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BACKGROUND: Gynecological cancers encompass all uncontrolled and aberrant cell growth in the female reproductive system, therapeutic interventions are constantly evolving, but there is still a high death rate, significant side effects and medication resistance, making the task of treatment challenging and complex. The essential oil extracted from the rhizome of Curcuma longa is a promising natural drug, which has excellent biological activity on cancer cells and is to be developed as a new type of anti-gynecological tumor therapeutic agent. PURPOSE: To systematically summarize the available evidence for the efficacy of Curcuma oil and its terpenoids (ß-elemene, curcumol, furanodiene, and germacrone) in gynecological cancers, primarily malignancies of the reproductive system, involving ovarian, cervical, and endometrial cancers, explain the underlying mechanisms of preventing and treating gynecological cancers, and assess the shortcomings of existing work. RESULTS: Through several signaling channels, Curcuma oil and its terpenoids can not only stop the growth of ovarian cancer, cervical cancer, and endometrial cancer cells, limit the formation of tumors, but also raise the effectiveness of chemotherapy drugs and improve the quality of life for patients. CONCLUSION: It provides a preclinical basis for the efficacy of Curcuma oil as a broad-spectrum anti-tumor agent for the prevention and treatment of gynecological cancers. Even so, further efforts are still needed to improve the bioavailability of Curcuma oil and upgrade related experiments.

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Alzheimer's disease (AD) is a neurodegenerative disease associated with aging, and the number of people affected is rapidly increasing. Abnormally hyperphosphorylated tau filaments and extracellular deposits of amyloid ß-peptides (Aß) fibrils are two important pathological hallmarks of AD. Currently, stopping the production of Aß and blocking its aggregation is the main strategy for the treatment of AD. Turmeric is effective in treating neurodegenerative diseases, but there is no effective way to identify active compounds from their complicated chemical compositions. Instead of using conventional extraction and separation methods with low efficiency and time-consuming, our group tried to use atomic materials in high-throughput chemical screening due to their structural characteristics and the unique advantages of surface atomic. Herein, a novel atomic zinc sites with hierarchical porous carbon (Zn-HPC) was synthesized to quickly screen potential inhibitors of Aß aggregation in turmeric. As-combined Aß@Zn-HPC demonstrates superior storage stability and high selectivity, outperforming the most reported supporters for ligand fishing. Five compounds with strong affinity on Aß@Zn-HPC were selected by high-performance liquid chromatography-hybrid linear ion trap/orbitrap mass spectrometer after incubation with turmeric extract. Finally, it was shown that curcumin and bisdemethoxycurcumin can inhibit Aß aggregation by using thioflavin-T fluorescence assay and biolayer interferometry. A new application for the accurate identification of Aß aggregation inhibitors from turmeric were developed based on the active compounds possessing binding affinity to Aß to inhibit its aggregation. The developed method could provide a promising tool for efficient drug discovery from natural product resources.

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Cancer is a fatal disease with high mortality and low survival rate worldwide. At present, there is still no known cure for most cancers. Traditional Chinese medicine (TCM) represents a noteworthy reservoir for anticancer agents in drug discovery and development. Curcumae Rhizoma (called Ezhu in Chinese) is widely prescribed in TCM for anticancer therapy owing to its broad-spectrum antineoplastic activities. Especially, the terpenoids isolated from the essential oil of Curcumae Rhizoma form an integral part of cancer research and are well established as a potential anticancer agent. For example, ß-elemene has been developed into a new drug for the treatment of solid tumors in China, and is currently undergoing clinical trials in the United States. The review aims to systematically summarize the recent advances on the anticancer effects and related molecular mechanisms of Curcumae Rhizoma, and its terpenoids (ß-elemene, Furanodiene, Furanodienone, Germacrone, Curcumol, Curdione). In addition, we evaluated and compared the anticancer efficacy and clinical use of the terpenoids with combination therapies and traditional therapies. Therefore, this review provides sufficient evidence for the anticancer therapeutic potential of Curcumae Rhizoma and its terpenoids, and will contribute to the development of potential anticancer drugs.

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Natural products have served as a limitless reservoir of bioactive scaffolds for drug discovery against several disorders. Furanodiene is a bioactive natural product isolated from several plants of genus Curcuma. Its therapeutic potential against cancer, inflammation, and angiogenesis has been well-documented. The current review is an update about the natural sources and anti-cancer action mechanism of furanodiene. Furanodiene exerts its anti-cancer effects via induction of apoptosis in several cancer types by modulating MAPKs/ERK, NF-κB, and Akt pathways. Furanodiene has been systematically studied for its anti-cancer potential. However, pharmacokinetics, pharmacodynamics, pre-clinical and clinical studies still needed to be conducted to completely validate the potential of furanodiene for the treatment of cancer.

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BACKGROUND: Chemotherapy is a primary approach in cancer treatment after routine surgery. However, chemo-resistance tends to occur with chemotherapy in clinic, resulting in poor prognosis and recurrence. Nowadays, Chinese medicine may shed light on design of new therapeutic modes to overcome chemo-resistance. Although Rhizoma Curcumae possesses anti-cancer activities in various types of cancers, the effects and underlying mechanisms of its bioactive components against chemo-resistance are not clear. Therefore, the present study aims to explore the potential effects of Rhizoma Curcumae on doxorubicin-resistant breast cancer cells. METHODS: The expression and function of ABC transporters in doxorubicin-resistant MCF-7 breast cancer cells were measured by western blotting and flow cytometry. Cell viability was detected using MTT assay. The combination index was analyzed using the CalcuSyn program (Biosoft, Ferguson, MO), based on the Chou-Talalay method. RESULTS: In our present study, P-gp was overexpressed at protein level in doxorubicin-resistant MCF-7 cell line, but short of MRP1 and BCRP1. Essential oil of Rhizoma Curcumae and the main bioactive components were assessed on doxorubicin-resistant MCF-7 cell line. We found that the essential oil and furanodiene both display powerful inhibitory effects on cell viability, but neither of these is the specific inhibitor of ABC transporters. Moreover, furanodiene fails to enhance the efficacy of doxorubicin to improve multidrug resistance. CONCLUSION: Overall, our findings fill the gaps of the researches on chemo-resistance improvement of Rhizoma Curcumae and are also beneficial for Rhizoma Curcumae being developed as a promising natural product for cancer adjuvant therapy in the future.

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Curcuma cf. viridiflora Roxb., also known as Mah-Lueang in Thai, belongs to the Zingiberaceae family and is grown from rhizomes. The rhizome of the plant has been used for medicinal purposes, in particular, to treat paralysis in Thai traditional medicine. However, no biologically active compounds have been reported from Mah-Lueang yet. In this study, natural compounds were isolated from Mah-Lueang and structurally determined by spectroscopic methods, including electrospray ionization mass spectrometry and nuclear magnetic resonance. The four isolated compounds were identified as furanodiene (1), dehydrocurdione (2), germacrone-4,5-epoxide (3), and zedoarondiol (4). These sesquiterpenes were investigated for antileukemic activities against KG1a and Molt4 cells. Leukemic cell proliferation is regulated by the Wilms' tumor 1 (WT1) transcription factor. Compound 1 showed the strongest cytotoxicity against both KG1a and Molt4 cells. Noncytotoxic concentrations (20% inhibitory concentration values) of all compounds were able to decrease the WT1 protein expression and total cell numbers in both cell lines. The four compounds showed good inhibitory activities for WT1 protein expression. Compounds 3 and 4 showed excellent antileukemic activities for both cell lines. In summary, four sesquiterpene compounds with antileukemic activities against the KG1a and Molt4 cell lines were identified in Mah-Lueang extracts.

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Chemotherapy is used as a primary approach in cancer treatment after routine surgery. However, chemo-resistance tends to occur when chemotherapy is used clinically, resulting in poor prognosis and recurrence. Currently, Chinese medicine may provide insight into the design of new therapies to overcome chemo-resistance. Furanodiene, as a heat-sensitive sesquiterpene, is isolated from the essential oil of Rhizoma Curcumae. Even though mounting evidence claiming that furanodiene possesses anti-cancer activities in various types of cancers, the underlying mechanisms against chemo-resistant cancer are not fully clear. Our study found that furanodiene could display anti-cancer effects by inhibiting cell viability, inducing cell cytotoxicity, and suppressing cell proliferation in doxorubicin-resistant MCF-7 breast cancer cells. Furthermore, furanodiene preferentially causes apoptosis by interfering with intrinsic/extrinsic-dependent and NF-κB-independent pathways in doxorubicin-resistant MCF-7 cells. These observations also prompt that furanodiene may be developed as a promising natural product for multidrug-resistant cancer therapy in the future.

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Furanodiene (FN) loaded FA-PEG2000-DSPE modified nanostructured lipid carriers (FA-FN-NLCs) were developed to increase the solubility and bioavailability of FN, prolong the circulation time in blood and improve the targeting ability. FA-FN-NLCs were prepared using emulsification-ultrasonic and low temperature-solidification method and optimized by central composition design (CCD). In vitro and in vivo characteristics of FA-FN-NLCs were investigated in detail. The optimized formulations exhibited a spherical shape with particle size of 127.4 ± 2.62 nm, PDI of 0.268 ± 0.04, zeta potential of -14.7 ± 1.08 mV, high encapsulation efficiency of 89.04 ± 2.26% and loading capacity of 8.46 ± 0.20%. Differential scanning calorimetry (DSC) indicated that FN was not in crystalline state in FA-FN-NLCs. In vitro drug release exhibited a biphasic release pattern which showed a relative burst drug release at the initial time and followed by a prolonged drug release. In vivo, compared with FN solution (FN-SOL) and FN loaded traditional NLCs (FN-NLCs), FA-FN-NLCs had a longer blood circulating time (t1/2) and higher area under the curve (AUC). NiR fluorescence imaging study demonstrated that FA-FN-NLCs specially accumulated in tumor site by the receptor-mediated endocytosis. This study showed that FA-FN-NLCs was a promising drug delivery system for FN in the treatment of cancer.

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[This corrects the article on p. 648 in vol. 8, PMID: 28959205.].

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Furanodiene is a natural product isolated from Rhizoma curcumae, and exhibits broad-spectrum anti-cancer activities in vitro and in vivo. Our previous study proved that furanodiene could increase growth inhibition of steroidal agent in ERα-positive breast cancer cells, but whether furanodiene can influence ER status is not clear. In this study, we confirmed that furanodiene down-regulated the ERα protein expression level and inhibited E2-induced estrogen response element (ERE)-driven reporter plasmid activity in ERα-positive MCF-7 cells. Actually, ERα-knockdown cells were more sensitive than ERα positive cells to furanodiene on the cytotoxicity effect. So the anti-cancer effects of furanodiene and non-steroidal agent in breast cancer cells still requires further investigation. Our results showed that furanodiene exposure could enhance growth inhibitory effects of doxorubicin in ERα-negative MDA-MB-231 cells and ERα-low expression 4T1 cells. However, furanodiene did not increase the cytotoxicity of doxorubicin in ERα-positive breast cancer cells, non-tumorigenic breast epithelial cells, macrophage cells, hepatocytes cells, pheochromocytoma cells and cardiac myoblasts cells. Furanodiene enhances the anti-cancer effects of doxorubicin in ERα-negative breast cancer cells through suppressing cell viability via inducing apoptosis in mitochondria-caspases-dependent and reactive oxygen species-independent manners. These results indicate that furanodiene may be a promising and safety natural agent for cancer adjuvant therapy in the future.

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OBJECTIVE:To establish a method for the simultaneous determination of curdione,germacrone and furanodiene of zedoray turmeric oil in Ruxiankang injection. METHODS:HPLC was performed on the column of Zorbax SB-C18 with mobile phase of acetonitrile-water (gradient elution) at a flow rate of 1.0 ml/min,detection wavelength was 216 nm,column temperature was 30℃,and the injection volume was 10 μl. RESULTS:The linear range was 60-480 μg/ml for curdione(r=0.999 0),40-320 μg/ml for germacrone(r=0.999 0)and 40-320 μg/ml(r=0.999 0);RSDs of precision,stability and reproducibility tests were lower than 2.0%;recoveries were 95.21%-99.89%(RSD=1.6%,n=6),102.33%-104.89%(RSD=1.0%,n=6)and 97.38%-99.06%(RSD=0.7%,n=6),respectively. CONCLUSIONS:The method is simple and accurate,and can be used for simultaneous contents deter-mination of curdione,germacrone and furanodiene of zedoray turmeric oil in Ruxiankang injection.

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OBJECTIVE To investigate the effect of furanodiene(FDE),a diterpene derived from the medicinal plant Zedoary,on apoptosis of human gastric cancer MGC-803 cells induced in vitro. METHODS MGC-803 cells were treated with FDE 46.29~740.74μmol·L-1 for 24,48 and 72 h,and the cell viability was detected with MTT assay. Cell morphology was observed by light microscopy and Hoechst33342 staining. Flow cytometry was used to detect cell apoptotic rate and cell cycle. Rh123 staining and fluorescence probe DCFH-DA were employed to detect the changes in mitochondrial membrane potential (MMP) and reactive oxygen species(ROS). RESULTS MTT Results showed that FDE 46.29-740.74μmol · L-1 exhibited significantly higher cytotoxicity to gastric cancer MGC-803 cells. IC50 for MGC-803 of 24,48 and 72 h treatment was 347.91,257.41 and 101.01μmol·L-1,respectively. Treatment with FDE 92.58-370.32μmol·L-1 for 24 h also caused significant morphological changes in MGC-803 cells. AnnexinⅤ-FITC/PI double staining showed that the apoptotic rate increased after FDE 92.58-370.32μmol·L-1 treatment for 24 h(P<0.05). FDE enabled MGC-803 cell cycle arrest in S phase. DCFH-DA staining showed that FDE resulted in an increase in intracellular ROS levels(P<0.05) when PDE concentration was 370.37μmol·L-1(P<0.05). MMP decreased after FDE treatment when PDE concen?tration was 370.37μmol·L-1(P<0.05). CONCLUSION FDE Possesses potent tumor selected toxicity and can induce apoptosis of MGC-803 cells through cell cycle arresting,which is related to inhibition of DNA biosynthesis.

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A simple, rapid and sensitive method was developed for the simultaneous quantification of curdione, furanodiene and germacrone in rabbit plasma using a LC-MS/MS analysis. The plasma sample preparation was a simple deproteinization by the addition of 3 vols of acetonitrile followed by centrifugation. The analytes and internal standard (IS) costunolide were separated on a Zorbax SB-C18 column (3.5 µm, 2.1 × 100 mm) with mobile phase of methanol-water (90:10, v/v) containing 0.1% formic acid at a flow rate of 0.3 mL/min with an operating temperature of 25°C. Detection was carried out by atmospheric pressure chemical ionization in positive ion selected reaction monitoring mode. Linear detection responses were obtained for the three test compounds ranging from 5 to 5000 ng/mL and the lower limits of quantitation were 5-10 ng/mL. The intra- and inter-day precisions (relative standard deviations) were within 9.4% for all analytes, while the deviation of assay accuracies was within ±10.0%. The average recoveries of analytes were >80.0%. All analytes were proved to be stable during all sample storage, preparation and analytical procedures. The method was successfully applied to the pharmacokinetic study of the three compounds after vaginal drug delivery of Baofukang suppository to rabbit.

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Furanodiene is a bioactive compound isolated from Curcuma wenyujin Y. H. Chen et C. Ling (C. wenyujin). It is one of the major components of volatile oil extracted from C. wenyujin. Furanodiene has anti-tumor activities in various cancer cell lines, as well as anti-metastatic activities. However, the underlying mechanisms of anti-metastatic activities of furanodiene have not been well investigated. In this study, we demonstrated that at low concentrations (5-25µM), furanodiene inhibited adhesion, migration and invasion of breast cancer cells, but it did not induce cytotoxicity, apoptosis and cell cycle arrest. Furthermore, the underlying mechanisms for the anti-metastatic activity of furanodinene were also investigated. Furanodiene down-regulated the integrin αV expression, ß-catenin expression, focal adhesion kinase (FAK) phosphorylation, Akt phosphorylation, and PI3 kinase p85 phosphorylation, and all of these were involved in modulation of the tumor metastasis process. In addition, an interference of metastasis was also observed in MDA-MB-231 cells through the regulation of the matrix metalloproteinase 9 (MMP-9) releases. Our results suggested that furanodiene might be the primary contributor to the anti-cancer effects of volatile oil extracts, and it might be a good therapeutic target for highly metastatic breast cancer.

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Furanodiene (FUR) is a natural terpenoid isolated from Rhizoma Curcumae, a well-known Chinese medicinal herb that presents anti-proliferative activities in several cancer cell lines. Recently, we found that the combined treatment of FUR with paclitaxel (TAX) showed synergetic anti-proliferative activities in 95-D lung cancer cells. Herein, we showed that FUR reduced the cell numbers distributed in mitosis phase induced by TAX while increased those in G1 phase. The protein levels of cyclin D1, cyclin B1, CDK6 and c-Myc were all down-regulated in the group of combined treatment. The dramatically down-regulated expression of integrin ß4, focal adhesion kinase and paxillin might partially contribute to the synergic effect. Though FUR alone obviously induced endoplasmic reticulum stress, this signaling pathway may not contribute to the synergetic anti-proliferative effect as the protein expression of CHOP and BIP was similar in FUR alone and combined treatment group.

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Furanodiene is an active ingredient of Rhizoma Curcumae, a very famous Traditional Chinese Medicine (TCM) widely used for the treatment of cancer. Although the anti-tumor effect of furanodiene has well been established, its metabolic profile in vivo and in vitro is still unclear. In the present study, the metabolites of furanodiene in rats were studied. After oral administration of furanodiene, the rats' urine, feces and bile were collected and produced seven metabolites by the use of macroporous adsorption resin chromatography, and semi-preparative high performance liquid chromatography. Their structures were identified by mass spectrometry and NMR data including (1)H, (13)C, and two-dimensional NMR data. All of these metabolites were phase I metabolites, with three new compounds including 2ß-hydroxyl-aeruginolactone (2), 14-hydroxyl-aeruginolactone (3), 1ß,8ß-dihydroxyeudesm-4,7(11)-dien-8α,12-olide (4a), and four known compounds, 1ß,10α,4α,5ß-diepoxy-8α-hydroxy-glechoman-8α,12-olide (1), 1ß,8ß-dihydroxyeudesm-4(14),7(11)-dien-8α,12-olide (4b), 1ß,8ß-dihydroxyeudesm-3,7(11)-dien-8α,12-olide (5) and aeruginolactone (6). Interestingly, the metabolite 6 was found to be a primary metabolite in urine, bile and feces. All metabolites were found to be both in urine and bile but only few metabolites except the metabolite 6 presented in feces after oral dose of furanodiene to rats. Furthermore, the metabolic pathways of furanodiene were proposed using an in vitro assay by incubation of furanodiene and its metabolites in vivo with rat liver S9 or liver microsomes. Clearly, aeruginolactone (6) seemed to be a major precursor for other metabolites.

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