Useful Cases of Patients With Developmental Disorders Improved by Oral Administration of LPS Derived from Pantoea agglomerans.

BACKGROUND: Developmental disorders are associated with microglial dysfunction. Oral administration of lipopolysaccharide derived from Pantoea agglomerans bacteria (LPSp) leads to normalization of phagocytic activity of microglia and suppression of inflammation in mice. In this article, we report on a successful trial in which we achieved a significant improvement of symptoms in patients with developmental disorders. PATIENTS AND METHODS: Five pediatric patients diagnosed with autism spectrum disorders (ASD)/attention deficit hyperactivity disorder (ADHD) who visited our clinic received either 0.75 or 1 mg/day LPSp for 6 months or more, in addition to our usual therapy regimens (detoxification therapy, nutritional therapy, and vibration therapy). A survey questionnaire was completed by the patients' parents and evaluated using the Numerical Rating Scale. RESULTS: Behavior, verbal ability, and communication disabilities associated with ASD/ADHD improved in all patients. CONCLUSION: Oral administration of LPSp may represent a new treatment option in the area of developmental disorders where there is currently no treatment available.

Synthesis of 1-alkynyl(diphenyl)onium salts of group 16 elements via heteroatom transfer reaction of 1-alkynyl(phenyl)-lambda 3-iodanes.

1-Alkynyl(phenyl)-lambda 3-iodanes undergo selective transfer of the alkynyl groups over the phenyl group onto diphenyl chalcogens. Exposure of 1-alkynyl(phenyl)-lambda 3-iodanes to diphenyl chalcogens (S, Se, and Te) in dichloromethane or 1,2-dichloroethane affords 1-alkynyl(diphenyl)sulfonium, -selenonium, and -telluronium salts in high yields.

Inhibitory effects of caffeic acid phenethyl ester analogues on experimental lung metastasis of murine colon 26-L5 carcinoma cells.

We have previously examined the antiproliferative activity of caffeic acid phenethyl ester (CAPE) and its 20 analogues against six tumor cell lines, and found that CAPE analogues possess selective antiproliferative activity toward the murine colon 26-L5 carcinoma cell line. To extend our study, the effects of CAPE analogues on the metastatic development of murine colon 26-L5 carcinoma cells in the lung were examined. The oral administration of CAPE (5 mg/mice/d) for 7 d after tumor inoculation decreased the tumor weight and the number of tumor nodules in the lung by 50% and 50%, respectively, compared to the control, while CAPE (5 mg/mice/d) administered for 7 d before tumor inoculation showed no significant effect. Besides CAPE, 4-phenylbutyl caffeate, 8-phenyl-7-octenyl caffeate, 2-cyclohexylethyl caffeate and n-octyl caffeate at an oral dose of 2 mg/mice/d caused a 55%, 43%, 55% and 35% reduction of the tumor nodules in their lung metastasis formation, respectively. These results further elaborate the possibility of CAPE and its analogues to become a new class of chemopreventive agents for the treatment of colon cancer metastasis.

Caffeic acid phenethyl ester (CAPE) analogues: potent nitric oxide inhibitors from the Netherlands propolis.

The MeOH and water extracts of the Netherlands propolis were tested for their inhibitory activity toward nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage-like J774.1 cells. Both of the extract possessed significant NO inhibitory activity with IC(50) values of 23.8 and 51.5 microg/ml, respectively. Then 13 phenolic compounds obtained from the MeOH extract showing stronger NO inhibition were examined on their NO inhibitory activities. Caffeic acid phenethyl ester (CAPE) analogues, i.e., benzyl caffeate, CAPE and cinnamyl caffeate, possessed most potent NO inhibitory activities with IC(50) values of 13.8, 7.64 and 9.53 microM, respectively, which were two- to four-fold stronger than the positive control N(G)-monomethyl-L-arginine (L-NMMA; IC(50), 32.9 microM). Further study on the synthetic analogues of CAPE revealed that both of 3-phenylpropyl caffeate (18; IC(50), 7.34 microM) and 4-phenylbutyl caffeate (19; IC(50), 6.77 microM) possessed stronger NO inhibitory activity than CAPE (10) and that elongation of alkyl side chain of alcoholic parts of caffeic acid esters enhance the NO inhibitory activity. In addition, it was found that CAPE analogues having longer carbon chain (>C(5)) in alcoholic part showed toxic effects toward J774.1 cells. This NO inhibitory effect may directly correlate with antiinflammatory properties of the Netherlands propolis.

In vivo action of novel alkyl methyl quinolone alkaloids against Helicobacter pylori.

Previously purified and isolated compounds of novel alkyl methyl quinolone alkaloids (AM quinolones) from Gosyuyu (Wu-Chu-Yu), a Chinese herbal medicine, have a strong and highly selective antibacterial activity against Helicobacter pylori in vitro. To clarify the antibacterial mechanism(s) of AM quinolones, we examined the effects of AM quinolones on respiration of H. pylori in vitro. One week after treatment with AM quinolones alone (2, 10 or 20 mg/kg/day, orally) or combinations of AM quinolones and omeprazole (30 mg/kg/day) for H. pylori (1 x 10(8) cfu)-infected Mongolian gerbils, we checked viable H. pylori and myeloperoxidase (MPO) activity in the gastric tissues. AM quinolones decreased the number of H. pylori and inhibited H. pylori respiration in a dose-dependent manner. AM quinolones decreased the number of viable H. pylori (AM quinolones alone: 46.0 +/- 22.6 x 10(4), 17.3 +/- 4.9 x 10(4) and 8.1 +/- 6.6 x 10(4) cfu/stomach, respectively; and combinations of AM quinolones and omeprazole: 8.0 +/- 5.6 x 10(4), 4.2 +/- 2.5 x 10(4) and 5.5 +/- 2.7 x 10(4) cfu/stomach) compared with the vehicle-treated group (control: 359.9 +/- 180.3 x 10(4) cfu/stomach). AM quinolones significantly decreased MPO activity of H. pylori-inoculated gastric tissues. These findings suggest that AM quinolones have a potent antibacterial effect against H. pylori through respiratory inhibition, and reduced bacterial growth in vivo. AM quinolones might be novel therapeutic agents for H. pylori eradication.

Selective antiproliferative activity of caffeic acid phenethyl ester analogues on highly liver-metastatic murine colon 26-L5 carcinoma cell line.

Caffeic acid phenethyl ester (CAPE, 2) and its twenty analogues (1, 3-21) were prepared. These esters were tested by MTT assay on growth of murine colon 26-L5 carcinoma, murine B16-BL6 malonoma, murine Lewis lung carcinoma, human HT-1080 fibrosarcoma, human lung A549 adenocarcinoma, and human cervix HeLa adenocarcinoma cell lines. It was found that CAPE analogues possessed selective antiproliferative activity toward highly liver-metastatic murine colon 26-L5 carcinoma cell line. Among them, 4-phenylbutyl caffeate (4), (Z)-8-phenyl-7-octenyl (10a) and (E)-8-phenyl-7-octenyl (10b) caffeate showed the most potent antiproliferative activity (EC50 value, 0.02 microM). In addition, CAPE (2) induced DNA fragmentation at concentrations of 1 to 10 microg/mL towards murine colon 26-L5 carcinoma cells.

Prevention of growth and metastasis of murine melanoma through enhanced natural-killer cytotoxicity by fatty acid-conjugate of protopanaxatriol.

Ginsenosides, the glycosides of Panax ginseng, are metabolized (deglycosylated) by intestinal bacteria after oral administration. 20(S)-Protopanaxatriol (M4) is the main bacterial metabolite of protopanaxatriol-type ginsenosides and mediates their antitumor effects. To clarify the mechanism of the M4-mediated antitumor effect, the antitumor activity and metabolism of M4 was examined, using the C57BL/6 mice implanted with B16-BL6 melanoma. The chronic oral administration of M4 inhibited the growth of B16-BL6 melanoma at the implanted site. Analyses using TLC, HPLC, MS and NMR suggest that orally administered M4 was absorbed from the small intestine into the mesenteric lymphatics followed by the rapid esterification of M4 with fatty acids and its accumulation in the tissues including the liver and lung. The administration of M4 prior to the intravenous injection of B16-BL6 cells abrogated the enhanced lung metastasis in the mice pretreated with 2-chloroadenosine more effectively than in those pretreated with anti-asialo GM1. The esterified M4 (EM4) did not directly affect tumor growth in vitro, whereas it stimulated splenic NK cells to become cytotoxic to tumor cells. These results indicate that the antitumor activity of M4 is based on the NK cell-mediated tumor lysis enhanced by EM4.

Antiproliferative activity of the Netherlands propolis and its active principles in cancer cell lines.

The MeOH extract of the Netherlands propolis showed promising antiproliferative activity toward highly liver-metastatic murine colon 26-L5 carcinoma with an EC(50) value of 3.5 microg/ml. Further, antiproliferative activity-guided purification of the MeOH extract led us to isolate four flavonoids (1-4), seven cinnamic acid derivatives (5-11) and two new glycerol derivatives (12, 13), whose structures were elucidated on the basis of spectral analysis. The isolated compounds were tested for their antiproliferative activity against murine colon 26-L5, murine B16-BL6 melanoma, human HT-1080 fibrosarcoma and human lung A549 adenocarcinoma cell lines. The benzyl (9), phenethyl (10) and cinnamyl caffeates (11) possessed potent antiproliferative activities with EC(50) values of 0.288, 1.76 and 0.114 microM, respectively, toward colon 26-L5 carcinoma. These caffeates were considered to be active constituents of the Netherlands propolis in their antiproliferative activity. The antioxidative activity of these caffeates may play an important role in their antiproliferative activities.

alpha-Vinylation of 1,3-Dicarbonyl Compounds with Alkenyl(aryl)iodonium Tetrafluoroborates: Effects of Substituents on the Aromatic Ring and of Radical Inhibitors.

Direct alpha-vinylations of enolate anions derived from 1,3-dicarbonyl compounds with 4-tert-butyl-1-cyclohexenyl(aryl)iodonium 2 and 1-cyclopentenyl(aryl)iodonium tetrafluoroborates 3 are reported. Frequently, alpha-phenylations compete with the vinylations in the reaction of 1,3-dicarbonyl compounds with alkenyl(phenyl)iodonium salts 2a and 3a. Use of alkenyl(p-methoxyphenyl)iodonium salts 2b and 3b, however, leads to selective alpha-vinylation at the expense of the competing arylation of 1,3-dicarbonyl compounds. Use of an efficient aryl radical trap, 1,1-diphenylethylene, inhibits radical-induced decomposition of the alkenyl(aryl)iodonium salts, thereby improving the yields of alpha-vinylations of enolate anions derived from 1,3-dicarbonyl compounds.