Association between angiogenic growth factor genetic polymorphisms and the risk of osteosarcoma.

The aim of this study was to assess the role of the VEGF -2578C/A, +936C/T, and -460T/C gene polymorphisms in the development of osteosarcoma. A total of 182 patients with osteosarcoma and 182 age- and gender-matched healthy controls were enrolled into our study during January 2011 and December 2013. Genotype frequencies of the VEGF -2578C/A and -460T/C alleles in controls were found to be within the parameters of Hardy-Weinberg equilibrium, but the genotype frequencies of +936C/T alleles were not. By conditional regression analysis, we detected a statistically significantly increased risk of osteosarcoma in patients with the AA genotype (OR = 1.97; 95%CI = 1.02-3.83) and the CA+AA genotype (OR = 1.57; 95%CI = 1.01-2.44) of -2578C/A when compared with CC genotype. Therefore, our study showed that the AA and CA+AA genotypes of the VEGF -2578C/A polymorphism might modify the risk of osteosarcoma in a Chinese population.

Association of programmed cell death factor 4 (PDCD4) with hepatocellular carcinoma and smoking in a Chinese male population.

Programmed cell death factor 4 (PDCD4) is one of the genes that has been found to be up-regulated during apoptosis and loss of PDCD4 expression has been found in many kinds of progressive carcinomas. The objective of this study was to investigate the interactions between PDCD4 and smoking status in hepatocellular carcinoma. This case-controlled study included 68 Chinese male patients with hepatocellular carcinoma who were classified as smokers or non-smokers according to their pack-years of smoking status. Samples were obtained from carcinoma and normal tissues and examined using Western blotting. The results indicated that levels of PDCD4 were significantly lower in hepatocellular carcinoma tissues compared with normal tissues and that, in normal tissue, PDCD4 levels in smokers were significantly lower than in non-smokers.

[PAF antagonistic benzofuran neolignans from Piper kadsura].

In a continuing search for PAF antagonists, five benzofuran neolignans have been isolated from the aerial part of Piper kadsura (Choisy) Ohwi, a Chinese traditional drug used for the treatment of inflammation and rheumatic conditions. The structure determination was based upon spectroscopic analysis. Two of the neolignans were found to have new structures and were named as (-)-denudatin B (the enantiomer of denudatin B, II) and kadsurenin M (7S,8S-3,4,3'-trimethoxy-7'-oxo-nor-8',9'-7.O. 4',8,5'-neolignan, V). The known compounds kadsurenon (I), (-)-acuminatin(III) and (+)-licarin A(IV) were also obtained from the same source. (-)-Denudatin B (II) showed potent PAF antagonistic activity in 3H-PAF receptor binding assay.

[Studies on PAF antagonistic bicyclo(3,2,1) octanoid neolignans from Piper kadsura].

As a continuation of our previous report dealing with the structures of novel neolignans from Piper kadsura (Choisy) Ohwi, two other new bicyclo(3,2,1) octanoid neolignans, named kadsurenin K and kadsurenin L, were isolated. On the basis of spectral analysis and chemical derivatization, their structures were established as 7R,8R,3'R,5'R-delta 8'-3,5'-dimethoxy-4-hydroxy-2',3',4',5'-tetrahydro-2', 4'-oxo-7.3',8.5'-neolignan and 7R, 8R, 3'S, 4'R, 5'R-delta 8'-3,4,5'- trimethoxy-4'-acetoxy-2',3',4',5'-tetrahydro-2'-oxo-7.3', 8.5'-neolignan respectively. Kadsurenin B and kadsurenin C were known compounds. In 3H-PAF receptor binding assay, kadsurenin B, C, K and L demonstrated significant PAF-antagonistic activity.

Platelet aggregation inhibitors from the seeds of Swietenia mahagoni: inhibition of in vitro and in vivo platelet-activating factor-induced effects of tetranortriterpenoids related to swietenine and swietenolide.

The ether extract from the seeds of Swietenia mahagoni Jacq. (Meliaceae) was found to inhibit platelet-activating factor (PAF)-induced platelet aggregation. Systematic separation of the extract afforded twenty eight tetranortriterpenoids related to swietenine and swietenolide. Among them, several new compounds, named swietemahonin A, D, E, and G and 3-O-acetylswietenolide and 6-O-acetylswietenolide, showed a strong inhibition against PAF-induced aggregation in vitro and in vivo assays.

[Neolignans from Piper polysyphorum C.DC].

Piper polysyphorum C.DC (Piperaceae) is indigenous to the southern part of China. In the course of screening for inhibitors of platelet activating factor (PAF), the nonpolar fraction was found to exhibit PAF inhibitory activity. One new neclignan named polysyphorin and three new enantiomeric forms of (+)-virolongin, (+)-grandisin and (+)-lancifolin D were isolated. Two known neolignans, wallichinine and hancinone D were also obtained from the same sources. The structure determination was based upon spectroscopic analysis (UV, IR, CD, MS, 1HNMR, 13CNMR, COSY) and derivative preparation. The structure for polysyphorin was established as threo-delta 7'-7-hydroxy-3,4,5,3',5'-pentamethoxy-8-O-4' -neolignan. It is a racemic enantiomer. The PAF inhibitory activities were reported.

Identification and isolation of medicarpin and a substituted benzofuran as potent leukotriene inhibitors in an anti-inflammatory Chinese herb.

In a search for new inhibitors of leukotriene formation, a methylene chloride extract of the plant Dalbergia odorifera (Jiangxiang) was found to be a potent inhibitor of LTC4 formation in AB-CXBG Mct-1 mastocytoma cells. Following LH-20 and reverse phase HPLC chromatography, two compounds were isolated that had potent LTC4 inhibitory activity: medicarpin and 6-hydroxy-2-(2-hydroxy-4-methoxyphenyl) benzofuran (IV) with IC50s of 0.5 and 0.05 microM respectively. IV was shown to be a specific inhibitor of 5-lipoxygenase with an IC50 against the soluble rat enzyme of 0.08 microM, whereas it was inactive against cyclooxygenase. In neutrophils IV inhibited LTB4 production at comparable concentrations but had no effect on neutrophil degranulation or adhesion.

[The isolation and identification of PAF inhibitors from Piper wallichii (Miq.) Hand-Mazz and P. hancei Maxim].

Platelet activating factor (PAF) is a highly potent endogenous phospholipid mediator, involved in various inflammatory and cardiovascular disorders. As part of a research program dealing with PAF inhibitors isolated from Piper plant species, we have isolated kadsurenone (I), denudatin B (II), and N-isobutyl-deca-trans-2-trans-4-dienamide (III) from Piped wallichii (Miq.) Hand-Mazz. and P. hancei Maxim. In a continuing search for potential PAF inhibitor from plants, using PAF induced platelet aggregation as a guide, a new neolignan named hancinone D (IV) was isolated from P. hancei maxim. By X-ray analysis it was identified as a racemate. The X-ray analysis led to a revision of the previously made structure assignment of hancinone C. Another new neolignan named wallichinine (V), which was identified as an analogue of (IV), along with the known compounds hancinone C (VI), galgravin (VII), dihydropiperlonguminine (VIII) and crotepoxide (IX) were isolated from P. wallichii (Miq.) Hand-Mazz. The structure determination was based upon spectroscopic analysis. All of the compounds were for the first time obtained from both plants. In the test of platelet aggregation caused by PAF, I, II, V, VI, VII showed inhibitory activity, whereas III, IV, VII, IX showed no activity.

Interaction of tetrandrine with slowly inactivating calcium channels. Characterization of calcium channel modulation by an alkaloid of Chinese medicinal herb origin.

Tetrandrine, a bis-benzylisoquinoline alkaloid derived from the Chinese medicinal herb Stephania tetrandra, is a putative Ca2+ entry blocker whose mechanism of action is unknown. To investigate this mechanism, the effects of tetrandrine were characterized on binding of three chemical classes of Ca2+ entry blockers in cardiac sarcolemmal membrane vesicles. In the range 25-37 degrees C, tetrandrine completely blocks diltiazem binding, partially inhibits D-600 binding, and markedly stimulates nitrendipine binding, with greatest enhancement occurring at 37 degrees C. The potency of tetrandrine is increased 10-fold as temperature is raised from 25 to 37 degrees C. Scatchard analyses indicate that inhibition of diltiazem binding and stimulation of nitrendipine binding result from changes in ligand affinities while inhibition of D-600 binding is due to both an increase in KD and decrease in Bmax of aralkylamine receptors. Ligand dissociation studies reveal that tetrandrine increases D-600 off-rates, decreases nitrendipine off-rates, but has no effect on diltiazem dissociation kinetics. In addition, tetrandrine reversibly blocks inward Ca2+ currents through L-type Ca2+ channels in GH3 anterior pituitary cells. These results indicate that tetrandrine interacts directly at the benzothiazepine-binding site of the Ca2+ entry blocker receptor complex and allosterically modulates ligand binding at other receptors in this complex. These findings suggest that tetrandrine is a structurally unique natural product Ca2+ entry blocker and provide a rationale explanation for the therapeutic effectiveness of this agent.

Characterization of a platelet-activating factor receptor antagonist isolated from haifenteng (Piper futokadsura): specific inhibition of in vitro and in vivo platelet-activating factor-induced effects.

Platelet-activating factor (PAF) is a potent lipid mediator of inflammation and asthma. Using a receptor preparation of rabbit platelet membranes, we identified a novel antagonist of PAF in the methylene chloride extract of a Chinese herbal plant, haifenteng (Piper futokadsura). The active antagonist, kadsurenone, was isolated and characterized in several in vitro and in vivo assays. It is a specific and competitive inhibitor of PAF binding to its receptor with a Ki of 5.8 X 10(-8) M vs. a Ki of 6.3 X 10(-9) M for PAF itself. It inhibits PAF-induced aggregation of rabbit platelets and human neutrophils at 2.4-24 microM, without showing any PAF agonistic activity. It potently inhibits PAF-induced degranulation of human neutrophils at 2.5-50 microM, also without any agonist activity. Kadsurenone is active orally at 25-50 mg/kg of body weight in blocking PAF-induced cutaneous permeability in the guinea pig. It also inhibits PAF-induced increases of hematocrit and circulating N-acetylglucosaminidase in the rat at greater than 10 mg/kg i.p. in a dose-dependent manner. Kadsurenone does not interfere with the function of several pharmacological mediators and receptors tested. Its structural specificity is evidenced by the poor PAF-antagonistic activities of three related structures isolated from the same haifenteng extract.