Characteristics of Cephalotaxus fortunei kernel oil and its digestion behaviors.

Cephalotaxus fortunei, a potential underutilized oil resource, contains various active ingredients that exert positive effects on human health. In the present study, characteristics of C. fortunei kernel oil and its digestion properties were systematically investigated. Results indicated that C. fortunei kernels contained high oil content (64.59%), of which over 90% was triacylglycerols (TAGs). The kernel oil was rich in oleic acid (C18:1n-9, 42.88%), linoleic acid (C18:2n-6, 31.05%), and sciadonic acid (C20:3n-6, 10.78%). The kernel oil also contained some beneficial fat-soluble nutrients, such as tocopherols (143 mg/kg) and phytosterols (1474 mg/kg). Thirty-five kinds of TAGs were identified, among which O-O-L (17.96%), O-O-O (12.12%), L-L-O (11.79%), O-L-Et (8.59%), and O-O-Et (8.76%) were the most abundant. In vitro digestion experiments showed that after 120 min of small intestine digestion, the maximum FFAs release level of the kernel oil was 75.02%, which was lower than that of soybean oil (89.63%).

[Lignans from stems and leaves of Cephalotaxus fortunei (â ¡)].

The present study aimed to explore the chemical constituents from the stems and leaves of Cephalotaxus fortunei. Seven lignans were isolated from the 75% ethanol extract of C. fortunei by various chromatographic methods, including silica gel, ODS column chromatography, and HPLC. The structures of the isolated compounds were elucidated according to physicochemical properties and spectral data. Compound 1 is a new lignan named cephalignan A. The known compounds were identified as 8-hydroxy-conidendrine(2), isolariciresinol(3), leptolepisol D(4), diarctigenin(5), dihydrodehydrodiconiferyl alcohol 9'-O-ß-D-glucopyranoside(6), and dihydrodehydrodiconiferyl alcohol 4-O-ß-D-glucopyranoside(7). Compounds 2 and 5 were isolated from the Cephalotaxus plant for the first time.

[Two novel cephalotaxine-type alkaloids from Cephalotaxus sinensis].

Silica gel, octadecyl-silica(ODS), Sephadex LH-20, and semi-preparative high performance liquid chromatography(HPLC) was performed to isolate nine cephalotaxine-type alkaloids from Cephalotaxus sinensis: 8-oxodeoxyharringtonine(1), 8-oxonordeoxyharringtonine(2), cephafortunine A(3), 8-oxocephalotaxine(4), deoxyharringtonine(5), acetylcephalotaxine(6), cephalotaxine(7), epicephalotaxine(8), and cephalotaxinone(9). Compounds 1 and 2 were identified for the first time and their structures were determined by high-resolution-electrospray ionization-mass spectrometry(HR-ESI-MS), nuclear magnetic resonance(NMR), and electronic circular dichroism(ECD). Compounds 1-3 and 5 significantly inhibited the transcription of nuclear factor kappa B(NF-κB), with the half-maximal inhibitory concentration(IC_(50)) of(3.91±0.70),(2.99±0.45),(7.84±0.51), and(1.46±0.17) µmol·L~(-1), respectively.

Cephalotaxine-type alkaloids with antiproliferation effects from the branches and leaves of Cephalotaxus fortunei var. alpina.

Eight cephalotaxine-type alkaloids (1-8), including two new compounds cephafortunines A and B (1-2), were isolated from the branches and leaves of Cephalotaxus fortunei var. alpina. Their structures were identified by a series of spectroscopic methods (MS, UV, IR, 1D, and 2D NMR) and comparison with the reported data of known analogs. The absolute configurations of 1 and 2 were determined by electronic circular dichroism (ECD) calculations. 1-8 were evaluated for their in vitro antiproliferation effects against two human leukemia cell lines (U937 and HL-60). All compounds showed different levels of antiproliferation effects against U937 cells with GI50 values of 4.21-23.70 µM. 4 and 5 were the most active against U937 cells with GI50 values of 4.21 and 6.58 µM and against HL-60 cells with GI50 values of 6.66 and 6.70 µM, respectively. 4 and 5 arrested HL-60 cell cycle in G0/G1 phase.

Curcumin in combination with homoharringtonine suppresses lymphoma cell growth by inhibiting the TGF-ß/Smad3 signaling pathway.

Both homoharringtonine (HHT) and curcumin exhibit anti-proliferative effects on lymphoma cells, but the effects of combined HHT and curcumin treatment remain unclear. Here, we investigated the effects of HHT/curcumin combination on the proliferation, apoptosis, and invasion in lymphoma cells. CCK-8, flow cytometry, and transwell assays were used to assess proliferation, apoptosis, and invasion of U937 and Raji cells. p-Smad3, E-cadherin, and N-cadherin expression were also measured in Raji cells using Western blot assays. Combination of HHT and curcumin synergistically inhibited U937 and Raji cell proliferation and invasion. In addition, the combination treatment markedly increased apoptosis of Raji cells as evidenced by increased Bax, cleaved caspase 3, and cleaved caspase 9 expression. Meanwhile, the combination treatment promoted anti-tumor mechanisms in Raji cells as indicated by decreases in p-Smad3 and N-cadherin and increases in E-cadherin. In vivo experiments showed that the combination treatment suppressed tumor growth in a mouse Raji xenograft model. Our findings indicate that combination of HHT and curcumin inhibited lymphoma cell growth by downregulating the TGF-ß/Smad3 pathway. These results suggest that HHT combined with curcumin might be a promising therapeutic approach for the treatment of lymphoma.

Ethnopharmacology, chemodiversity, and bioactivity of Cephalotaxus medicinal plants.

Cephalotaxus is the only genus of Cephalotaxaceae family, and its natural resources are declining due to habitat fragmentation, excessive exploitation and destruction. In many areas of China, folk herbal doctors traditionally use Cephalotaxus plants to treat innominate swollen poison, many of which are cancer. Not only among Han people, but also among minority ethnic groups, Cephalotaxus is used to treat various diseases, e.g., cough, internal bleeding and cancer in Miao medicine, bruises, rheumatism and pain in Yao medicine, and ascariasis, hookworm disease, scrofula in She medicine, etc. Medicinal values of some Cephalotaxus species and compounds are acknowledged officially. However, there is a lack of comprehensive review summarizing the ethnomedicinal knowledge of Cephalotaxus, relevant medicinal phytometabolites and their bioactivities. The research progresses in ethnopharmacology, chemodiversity, and bioactivities of Cephalotaxus medicinal plants are reviewed and commented here. Knowledge gaps are pinpointed and future research directions are suggested. Classic medicinal books, folk medicine books, herbal manuals and ethnomedicinal publications were reviewed for the genus Cephalotaxus (Sanjianshan in Chinese). The relevant data about ethnobotany, phytochemistry, and pharmacology were collected as comprehensively as possible from online databases including Scopus, NCBI PubMed, Bing Scholar, and China National Knowledge Infrastructure (CNKI). "Cephalotaxus", and the respective species name were used as keywords in database search. The obtained articles of the past six decades were collated and analyzed. Four Cephalotaxus species are listed in the official medicinal book in China. They are used as ethnomedicines by many ethnic groups such as Miao, Yao, Dong, She and Han. Inspirations are obtained from traditional applications, and Cephalotaxus phytometabolites are developed into anticancer reagents. Cephalotaxine-type alkaloids, homoerythrina-type alkaloids and homoharringtonine (HHT) are abundant in Cephalotaxus, e.g., C. lanceolata, C. fortunei var. alpina, C. griffithii, and C. hainanensis, etc. New methods of alkaloid analysis and purification are continuously developed and applied. Diterpenoids, sesquiterpenoids, flavonoids, lignans, phenolics, and other components are also identified and isolated in various Cephalotaxus species. Alkaloids such as HHT, terpenoids and other compounds have anticancer activities against multiple types of human cancer. Cephalotaxus extracts and compounds showed anti-inflammatory and antioxidant activities, immunomodulatory activity, antimicrobial activity and nematotoxicity, antihyperglycemic effect, and bone effect, etc. Drug metabolism and pharmacokinetic studies of Cephalotaxus are increasing. We should continue to collect and sort out folk medicinal knowledge of Cephalotaxus and associated organisms, so as to obtain new enlightenment to translate traditional tips into great therapeutic drugs. Transcriptomics, genomics, metabolomics and proteomics studies can contribute massive information for bioactivity and phytochemistry of Cephalotaxus medicinal plants. We should continue to strengthen the application of state-of-the-art technologies in more Cephalotaxus species and for more useful compounds and pharmacological activities.

Diterpenoids and Flavonoids from the Twigs of Cephalotaxus fortunei var. alpina.

Three new diterpenoids (a cephalotane, an abietane and a 9(10→20)-abeo-abietane) and one new flavonoid, together with 11 known compounds, were isolated from the twigs of Cephalotaxus fortunei var. alpina. The new compounds were identified by comprehensive spectroscopic (including 1D and 2D-NMR and HR-ESI-MS) analysis. Anti-inflammatory, immunosuppressive and cytotoxic activities of three new compounds were evaluated. 3ß,20-epoxyabieta-8,11,13-triene-3α,12-diol showed weak cytotoxicity against tumor cell lines NCI-H1975, HepG2, MCF-7, while fortalpinoid R and 3-acetonyl-3,5,7,4'-tetrahydroxy-2-methoxyflavanone were not active at 80 µM. None of these compounds showed anti-inflammatory and immunosuppressive activities.

Chinese Herbal Formulas Miao-Yi-Ai-Tang Inhibits the Proliferation and Migration of Lung Cancer Cells through Targeting ß-Catenin/AXIN and Presents Synergistic Effect with Cisplatin Suppressing Lung Cancer.

OBJECTIVE: Lung cancer is one of the major causes of cancer deaths worldwide, and the five-year survival still remains low despite the improvement of screening, prevention, and treatment methods. Chinese herbal medicines have been widely used for tumor prevention and treatment. Miao-Yi-Ai-Tang (Miao) is a novel herbal formulation and shows a potential anticancer effect. Materials and Methods. Human Small Cell Lung Cancer Cell was used for study in vitro. After treatments by Miao and Cisplatin (DDP), the invasion, migration, proliferation, and apoptosis of cells were detected by transwell, wound healing, CCK-8, and flow cytometry, respectively. The expression of ß-catenin, AXIN, and c-myc was detected by qRT-PCR and immunohistochemistry staining. Western blotting was applied for measuring the protein expression of ß-catenin, AXIN, and c-myc was detected by qRT-PCR and immunohistochemistry staining. Western blotting was applied for measuring the protein expression of. RESULTS: We found that Miao could inhibit invasion, migration, and proliferation and promote apoptosis of human lung cancer cells. Meanwhile, Miao and DDP presented synergy regulating the proliferation and apoptosis of lung cancer cells. The percentage of lung cancer cells in S and G2 stages was increased markedly by Miao. Besides, the expression of c-myc, AXIN, and ß-catenin, AXIN, and c-myc was detected by qRT-PCR and immunohistochemistry staining. Western blotting was applied for measuring the protein expression of. CONCLUSIONS: Chinese herbal formulas Miao could suppress lung cancer through targeting the ß-catenin/AXIN signaling pathway. Therefore, our findings may provide a novel strategy for the prevention and treatment of lung cancer.ß-catenin, AXIN, and c-myc was detected by qRT-PCR and immunohistochemistry staining. Western blotting was applied for measuring the protein expression of.

Isolation and identification of two new compounds from the twigs and leaves of Cephalotaxus fortunei.

Two new compounds, namely 5-hydroxy-7-methoxy-6-methylchromone (1), and sesquiterpene X (6), together with 21 known compounds were isolated from the twigs and leaves of Cephalotaxus fortunei Hook. f. The structures of 1-23 were elucidated on the basis of spectroscopic analysis (1D/2D NMR, HR-ESI-MS and IR) and comparison with literature. The absolute configuration of compound 6 was determined by means of electronic circular dichroism calculation. The in vitro anti-inflammatory activities of all compounds were assayed in RAW 264.7 cells by assessing lipopolysaccharide-induced nitric oxide production. Compounds 1 and 6 exhibited weak effects with percentage inhibitions of 24% and 35.60%, respectively. In addition, compounds 4, 9, and 14 have the potential to be developed as therapeutic agents for inflammatory diseases because of their significant anti-inflammatory activities and high content in C. fortunei.

Anti-varicella-zoster virus activity of cephalotaxine esters in vitro.

Harringtonine (HT) and homoharringtonine (HHT), alkaloid esters isolated from the genus Cephalotaxus, exhibit antitumor activity. A semisynthetic HHT has been approved for treatment of chronic myelogenous leukemia. In addition to antileukemic activity, HT and HHT are reported to possess potent antiviral activity. In this study, we investigated the effects of HT and HHT on replication of varicella-zoster virus (VZV) in vitro. HT and HHT, but not their biologically inactive parental alkaloid cephalotaxine (CET), significantly inhibited replication of recombinant VZV-pOka luciferase. Furthermore, HT and HHT, but not CET, strongly induced down-regulation of VZV lytic genes and exerted potent antiviral effects against a VZV clinical isolate. The collective data support the utility of HT and HHT as effective antiviral candidates for treatment of VZV-associated diseases.

Trichodermadiones A and B from the solid culture of Trichoderma atroviride S361, an endophytic fungus in Cephalotaxus fortunei.

Chemical investigation on the solid rice culture of Trichoderma atroviride S361, an endophyte isolated from Cephalotaxus fortunei, has afforded a pair of novel N-furanone amide enantiomers, (-)-trichodermadione A (1a) and (+)-trichodermadione A (1b), and a new cyclohexenone sesquiterpenoid, trichodermadione B (2), together with six known secondary metabolites. Chiral separation of compound 1 was successfully performed on a Lux Cellulose-2 column. Their structures were elucidated by detailed spectroscopic analyses on the basis of NMR, HRMS, and ECD data, and the absolute configurations of the new compounds were determined by computational analyses of their electronic circular dichroism (ECD) spectra and Snatzke's method. Compounds 1a, 1b and 2 were also evaluated for their cytotoxicity against DU145 and PC3 cell lines, as well as inhibitory effects against the production of NO in LPS-stimulated RAW264.7 cells.

Bizarre and scary ECG in yew leaves poisoning: Report of successful treatment.

Yew leaves poisoning is a rare life-threatening intoxication, whose diagnosis can be difficult. Initial symptoms are nausea, vomiting, abdominal pain, dizziness, tachycardia, muscle weakness, confusion, beginning within 1 hr from ingestion and followed by bradycardia, ventricular arrhythmias, ventricular fibrillation, severe hypotension, and death. Taxine-derived alkaloids are responsible for the toxicity of the yew leaves, blocking sodium and calcium channels, and causing conduction abnormalities. Because of lack of a specific antidote and limited efficacy of common antiarrhythmic drugs, prompt diagnosis, detoxification measures, and immediate hemodynamic support (also with transvenous cardiac stimulation) are essential.

Paciente joven diagnosticada de intoxicación grave por hojas de tejo / Young patient diagnosed with severe poisoning caused by yew leaves

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Ester alkaloids from Cephalotaxus interfere with the 2'3'-cGAMP-induced type I interferon pathway in vitro.

Dysregulated activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway by self-DNA contributes to interferonopathy and promotes autoimmune diseases. To identify potential suppressors of STING-induced type I interferon (IFN) induction, ethanol extracts of medicinal plants were screened for inhibitory activity against IFN-ß promoter activation. Notably, 70% ethanol extract of Cephalotaxus koreana specifically down-regulated STING-induced, but not TBK1- or IRF3-induced, IFN-ß promoter activity. The compounds exerting inhibitory activity specifically against STING-mediated IFN-ß promoter activation were identified as ester alkaloids isolated from the genus, Cephalotaxus, homoharringtonine and harringtonine. Furthermore, these two compounds inhibited 2'3'-cGAMP-induced IFN-stimulated gene expression and interaction between STING and TBK1. These suppressive effects were not observed with cephalotaxine devoid of the ester side-chain. Our data support the potential utility of homoharringtonine and harringtonine to treat STING-associated interferonopathy and autoimmune diseases.

Cephalotanins A-D, Four Norditerpenoids Represent Three Highly Rigid Carbon Skeletons from Cephalotaxus sinensis.

Four polycyclic norditerpenoids, cephalotanins A-D (1-4) representing three unprecedented carbon skeletons with highly rigid ring systems, were isolated from Cephalotaxus sinensis and structurally characterized by a combination of various methods. Compounds 1 and 2 are new skeletal norditerpenoid trilactones, while 3 and 4 are two norditerpenoids featuring different new carbon skeletons. Biosynthetic pathways for 1-4 were proposed by involving diverse and very fascinating chemical events with the coexisting cephalotane troponoids as the precursors. Compound 1 exhibited good NF-κB inhibition with an IC50 value of 4.12±0.61 µΜ.

Antimicrobial and antitumor activity and diversity of endophytic fungi from traditional Chinese medicinal plant Cephalotaxus hainanensis Li.

Endophytes from Cephalotaxus hainanensis Li, an important source of anti-leukemia drugs, have not been widely explored. In this study, 265 endophytic fungal isolates from C. hainanensis Li were screened for antimicrobial activities against tilapia, banana, rice, and rape and for antitumor activities against human leukemia cell lines (K562, NB4, and HL-60). Diversity was also analyzed. The results showed that 17.7% of the endophytic fungi had antimicrobial activities against at least three different test microbes, and activity against Fusarium oxysporum RKY102 was the highest at 15.8%. Cytotoxicity against at least one tumor cell line tested was observed in 18.5% of the endophytic fungi; with the highest value of 10.6% against K562. The endophytic fungal strains also showed relatively high activities against K562, NB4, and HL-60 while relatively fewer strains were cytotoxic against the human hepatic Hep-G2 and colon LoVo cancer cell lines. Thirty endophytic fungal strains showed both high antimicrobial and antitumor activities. Moreover, the analyses of the diversity of the 30 highly active strains showed they belonged to 20 species from 14 genera, and this is the first report of endophytic fungi Albonectria rigidiuscula, Colletotrichum magnisporum, and Nemania diffusa being isolated from Cephalotaxus plants. These findings suggest that natural antibacterial products for humans and tilapia; antifungal compounds for rice, rape, and banana; and antitumor compounds for leukemia therapy could be isolated from fungal strains derived from C. hainanensis Li.

Diversity and antimicrobial activity of endophytic fungi isolated from Cephalotaxus hainanensis Li, a well-known medicinal plant in China.

UNLABELLED: About 1051 endophytic fungi were isolated from leaves, branches, barks and stems of Cephalotaxus hainanensis Li from four sites in Hainan, China. The fungi were identified as 21 genera by morphology and ITS sequences. One dominant species was Phomopsis quercella in Hainan Tropical Botanical Garden and Bawangling Nature Reserve, with relative frequency of 42·06 and 34·88% respectively. Another dominant species was Colletotrichum boninense in Wuzhishan and Jianfengling Nature Reserves, with relative frequency of 36·84 and 46·97% respectively. Among the selected 21 endophytic fungi, 17 strains (80·95%) had activity against at least one pathogenic bacteria, and 14 strains (66·67%) exhibited activity against at least one fungal pathogens. Neonectria macroconidialis showed strong inhibition against Staphylococcus aureus (inhibition zone being 20 mm), Bacillus subtilis (14 mm) and Streptococcus agalactiae (28 mm). Xylaria sp. showed strong inhibition against Escherichia coli (20 mm), Rhizoctonia solani (20 mm) and Sclerotinia sclerotiorum (17 mm). Verticillium bulbillosum showed great activity against Strep. agalactiae (32 mm) and Fusarium oxysporum (22 mm). These endophytic fungi showed potentials in medicine development. SIGNIFICANCE AND IMPACT OF THE STUDY: Endophytic fungi from medicinal plants are an important source of novel and viable drugs. Cephalotaxus hainanensis Li is well known for leukaemia treatment and its endophytic fungi were isolated to investigate the diversity and antimicrobial activity. It was found that Ce. hainanensis Li had rich endophytic fungi, and some fungi showed strong antimicrobial activity against certain pathogens. These fungi can be used in medicine development.

Essential oil of Cephalotaxus griffithii needle inhibits proliferation and migration of human cervical cancer cells: involvement of mitochondria-initiated and death receptor-mediated apoptosis pathways.

This study was conducted to determine the effect of Cephalotaxus griffithii needle essential oil (CGNO) on proliferation and migration of human cervical cancer (HCC) cells. CGNO treatment decreased the viability of all the tested HCC (HeLa, ME-180 and SiHa) cells. Morphological and DNA fragmentation analysis of CGNO-treated HeLa cells indicated the involvement of apoptosis in inducing HCC cell death. CGNO increased mitochondrial membrane depolarisation and upregulated the expression of caspase-9, caspase-8, caspase-3 and cleaved-PARP. The activity of caspase-8 and caspase-9 was also significantly increased. Wound healing and transwell migration assay demonstrated that CGNO significantly inhibited the migration of HeLa cells to close a scratched wound and also inhibited their migration through filter towards a chemotactic stimulus. Taken together, these results indicated that CGNO inhibited the proliferation and migration of HCC cells. Of note, CGNO induced HeLa cell death through mitochondria-initiated and death receptor-mediated apoptosis pathway.

Cephalotaxus griffithii Hook.f. needle extract induces cell cycle arrest, apoptosis and suppression of hTERT and hTR expression on human breast cancer cells.

BACKGROUND: Cephalotaxus spp. are known to possess anticancer potential. In this present work, for the first time the effects of C. griffithii needle (CGN) extracts on human cancer cells were examined. METHODS: The CGN was successively extracted with petroleum ether (PE), acetone and methanol. The extracts were tested for its effect on proliferation of cancer cells (MTT assay on HeLa, ZR751 and HepG2). Extract that showed the maximum growth inhibitory effect was subjected for mechanism of action study. These included apoptosis (morphological and DNA fragmentation assay), cell cycle (flow cytometry), caspase expression (Western blot) and activity (assay kit), p53 (western blot and TP53 siRNA interference) and telomerase expression (reverse transcriptase PCR) analysis. RESULTS: Among the extracts, PE extract induced maximum cytotoxicity, with highest death occurred in ZR751 cells. Since, PE extract induced cell death was highest among the CGN extracts, with maximum cancer cell death occurred in ZR751 cells; we carried out mechanism study of PE extract induced ZR751 cell death. It was observed that PE extract induced ZR751 cell death was associated with cell cycle arrest and apoptosis by activating both intrinsic and extrinsic apoptotic pathways. Knock down study revealed that p53 is essential for loss of ZR751 cell viability induced by PE extract. Further, PE extract down-regulated hTERT, hTR, and c-Myc expression. Thin layer chromatography analysis indicated the presence of unique phytochemicals in PE extract. CONCLUSION: Based on the observations, we concluded that PE extract of C. griffithii needle contains important phyto-components with multiple cellular targets for control of breast cancer and is worthy of future studies.

Nematotoxicity of drupacine and a Cephalotaxus alkaloid preparation against the plant-parasitic nematodes Meloidogyne incognita and Bursaphelenchus xylophilus.

BACKGROUND: Species of Cephalotaxus (the plum yews) produce nematotoxic compounds of unknown identity. Consequently, bioassay-guided fractionation was employed to identify the compound(s) in Cephalotaxus fortunei twigs and leaves with activity against plant-parasitic nematodes. RESULTS: A crude alkaloid extract, particularly drupacine, was responsible for much of the nematotoxicity. The ED50 of drupacine for Bursaphelenchus xylophilus was 27.1 µg mL⁻¹, and for Meloidogyne incognita it was 76.3 µg mL⁻¹. Immersion of M. incognita eggs in 1.0 mg mL⁻¹ crude alkaloid extract (the highest tested concentration) reduced hatch by 36%; immersion of second-stage juveniles (J2) resulted in 72-98% immobility. Crude alkaloid extract and drupacine suppressed protease activity in extracts of the microbivorous nematode Panagrellus redivivus by 50% and 80%, respectively. Application of 0.02-0.5 mg mL⁻¹ crude alkaloid extract to soil with M. incognita inoculum did not significantly reduce pepper plant shoot length or weight, compared with nematode-inoculated, water-treated controls, but the number of eggs and J2 per root system respectively decreased by 69% and 73% at 0.5 mg mL⁻¹. CONCLUSION: Drupacine and a crude alkaloid extract suppress nematode hatch, activity of mixed life stages, and population numbers on plant roots. This is the first demonstration of nematotoxicity of crude Cephalotaxus alkaloids and drupacine.