Functional analyses of a flavonol synthase-like gene from Camellia nitidissima reveal its roles in flavonoid metabolism during floral pigmentation.

The flavonoids metabolic pathway plays central roles in floral coloration, in which anthocyanins and flavonols are derived from common precursors, dihydroflavonols. Flavonol synthase (FLS) catalyses dihydroflavonols into flavonols, which presents a key branch of anthocyanins biosynthesis. The yellow flower of Camellia nitidissima Chi. is a unique feature within the genus Camellia, which makes it a precious resource for breeding yellow camellia varieties. In this work, we characterized the secondary metabolites of pigments during floral development of C. nitidissima and revealed that accumulation of flavonols correlates with floral coloration. We first isolated CnFLS1 and showed that it is a FLS of C. nitidissima by gene family analysis. Second, expression analysis during floral development and different floral organs indicated that the expression level of CnFLS1 was regulated by developmental cues, which was in agreement with the accumulating pattern of flavonols. Furthermore, over-expression of CnFLS1 in Nicotiana tabacum altered floral colour into white or light yellow, and metabolic analysis showed significant increasing of flavonols and reducing of anthocyanins in transgenic plants. Our work suggested CnFLS1 plays critical roles in yellow colour pigmentation and is potentially a key point of genetic engineering toward colour modification in Camellia.

Design, synthesis and potent cytotoxic activity of novel podophyllotoxin derivatives.

Twenty new acyl thiourea derivatives of podophyllotoxin and 4'-demethylepipodophyllotoxin were prepared and screened for their cytotoxicity against four human tumor cell lines, A-549, DU-145, KB, and KBvin. With IC50 values of 0.098-1.13 µM, compounds 13b, 13c, and 13o displayed much better cytotoxic activity than the control etoposide. Most importantly, 13b and 13o exhibited promising cytotoxicity against the drug resistant tumor cell line KBvin with IC50 values of 0.098 and 0.13 µM, respectively, while etoposide lost activity completely. Structure-activity relationship (SAR) correlations of the new derivatives have been established. Compounds 13b and 13o merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates.

Synthesis and mechanistic studies of novel spin-labeled combretastatin derivatives as potential antineoplastic agents.

Two series (14a-d and 21a-h) of novel spin-labeled combretastatin derivatives were synthesized and evaluated for cytotoxicity against four tumor cell lines (K562, SGC-7901, Hela and HepG-2). Simultaneously, a representative compound 21a was selected to investigate the antitumor mechanisms of these synthetic compounds. The results indicated that some of the compounds showed significant cytotoxicity against four tumor cell lines in vitro and were more active than etoposide, a clinically available anticancer drug. Among the newly synthesized compounds, 21a, 21b and 21c displayed the greatest cytotoxicity against three tested tumor cell lines (HEPG-2, BGC-832 and Hela), with IC(50) values ranging from 0.15 to 1.05 µM, compared with values of 0.014-0.403 µM for 3-amino-deoxycombretastatin A-4 (3). In addition, the mechanistic analysis revealed that compound 21a effectively interfered with tubulin dynamics to prevent mitosis in cancer cells, leading to cell cycle arrest and, eventually, dose dependent apoptosis.

Design and one-pot synthesis of new 7-acyl camptothecin derivatives as potent cytotoxic agents.

New 7-acyl camptothecin derivatives were designed and synthesized from camptothecin in a one-pot reaction through a Minisci type-reaction and were evaluated for cytotoxicity against four tumor cell lines, A-549, DU-145, KB, and KB-vin. All of the new compounds showed significant inhibition of human tumor cell growth, with IC(50) values ranging from 0.01538 to 13.342 µM. Most of the derivatives were more cytotoxic than irinotecan, and the (7a) and 7-propionyl (7b) analogs exhibited the highest cytotoxic activity against the tumor cell lines tested. This compound class merits further development as anticancer clinical trial candidates.

[PTEN/PI3K pathways are involved in the signal transduction of myocardial remodeling in patients with congestive heart failure].

OBJECTIVE: To investigate the roles of PTEN (phosphatase and tensin homologue deleted on chromosome ten)/PI3K (phosphatidylinositol 3 kinase) signal transduction pathways in myocardium remodeling in patients with congestive heart failure (CHF). METHODS: A small amount of papillary muscle tissue was collected during mitral valve displacement from 39 patients of mitral valve disease with CHF, 12 cases with grade II, 15 cases with grade III, and 12 cases with grade IV cardiac function. 30 cases of healthy persons and 8 cases of heart donors who died of accident were included as controls. Pathological examination was conducted. Immunoprecitipation was used to assay the protein expression and phosphorylation of PTEN, PI3K and Akt (protein kinase B), and protein expression of alpha-skeletal-actin in myocardial tissues. RESULTS: Typical myocardial remodeling was shown in the myocardial tissues from the valvular heart disease patients with CHF. Hypertrophy was dominant in the myocardial tissues at early stagy of CHF, the myocardial tissues in the end stage of CHF was characterized by disordered alignment of myocytes, discontinuity and dissolving of cardiac fiber, destroyed subcellular organs, and hyperplasia of interstitial tissue. The protein expression of PTEN [absorbance value (A) ratio of PTEN and beta-actin] in control group was 3.29 +/- 0.11, grade II cardiac function was 2.56 +/- 0.19, grade III was 1.52 +/- 0.35, grade IV was 0.91 +/- 0.10, PTEN protein expressions in CHF groups were lower than that of control group and negatively correlated to the levels of cardiac function (P < 0.05 or 0.01). On the contrary, The phosphorylation of PI3K (PI3K/beta-actin) in control group was 0.21 +/- 0.04, grade II cardiac function was 0.52 +/- 0.09, grade III was 1.12 +/- 0.29, grade IV was 1.62 +/- 0.54; The phosphorylation of Akt (Akt/beta-actin) in control group was 0.75 +/- 0.13, grade II cardiac function was 1.21 +/- 0.34, grade III was 2.45 +/- 0.71, grade IV was 3.55 +/- 0.80; The protein expression of alpha-skeletal-actin (alpha-skeletal-actin/beta-actin) in control group was 0.20 +/- 0.03, grade II cardiac function was 0.41 +/- 0.04, grade III was 0.82 +/- 0.09, grade IV was 1.56 +/- 0.11, their expressions in CHF groups were higher than that of control group and positively correlated to the levels of cardiac function (P < 0.05 or 0.01). CONCLUSION: Both the PTEN and PI3K signal pathways are involved in the pathogenesis of myocardial remodeling in CHF patients with valvular heart disease, which play an important role in the pathogenesis of myocardial hypertrophy. PTEN may play a negative regulation role in the process of myocardial remodeling.