilities of SGC7901 cells.
CONCLUSIONS:
TIIA can reverse the malignant phenotype of SGC7901 gastric cancer cells, indicating that it may be a promising therapeutic agent....(more)
Xu M, et al. Asian Pac J Cancer Prev 2013;14(1):173-7.
Related Products: Tanshinone IIA
- 19. Anti-tumor efficacy of chitosan-g-poly(ethylene glycol) nanocapsules containing docetaxel: anti-TMEFF-2 functionalized nanocapsules vs. non-functionalized nanocapsules.
The development and evaluation of PEGylated chitosan (CS) nanocapsules (NCs) conjugated to a monoclonal antibody anti-TMEFF-2 (CS-PEG-anti-TMEFF-2 mAb NCs) for targeted delivery of docetaxel (DCX) is presented. CS-PEG-Biotin NCs, displaying biotin tags at their surface, were obtained and efficiently functionalized with an anti-TMEFF-2 mAb through a convenient avidin-biotin approach. Cell cycle analysis after treatment with different DCX-loaded CS-PEG NC formulations indicated that the encapsulated drug remained fully active, showing a similar functional behavior to free DCX. In vivo efficacy studies using a non-small cell lung carcinoma xenograft revealed that CS-PEG-anti-TMEFF-2 NCs resulted as effective as free DCX (Taxotere®). Interestingly, differences on the pharmacodynamic behavior among the different DCX formulations were observed. Thus, while free DCX exhibited a fast and short effect on tumor volume reduction, CS-PEG-anti-TMEFF-2 mAb NCs showed a delayed and prolonged action, with no significant side effects of treatments....(more)
Torrecilla D, et al. Eur J Pharm Biopharm 2013 Apr;83(3):330-7.
Related Products: Taxotere
- 20. Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial.
Background In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes. Methods Patients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m(2)) × 4 →classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF); (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m(2)) × 4 →CMF; (iii) sequential docetaxel: A (75 mg/m(2)) × 3 → docetaxel (T) (100 mg/m(2)) × 3 → CMF and (iv) concurrent docetaxel: AT(50/75 mg/m(2)) × 4 →CMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes. Results Two thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80-1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67-0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72-0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65-0.98, P = 0.028) compared with concurrent doxorubicin-docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A; but this observation was not statistically supported because of limited numbers. Conclusion With further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin-docetaxel, and continued to show better DFS than sequential doxorubicin-based control....(more)
Oakman C, et al. Ann Oncol 2013 May;24(5):1203-11.
Related Products: Taxotere
- 21. Pluronic P105/F127 mixed micelles for the delivery of docetaxel against Taxol-resistant non-small cell lung cancer: optimization and in vitro, in vivo evaluation.
The aim of this work was to establish a novel polymeric mixed micelle composed of Pluronic P105 and F127 copolymers loaded with the poorly soluble antitumor drug docetaxel (DTX) against Taxol-resistant non-small cell lung cancer. A central composite design was utilized to optimize the preparation process, helping to improve drug solubilization efficiency and micelle stability. Prepared by a thin-film hydration method, the average size of the optimized mixed micelle was 23 nm, with a 92.40% encapsulation ratio and a 1.81% drug-loading efficiency. The optimized formulation showed high storage stability in lyophilized form, with 95.7% of the drug content remaining after 6 months' storage at 4°C. The in vitro cytotoxicity assay showed that the IC50 values for Taxotere(®) and mixed micelles were similar for A549, while on A549/Taxol cell lines, DTX-loaded P105/F127 mixed micelles showed a superior hypersensitizing effect; their IC50 value (0.059 μg/mL) was greatly reduced compared to those of Taxotere injections (0.593 μg/mL). The in vivo pharmacokinetic study showed that the mixed-micelle formulation achieved a 1.85-fold longer mean residence time in circulation and a 3.82-fold larger area under the plasma concentration-time curve than Taxotere. In addition, therapeutic improvement of mixed micelles in vivo against A549/Taxol was obtained. The tumor inhibition rate of the micelles was 69.05%, versus 34.43% for Taxotere (P < 0.01). Therefore, it could be concluded from the results that DTX-loaded P105/F127 mixed micelles might serve as a potential antitumor drug delivery system to overcome multidrug resistance in lung cancer....(more)
Chen L, et al. Int J Nanomedicine 2013;8:73-84.
Related Products: Taxotere
- 22. The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate.
The biodegradable polymer medium chain length polyhydroxyalkanoate (mclPHA), produced by Pseudomonas putida CA-3, was depolymerised and the predominant monomer (R)-3-hydroxydecanoic acid (R10) purified. R10 was conjugated to a d-peptide DP18 and its derivatives. All peptides conjugated with R10 exhibited greater anti-cancer activity compared to the unconjugated peptides. Unconjugated and conjugated peptides were cytocidal for cancer cells. Conjugation of R10 to peptides was essential for enhanced anti-proliferation activity, as unconjugated mixes did not result in enhancement of anti-cancer activity. The conjugation of R10 resulted in more rapid uptake of peptides into HeLa and MiaPaCa cells compared to unconjugated peptide. Both unconjugated and R10 conjugated peptides localized to the mitochondria of HeLa and MiaPaCa cells and induced apoptosis. Peptide conjugated with a terminally hydroxylated decanoic acid (ω-hydroxydecanoic acid) exhibited 3.3 and 6.3 fold higher IC(50) values compared to R10 conjugated peptide indicating a role for the position of the hydroxyl moiety in enhancement of anti-cancer activity. Conjugation of decanoic acid (C10) to peptides resulted in similar or higher IC(50) values compared to R10 conjugates but C10 conjugates did not exhibit any cancer selectivity. Combination studies showed that R10DP18L exhibited synergy with cisplatin, gemcitabine, and taxotere with IC(50) values in the nanomolar range....(more)
O'Connor S, et al. Biomaterials 2013 Apr;34(11):2710-8.
Related Products: Taxotere
- 23. Targeted co-delivery of docetaxel and siPlk1 by herceptin-conjugated vitamin E TPGS based immunomicelles.
We developed a drug delivery system of herceptin-conjugated micelles, which consist of vitamin E TPGS and TPGS-siRNA conjugates, for targeted co-delivery of docetaxel and polo-like kinase 1 siRNA to achieve synergistic effects between the anticancer drug and the small interfering RNA responsible for multidrug resistance. The TPGS-siRNA conjugate is made through disulfide bond that could enable a pH-sensitive intracellular release. The load ratio between siPlk1 and docetaxel could be controlled by adjusting the siPlk1-TPGS to TPGS ratio as well as the drug to polymer ratio. NIH3T3, MCF7, and SK-BR-3 cell lines, which are of low, moderate and high HER2 overexpression, were employed to obtain proof-of-concept experimental results for the advantages of such a design. It has been shown that the IC(50), which is the drug concentration needed to kill 50% of the cancer cells in a designated time period, was 1.72, 0.042, 0.0032 and 0.000671 μg/mL for SK-BR-3 cells after 24 h treatment by Taxotere(®), and docetaxel formulated in the TPGS micelles, the TPGS-siPlk1/TPGS micelles and the herceptin-conjugated TPGS-siPlk1/TPGS micelles, respectively....(more)
Zhao J, et al. Biomaterials 2013 Apr;34(13):3411-21.
Related Products: Taxotere
- 24. Targeted co-delivery of docetaxel, cisplatin and herceptin by vitamin E TPGS-cisplatin prodrug nanoparticles for multimodality treatment of cancer.
We developed a nanocarrier system of herceptin-conjugated nanoparticles of d-alpha-tocopheryl-co-poly(ethylene glycol) 1000 succinate (TPGS)-cisplatin prodrug (HTCP NPs) for targeted co-delivery of cisplatin, docetaxel and herceptin for multimodality treatment of breast cancer of high human epidermal growth factor receptor 2 (HER2) overexpression. Co-polymers poly(lactic acid)-TPGS (PLA-TPGS) and carboxyl group-terminated TPGS (TPGS-COOH) were also added in the polymeric matrix to stabilize the prodrug nanoparticles and to facilitate herceptin conjugation. The HTCP NPs of high, moderate and low docetaxel versus cisplatin ratio were prepared by the nanoprecipitation method, which showed a pH-sensitive release for both anticancer drugs. The therapeutic effects of HTCP NPs were evaluated in vitro and compared with Taxotere® and cisplatin. The HTCP NPs of high docetaxel versus cisplatin ratio were found to have better efficacy than those of moderate and low docetaxel versus cisplatin ratio. The targeting effects of the HTCP NPs were demonstrated by a much lower IC50 value of 0.0201+0.00780+0.1629μg/mL of docetaxel+cisplatin+herceptin for SK-BR-3 cells, which are of high HER2 overexpression, than that of 0.225+0.0875+1.827μg/mL for NIH3T3 cells, which are of low HER2 overexpression, after 24h incubation. The same design of TPGS prodrug nanoparticles can also be applied for targeted co-delivery of other hydrophilic and hydrophobic drugs....(more)
Mi Y, et al. J Control Release 2013 Feb 10.
Related Products: Taxotere
- 25. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma.
BACKGROUND:
PEP02 is a novel highly stable liposomal nanocarrier formulation of irinotecan. This randomized phase II study evaluated the efficacy and safety of single agent PEP02 compared with irinotecan or docetaxel in the second-line treatment of advanced oesophago-gastric (OG) cancer.
PATIENTS AND METHODS:
Patients with locally advanced/metastatic disease who had failed one prior chemotherapy regimen were randomly assigned to PEP02 120 mg/m<sup>2</sup>, irinotecan 300 mg/m<sup>2</sup> or docetaxel (Taxotere) 75 mg/m<sup>2</sup> every 3 weeks. The primary end point was objective response rate (ORR). Simon's two-stage design was used and the ORR of interest was 20% (α = 0.05, type II error β = 0.10, null hypothesis of ORR was 5%).
RESULTS:
Forty-four patients per arm received treatment, and 124 were assessable for response. The ORR statistical threshold for the first stage was reached in all arms. In the intent-to-treat (ITT) population, ORRs were 13.6% (6/44), 6.8% (3/44) and 15.9% (7/44) in the PEP02, irinotecan and docetaxel arms, respectively. The median progression-free survival (PFS) and overall survival were similar between the trial arms. Commonest grade 3-4 adverse event reported was diarrhoea in the PEP02 and irinotecan groups (27.3% versus 18.2%).
CONCLUSION:
The ORR associated with PEP02 was comparable with docetaxel and numerically greater than that of irinotecan. PEP02 warrants further evaluation in the advanced gastric cancer setting....(more)
Roy AC, et al. Ann Oncol 2013 Feb 13.
Related Products: Taxotere
- 26. Visualization of Mitotic Arrest of Cell Cycle with Bioluminescence Imaging in Living Animals.
PURPOSE:
Visualization of the cell cycle in living subjects has long been a big challenge. The present study aimed to noninvasively visualize mitotic arrest of the cell cycle with an optical reporter in living subjects.
PROCEDURES:
An N-terminal cyclin B1-luciferase fusion construct (cyclin B-Luc) controlled by the cyclin B promoter, as a mitosis reporter, was generated. HeLa or HCT116 cells stably expressing cyclin B-Luc reporter were used to evaluate its cell cycle-dependent regulation and ubiquitination-mediated degradation. We also evaluated its feasibility to monitor the mitotic arrest caused by Taxotere both in vitro and in vivo.
RESULTS:
We showed that the cyclin B-Luc fusion protein was regulated in a cell cycle-dependent manner and accumulated in the mitotic phase (M phase) in cellular assays. The regulation of cyclin B-Luc reporter was mediated by proteasome ubiquitination. In the present study, in vitro imaging showed that antimitotic reagents like Taxotere upregulated the reporter through cell cycle arrest in the M phase. Noninvasive longitudinal bioluminescence imaging further demonstrated an upregulation of the reporter consistent with mitotic arrest induced in tumor xenograft models. Induction of this reporter was also observed with a kinesin spindle protein inhibitor, which causes cell cycle blockage in the M phase.
CONCLUSIONS:
Our results demonstrate that the cyclin B-Luc reporter can be used to image whether compounds are capable, in vivo, of causing an M phase arrest and/or altering cyclin B turnover. This reporter can also be potentially used in high-throughput screening efforts aimed at discovering novel molecules that will cause cell cycle arrest at the M phase in cultivated cell lines and animal models....(more)
Zhang GJ, et al. Mol Imaging Biol 2013 Feb 26.
Related Products: Taxotere
- 27. Chemotherapeutic drug delivery to cancer cells using a combination of folate targeting and tumor microenvironment-sensitive polypeptides.
Chemotherapeutic agents often cause severe side effects because they produce a similar cytotoxicity in both cancerous and healthy cells. In this study, a rational strategy was implemented to take advantage of a combination of both tumor microenvironment-sensitive polypeptides (TMSP) and folate to create a more selective and efficient drug delivery system to target cancer cells. TMSP and folate were conjugated to the distal ends of DSPE-PEG2000-maleimide and DSPE-PEG5000-amine to create DSPE-PEG2000-TMSP and DSPE-PEG5000-folate, respectively, which were incorporated onto the surface of a docetaxel-loaded nanostructured lipid carrier (F/TMSP-DTX-NLC). TMSP are comprised of polycationic cell-penetrating peptides (CPP) and polyanionic inhibitory peptides, which are coupled via a proteinase-sensitive cleavable linker. The linker can be cleaved in the presence of matrix metalloprotease-2 and -9 (MMP-2/9). TMSP provides the ability to enhance specific cancer cellular uptake after selectively unmasking polyanionic inhibitory peptides in MMP-2/9 protease-oversecretion tumor tissue, whereas in circulation, the penetration is shielded. The folate moiety binds selectively to folate receptor-positive tumors. The cleaved dual-modified nanocarriers are then taken up by the tumor cells via both receptor-mediated endocytosis and CPP penetrating action to overcome the higher interstitial pressure in the tumor. The nanocarrier system demonstrated a small size, high encapsulation efficiency (>95%), sustained release and targeted delivery. The strong cellular uptake and cytotoxic activity of dual-modified F/TMSP-DTX-NLC in KB, HT-1080, MCF-7 and A549 cells verified the correlation with folate receptor expression and MMP-2/9 secretion. The remarkable penetration into KB and HT-1080 multicellular tumor spheroids confirmed that the temporary mask of the polyanionic inhibitory peptide in TMSP does not disturb the penetration ability of CPP in the tumor microenvironment with abundant proteases. Furthermore, the active targeting and triggered activation exhibited higher antitumor efficacy and lower systemic toxicity with the KB tumor model in nude mice compared to the nonmodified DTX-NLC and Taxotere(®). These results suggested that the application of combined TMSP and folate modifications may be an approach in the selectively targeted delivery of anticancer drugs with low systemic toxicity....(more)
Gao W, et al. Biomaterials 2013 May;34(16):4137-49.
Related Products: Taxotere
- 28. Ulinastatin exerts synergistic effects with taxotere and inhibits invasion and metastasis of breast cancer by blocking angiogenesis and the epithelial-mesenchymal transition.
Abstract Urinary trypsin inhibitor (UTI) ulinastatin as a broad-spectrum protease inhibitor has been widely used to treat acute pancreatitis and shock and to improve the surgical outcome in the clinic. In the present study, we investigated the potential antihuman breast cancer effects of UTI and its combination with taxotere (TXT). Human primary breast cancer cells and breast cancer cell line MDA-MB-231 cells were treated with UTI with or without TXT, and invasion and metastasis ability of these cells were evaluated, respectively, by a transwell assay. Reverse transcription-polymerase chain reaction was used to detect fibroblast growth factor, vascular endothelial growth factor c, epidermal growth factor, epidermal growth factor receptor, transforming growth factor-β1, and protein kinase B/AKT. We also investigated the in vivo role of UTI by using a xenograft mouse model, and immunohistochemical assay was employed to show the expression of factors involved in either angiogenesis or the epithelial-mesenchymal transition (EMT). Our results showed that UTI inhibited invasion and metastasis in both primary and MDA-MB-231 cells both in vivo and in vitro. Especially, UTI presented the significant combined effects with TXT on these cells in terms of angiogenesis blocking and EMT inhibition. These results suggest that UTI and its combination with TXT present therapeutic potential against breast cancer and deserve further preclinical and clinical studies....(more)
Gao F, et al. Cancer Biother Radiopharm 2013 Apr;28(3):218-25.
Related Products: Taxotere
- 29. Sciadopitysin: active component from Taxus chinensis for anti-Alzheimer's disease.
Five taxane diterpenoids derived from the 95% ethanol extract of Taxus chinensis were tested for the inhibitory activities on amyloid-beta (Aβ) peptide aggregation. Using thioflavin-T fluorescence assay, sciadopitysin was found to exhibit the most potency against Aβ aggregation and the formation of fibrils. Further cellular assay indicated that sciadopitysin increased the cell viability of SH-SY5Y cell and demonstrated neuroprotection against Aβ protein-induced insult in primary cortical neurons. According to the authors' best knowledge, this is the first report that sciadopitysin can inhibit the Aβ aggregation and reduce Aβ-induced toxicity in the primary cortical neurons....(more)
Gu Q, et al. Nat Prod Res 2013 Apr 29.
Related Products: Taxus Chinensis Extract
- 30. Indole-3-Acetic Acid Production by Endophytic Streptomyces sp. En-1 Isolated from Medicinal Plants.
Plant-associated actinobacteria are rich sources of bioactive compounds including indole-derived molecules such as phytohormone indole-3-acetic acid (IAA). In view of few investigations concerning the biosynthesis of IAA by endophytic actinobacteria, this study evaluated the potential of IAA production in endophytic streptomycete isolates sourced from medicinal plant species Taxus chinensis and Artemisia annua. By HPLC analysis of IAA combined with molecular screening approach of iaaM, a genetic determinant of streptomycete IAA synthesis via indole-3-acetamide (IAM), our data showed the putative operation of IAM-mediated IAA biosynthesis in Streptomyces sp. En-1 endophytic to Taxus chinensis. Furthermore, using the co-cultivation system of model plant Arabidopsis thaliana and streptomycete, En-1 was found to be colonized intercellularly in the tissues of Arabidopsis, an alternative host, and the effects of endophytic En-1 inoculation on the model plant were also assayed. The phytostimulatory effects of En-1 inoculation suggest that IAA-producing Streptomyces sp. En-1 of endophytic origin could be a promising candidate for utilization in growth improvement of plants of economic and agricultural value....(more)
Lin L, et al. Curr Microbiol 2013 Mar 20.
Related Products: Taxus Chinensis Extract
- 31. Geographic and tissue influences on endophytic fungal communities of Taxus chinensis var. mairei in China.
Endophytc fungi were collected from the barks, branches and leaves of Taxus chinensis var. mairei from the Jiangxi, Zhejiang and Chongqing regions of China and their influences on geographic and tissue investigated. A total of 145 fungal taxa were identified based on molecular techniques, of these 125 taxa (86.2 %) belonging to Ascomycota, 14 (9.7 %) to Basidiomycota, 5 (3.4 %) to Zygomycota, and 1 (0.7 %) to undefined fungi. The species richness and diversity of endophytic fungi were significantly affected by tissue, and were 1.2-2.5-fold higher in the branches and barks when compared to the leaves. The locality affected the species richness per tree and the shannon diversity index per tree by longitude. The endophyte assemblages were strongly shaped by locality and tissue according to partial least squares discriminant analysis. In addition, the distributions of dominant fungi at orders and genera levels differed as a function of locality and tissue. Most of the dominant taxa showed spatial heterogeneity and tissue specificity or preference and many fungal taxa with low frequency were special to one locality or one tissue....(more)
Wu L, et al. Curr Microbiol 2013 Jan;66(1):40-8.
Related Products: Taxus Chinensis Extract
- 32. Functional analysis of a WRKY transcription factor involved in transcriptional activation of the DBAT gene in Taxus chinensis.
Although the regulation of taxol biosynthesis at the transcriptional level remains unclear, 10-deacetylbaccatin III-10 β-O-acetyl transferase (DBAT) is a critical enzyme in the biosynthesis of taxol. The 1740 bp fragment 5'-flanking sequence of the dbat gene was cloned from Taxus chinensis cells. Important regulatory elements needed for activity of the dbat promoter were located by deletion analyses in T. chinensis cells. A novel WRKY transcription factor, TcWRKY1, was isolated with the yeast one-hybrid system from a T. chinensis cell cDNA library using the important regulatory elements as bait. The gene expression of TcWRKY1 in T. chinensis suspension cells was specifically induced by methyl jasmonate (MeJA). Biochemical analysis indicated that TcWRKY1 protein specifically interacts with the two W-box (TGAC) cis-elements among the important regulatory elements. Overexpression of TcWRKY1 enhanced dbat expression in T. chinensis suspension cells, and RNA interference (RNAi) reduced the level of transcripts of dbat. These results suggest that TcWRKY1 participates in regulation of taxol biosynthesis in T. chinensis cells, and that dbat is a target gene of this transcription factor. This research also provides a potential candidate gene for engineering increased taxol accumulation in Taxus cell cultures.
© 2012 German Botanical Society and The Royal Botanical Society of the Netherlands....(more)
Li S, et al. Plant Biol (Stuttg) 2013 Jan;15(1):19-26.
Related Products: Taxus Chinensis Extract
- 33. Cytotoxic metabolites from Perenniporia tephropora, an endophytic fungus from Taxus chinensis var. mairei.
Based on bioactivity-oriented isolation, the EtOAc extract of a culture broth of the endophytic fungus Perenniporia tephropora Z41 from Taxus chinensis var. mairei, with strong anti-Pyricularia oryzae activity, afforded a new sesquiterpenoid, perenniporin A (1), together with three known compounds, ergosterol (2), rel-(+)-(2aR,5R,5aR,8S,8aS,8bR)-decahydro-2,2,5,8-tetramethyl-2H-naphtho[1,8-bc]genfuran-5-ol (3), and albicanol (4). Their structures were elucidated by means of spectroscopic methods. All the isolated compounds and the EtOAc extract of P. tephropora Z41 (EPT) were evaluated for their cytotoxic activity against three human cancer cell lines (HeLa, SMMC-7721, and PANC-1). EPT demonstrated significant cytotoxicity with IC(50) values ranging from 2 to 15 μg/mL. Compound 2 was the most cytotoxic constituent against the tested cell lines with IC(50) values of 1.16, 11.63, and 11.80 μg/mL, respectively, while compounds 1, 3, and 4 exhibited moderate cytotoxicity with IC(50) values ranging from 6 to 58 μg/mL. We conclude that the endophytic fungus P. tephropora is a promising source of novel and cytotoxic metabolites....(more)
Wu LS, et al. Appl Microbiol Biotechnol 2013 Jan;97(1):305-15.
Related Products: Taxus Chinensis Extract
- 34. [Content and distribution of active components in cultivated and wild Taxus chinensis var. mairei plants].
Taxus chinensis var. mairei is an endemic and endangered plant species in China. The resources of T. chinensis var. mairei have been excessively exploited due to its anti-cancer potential, accordingly, the extant T. chinensis var. mairei population is decreasing. In this paper, ultrasonic extraction and HPLC were adopted to determine the contents of active components paclitaxel, 7-xylosyltaxol and cephalomannine in cultivated and wild T. chinensis var. mairei plants, with the content distribution of these components in different parts of the plants having grown for different years and at different slope aspects investigated. There existed obvious differences in the contents of these active components between cultivated and wild T. chinensis var. mairei plants. The paclitaxel content in the wild plants was about 0.78 times more than that in the cultivated plants, whereas the 7-xylosyltaxol and cephalomannine contents were slishtly higher in the cultivated plants. The differences in the three active components contents between different parts and tree canopies of the plants were notable, being higher in barks and upper tree canopies. Four-year old plants had comparatively higher contents of paclitaxel, 7-xylosyltaxol and cephalomannine (0.08, 0.91 and 0.32 mg x g(-1), respectively), and the plants growing at sunny slope had higher contents of the three active components, with significant differences in the paclitaxel and 7-xylosyltaxol contents and unapparent difference in the cephalomannine content of the plants at shady slope. It was suggested that the accumulation of the three active components in T. chinensis var. mairei plants were closely related to the sunshine conditions. To appropriately increase the sunshine during the artificial cultivation of T. chinensis var. mairei would be beneficial to the accumulation of the three active components in T. chinensis var. mairei plants....(more)
Yu SS, et al. Ying Yong Sheng Tai Xue Bao 2012 Oct;23(10):2641-7. Chinese.
Related Products: Taxus Chinensis Extract
- 35. Transcriptional profile of Taxus chinensis cells in response to methyl jasmonate.
BACKGROUND:
Methyl jasmonate (MeJA) has been successfully used as an effective elicitor to enhance production of taxol and other taxanes in cultured Taxus cells. However the mechanism of MeJA-mediated taxane biosynthesis remains unclear. Genomic information for species in the genus Taxus is currently unavailable. Therefore, information about the transcriptome of Taxus cells and specifically, description of changes in gene expression in response to MeJA, is needed for the better exploration of the biological mechanisms of MeJA-mediated taxane biosynthesis.
RESULTS:
In this research, the transcriptome profiles of T. chinensis cells at 16 hours (T16) after MeJA treatment and of mock-treated cells (T0) were analyzed by "RNA-seq" to investigate the transcriptional alterations of Taxus cell in response to MeJA elicitation. More than 58 million reads (200 bp in length) of cDNA from both samples were generated, and 46,581 unigenes were found. There were 13,469 genes found to be expressed differentially between the two timepoints, including all of the known jasmonate (JA) biosynthesis/JA signaling pathway genes and taxol-related genes. The qRT-PCR results showed that the expression profiles of 12 randomly selected DEGs and 10 taxol biosynthesis genes were found to be consistent with the RNA-Seq data. MeJA appeared to stimulate a large number of genes involved in several relevant functional categories, such as plant hormone biosynthesis and phenylpropanoid biosynthesis. Additionally, many genes encoding transcription factors were shown to respond to MeJA elicitation.
CONCLUSIONS:
The results of a transcriptome analysis suggest that exogenous application of MeJA could induce JA biosynthesis/JA signaling pathway/defence responses, activate a series of transcription factors, as well as increase expression of genes in the terpenoid biosynthesis pathway responsible for taxol synthesis. This comprehensive description of gene expression information could greatly facilitate our understanding of the molecular mechanisms of MeJA-mediated taxane biosynthesis in Taxus cells....(more)
Li ST, et al. BMC Genomics 2012 Jul 2;13:295.
Related Products: Taxus Chinensis Extract