Magnolol (MG) and honokiol (HK), two lignans showing anti-inflammatory and anti-oxidant properties and abundantly available in the medicinal plants
Magnolia officinalis and
M. obovata, were found to ...enhance HL-60 cell differentiation initiated by low doses of 1,25-dihydroxyvitamin D
3 (VD
3) and all-
trans-retinoic acid (ATRA). Cells expressing membrane differentiation markers CD11b and CD14 were increased from 4% in non-treated control to 8–16% after being treated with 10–30
μM MG or HK. When added to 1
nM VD
3, MG or HK increased markers expressing cells from approximately 30% to 50–80%. When either MG or HK was added to 20
nM ATRA, only CD11b, but not CD14, expressing cells were increased from 9% to 24–70%. Under the same conditions, adding MG or HK to VD
3 or ATRA treatment further enlarged the G
0/G
1 cell population and increased the expression of p27
Kip1, a cyclin-dependent kinase inhibitor. Pharmacological studies using PD098059 (a MEK inhibitor), SB203580 (a p38 MAPK inhibitor) and SP600125 (a JNK inhibitor) suggested that the MEK pathway was important for VD
3 and ATRA-induced differentiation and also its enhancement by MG or HK, the p38 MAPK pathway had a inhibitory effect and the JNK pathway had little influence. It is evident that MG and HK are potential differentiation enhancing agents which may allow the use of low doses of VD
3 and ATRA in the treatment for acute promyelocytic leukemia.
Despite advances in technology, drug discovery is still a lengthy, expensive, difficult, and inefficient process, with a low rate of success. Today, advances in biomedical science have brought about ...great strides in therapeutic interventions for a wide spectrum of diseases. The advent of biochemical techniques and cutting-edge bio/chemical technologies has made available a plethora of practical approaches to drug screening and design. In 2010, the total sales of the global pharmaceutical market will reach 600 billion US dollars and expand to over 975 billion dollars by 2013. The aim of this review is to summarize available information on contemporary approaches and strategies in the discovery of novel therapeutic agents, especially from the complementary and alternative medicines, including natural products and traditional remedies such as Chinese herbal medicine.
Over recent decades, sulfur fumigation is becoming abused in processing some freshly harvested herbs used as both medicine and food, although it has been questioned whether sulfur fumigation will ...change the efficacy and safety of the herbs. One of the herbs commonly processed by sulfur fumigation is Platycodonis Radix (Jiegeng in Chinese). Glycosides are the main bioactive components of Jiegeng. Up to the present, no study has been carried out to evaluate the impact of sulfur fumigation on glycoside profile of Jiegeng.
A rapid and versatile ultra-high performance liquid chromatography coupled with ultra-high resolution quadrupole time-of-flight mass spectrometry (UHPLC UHD Q-TOF MS/MS) method was developed for comprehensive analysis of the glycoside profiles of sulfur-fumigated and air-dried Jiegeng samples.
Twenty-three glycosides were detected in air-dried and sulfur-fumigated Jiegeng samples. After sulfur fumigation, the peak heights of eight glycosides, namely platycogenin A, platycodin D, platycodin D2, platycodin D3, polygalacin D, polygalacin D2, deapio-platycodin D and 3″-O-acetylplatycodin D2, remarkably decreased; while peak heights of five glycosides, namely syringin, lobetyolin, platycoside E, deapio-platycodin D2 and deapio-platycoside E, slightly increased; in addition, peaks of ten glycosides, platycodin A, platycodin C, platycodin V, platycoside C, 16-oxoplatycodin D, 2″-O-acetylpolygalacin D, 2″-O-acetylpolygalacin D2, 3″-O-acetylpolygalacin D, 3″-O-acetylpolygalacin D2, and platycogenic acid B, disappeared.
Sulfur fumigation caused significant changes of glycoside components of Jiegeng. Further investigations are warranted to explore how these chemical changes occurred and whether these changes would affect the efficacy and safety of Jiegeng.
Six new protopanaxadiol‐type ginsenosides, named ginsenosides Ra4–Ra9 (1–6, resp.), along with 14 known dammarane‐type triterpene saponins, were isolated from the root of Panax ginseng, one of the ...most important Chinese medicinal herbs. The structures of the new compounds were determined by spectroscopic methods, including 1D‐ and 2D‐NMR, HR‐MS, and chemical transformation as (20S)‐ 3‐O‐{β‐D‐6‐O‐(E)‐but‐2‐enoylglucopyranosyl‐(1→2)‐β‐D‐glucopyranosyl}‐20‐O‐β‐D‐xylopyranosyl‐(1→4)‐α‐L‐arabinopyranosyl‐(1→6)‐β‐D‐glucopyranosylprotopanaxadiol (1), (20S)‐3‐O‐β‐D‐6‐O‐acetylglucopyranosyl‐(1→2)‐β‐D‐glucopyranosyl‐20‐O‐β‐D‐xylopyranosyl‐(1→4)‐α‐L‐arabinopyranosyl‐(1→6)‐β‐D‐glucopyranosylprotopanaxadiol (2), (20S)‐3‐O‐{β‐D‐6‐O‐(E)‐but‐2‐enoylglucopyranosyl‐(1→2)‐β‐D‐glucopyranosyl}‐20‐O‐β‐D‐glucopyranosyl‐(1→6)‐β‐D‐glucopyranosylprotopanaxadiol (3), (20S)‐3‐O‐{β‐D‐6‐O‐(E)‐but‐2‐enoylglucopyranosyl‐(1→2)‐β‐D‐glucopyranosyl}‐20‐O‐α‐L‐arabinopyranosyl‐(1→6)‐β‐D‐glucopyranosylprotopanaxadiol (4), (20S)‐3‐O‐{β‐D‐4‐O‐(E)‐but‐2‐enoylglucopyranosyl‐(1→2)‐β‐D‐glucopyranosyl}‐20‐O‐α‐L‐arabinofuranosyl‐(1→6)‐β‐D‐glucopyranosylprotopanaxadiol (5), (20S)‐3‐O‐{β‐D‐6‐O‐(E)‐but‐2‐enoylglucopyranosyl‐(1→2)‐β‐D‐glucopyranosyl}‐20‐O‐α‐L‐arabinofuranosyl‐(1→6)‐β‐D‐glucopyranosylprotopanaxadiol (6). The sugar moiety at C(3) of the aglycone of each new ginsenoside is butenoylated or acetylated.
Purpose
Overexpression of EGFR and HER2 is seen in breast cancers and results in poor prognosis and decreased patient survival. Clinically, EGFR and HER2 are effective therapeutic targets. The ...objective of this study is to investigate the in vitro effects of furanodienone, an active chemical component isolated from Rhizoma Curcumae, on the activation of EGFR/HER2 signaling, cell cycle, and apoptosis in HER2-overexpressing BT474 and SKBR3 cells.
Methods
Cell growth was assessed by SRB protein assay. Cell cycle analysis was carried out by flow cytometry, and apoptosis was observed by Annexin V and DAPI staining. Effects of furanodienone on the activation of EGFR/HER2 signaling-related proteins were analyzed by western blotting.
Results
Furanodienone inhibited cell growth in BT474 and SKBR3 cells. Furanodienone caused G1 arrest in BT474 cells and induced apoptosis in SKBR3 cells. Furanodienone interfered with EGFR/HER2 signaling in treated cells as shown by decreases in phosphorylated EGFR, HER2, Akt, Gsk3β and an increase in p27
kip1
protein. Accordingly, furanodienone inhibited EGF-induced phosphorylation of EGFR, HER2, Akt, and Gsk3β. EGFR-specific siRNA knockdown did not affect the cell growth inhibitory effect of furanodienone. On the contrary, specific siRNA knockdown of HER2 increased cellular resistance to furanodienone toxicity. In HER-2-deficient MDA-MB-231 cells, the transfection and expression of HER2 increased the sensitivity of cells to furanodienone toxicity.
Conclusion
Furanodienone inhibited EGFR/HER2 signaling pathway in BT474 and SKBR3 cells. More importantly, the effect of furanodienone was specifically dependent on HER2, but not EGFR, expression.
Stereoselective Biotransformation of Timosaponin A-Ⅲ by Saccharomyces cerevisiae Hu, Yong-Mei, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Yu, Zhi-Ling, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Fong, Wang-Fun, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
Journal of microbiology and biotechnology,
06/2011, Letnik:
21, Številka:
6
Journal Article
Recenzirano
Bioconversion of timosaponin A-Ⅲ (TA-Ⅲ), one of the major steroidal saponins isolated from the rhizomes of Anemarrhenae asphodeloides Bunge (Liliaceae), was investigated in Saccharomyces cerevisiae. ...Five bioconversion products, denoted compounds 2-6, were obtained. Biotransformation metabolite 2 was a stereoisomer of TA-Ⅲ with a specific isotype F-ring and β-ranged CH₃-21, which rarely occurs in nature. The structure of 2 was elucidated by extensive spectroscopic analysis (H-H COSY, HSQC, HMBC), as well as by high-resolution mass spectral analysis. The growth inhibitory activity of compounds 1-6 was assayed against four human cancer cell lines, HepG2, H-1299, HT-29, and HCT-116. Compounds 1 and 2 obviously inhibited the growth of the four types of cancer cells with IC∧50 values being less than 19 μM. A structure-activity relationship is discussed, and the spirostane-ring F in compounds 1 and 2 appears to be the critical bioactive moiety for the cell growth inhibitory property.
The overexpression of P-glycoprotein (Pgp), an ATP-driven membrane exporter of hydrophobic xenobiotics, is one of the major causes of multidrug resistance (MDR) in cancer cells. Through extensive ...screening we have found that the extracts of
Peucedanum praeruptorum Dunn. and one of the major components (±)-praeruptorin A (PA) may reverse Pgp-mediated multidrug resistance. Studies on novel PA derivatives have shown that (±)-3′-
O,4′-
O-dicinnamoyl-
cis-khellactone (DCK) is more active than PA or verapamil and is a non-competitive inhibitor of Pgp. Here, we report that methoxylation of the cinnamoyl groups on DCK may further enhance its bioactivity. The structure–activity relationship is demonstrated by comparing two new pyranocoumarins (±)-3′-
O,4′-
O-bis(3,4-dimethoxycinnamoyl)-
cis-khellactone (DMDCK) and (±)-3′-
O,4′-
O-bis(4-methoxycinnamoyl)-
cis-khellactone (MMDCK). While the co-existence of 3- and 4-methoxy groups on cinnamoyl remarkably enhanced the Pgp-inhibitory activity, the lone existence of the 4-methoxy group on cinnamoyl reduced the activity. Contrary to DCK, DMDCK promoted the binding of UIC2 antibody to Pgp which signifies a conformational change of Pgp similar to that induced by transport substrates. While DCK moderately stimulated the basal Pgp-ATPase activity, DMDCK inhibited the activity. A pharmacophore search with verapamil-based template revealed that four functional groups of DMDCK could be simultaneously involved in interaction with Pgp whereas for DCK or MMDCK only three groups were involved. It is speculated that the additional 3-methoxy group on cinnamoyl allows DMDCK to interact more efficiently with Pgp substrate site(s). If DMDCK was tightly bind to Pgp substrate site(s) the complexes could be inactive with regard to transportation and ATP hydrolysis could also be inhibited.
Tumorigenesis involves constant communication between tumor cells and neighboring normal cells such as adipocytes. The canonical function of adipocytes is to store triglyceride and release fatty ...acids for other tissues. This study was aimed to find out if adipocytes promoted melanoma cell growth and to investigate the underlying mechanism. Here we isolated adipocytes from inguinal adipose tissue in mice and co-cultured with melanoma cells. We found that the co-cultured melanoma had higher lipid accumulation compared with mono-cultured melanoma. In addition, fluorescently labeled fatty acid BODIPY® FLC16 signal was detected in melanoma co-cultured with the adipocytes that had been loaded with the fluorescent dye, suggesting that the adipocytes provide fatty acids to melanoma cells. Compared with mono-cultured melanoma, co-cultured melanoma cells had a higher proliferation and phospho-Akt (Ser-473 and Thr-450) expression. Overexpression of Akt mutants in melanoma cells reduced the co-culture-enhanced proliferation. A lipidomic study showed that the co-cultured melanoma had an elevated palmitic acid level. Interestingly, we found that palmitic acid stimulated melanoma cell proliferation, changed the cell cycle distribution, and increased phospho-Akt (Ser-473 and Thr-450) and PI3K but not phospho-PTEN (phosphophosphatase and tensin homolog) expressions. More importantly, the palmitic acid-stimulated proliferation was further enhanced in the Akt-overexpressed melanoma cells and was reduced by LY294002 or knockdown of endogenous Akt or overexpression of Akt mutants. We also found that palmitic acid-pretreated B16F10 cells were grown to a significantly larger tumor in mice compared with control cells. Taken together, we suggest that adipocytes may serve as an exogenous source of palmitic acid that promotes melanoma cell growth by activating Akt.
We have investigated the potential
in vivo anti-tumour activity of corilagin using the Hep3B hepatocellular carcinoma cell line and an athymic nude mice xenograft model. The purity of corilagin was ...confirmed by high performance liquid chromatographic analysis. Corilagin was administrated intraperitoneally for a continuous period of 7 days at a concentration of 15
mg/kg of body weight per day. A significant inhibition of tumour growth was observed when treated mice are compared with control groups. Furthermore, analysis of enzymes markers of liver function, including alanine aminotransferase and asparate aminotransferase, suggested that current therapeutic dosage of corilagin did not exert adverse effect on liver. Our observations support the view that corilagin is considerably effective to retard the
in vivo growth of xenografted Hep3B hepatocellular carcinoma.
The mis-regulation of nuclear factor-kappa B (NF-κB) signal pathway is involved in a variety of inflammatory diseases that leds to the production of inflammatory mediators. Our studies using human ...U937 promonocytes cells suggested that magnolol, a low molecular weight lignan isolated from the medicinal plant Magnolia officinalis, differentially down-regulated the pharmacologically induced expression of NF-κB-regulated inflammatory gene products MMP-9, IL-8, MCP-1, MIP-1α, TNF-α. Pre-treatment of magnolol blocked TNF-α-induced NF-κB activation in different cell types as evidenced by EMSA. Magnolol did not directly affect the binding of p65/p50 heterodimer to DNA. Immunoblot analysis demonstrated that magnolol inhibited the TNF-α-stimulated phosphorylation and degradation of the cytosolic NF-κB inhibitor IκBα and the effects were dose-dependent. Mechanistically, a non-radioactive IκB kinases (IKK) assay using immunoprecipitated IKKs protein demonstrated that magnolol inhibited both intrinsic and TNF-α-stimulated IKK activity, thus suggesting a critical role of magnolol in abrogating the phosphorylation and degradation of IκBα. The involvement of IKK was further verified in a HeLa cell NF-κB-dependent luciferase reporter system. In this system magnolol suppressed luciferase expression stimulated by TNF-α and by the transient transfection and expression of NIK (NF-κB-inducing kinase), wild type IKKβ, constitutively active IKKα and IKKβ, or the p65 subunit. Magnolol was also found to inhibit the nuclear translocation and phosphorylation of p65 subunit of NF-κB. In line with the observation that NF-κB activation may up-regulate anti-apoptotic genes, it was shown in U937 cells that magnolol enhanced TNF-α-induced apoptotic cell death. Our results suggest that magnolol or its derivatives may have potential anti-inflammatory actions through IKK inactivation.
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