Several chemically defined plant extracts were investigated for their antiviral action on herpes simplex virus (HSV-1, HSV-2)-infected African green monkey kidney cells and human adenocarcinoma cells, using a plaque formation assay. Among them, the monomeric hydrolyzable tannins, oligomeric ellagitannins and condensed tannins, having galloyl groups or hexahydroxydiphenoyl groups, had the most potent anti-HSV activity. Their 50% effective doses (0.03-0.1 microgram/ml) were by two-three orders of magnitude lower than their 50% cytotoxic doses (greater than 10 micrograms/ml). On the other hand, gallic acid, neutral polysaccharides, chemically modified (N,N-dimethylaminoethyl-, carboxymethyl-, and sulfated-) glucans, sialic acid-rich glycoproteins, and uronic acid-rich pine cone polysaccharide showed little or no activity. Using radiolabeled virus particles, we demonstrated that the anti-HSV effect of the tannins is due to inhibition of virus adsorption to the cells.

Adsorption↗

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Organ distribution and toxicity of lignin.

It is suggested that 125I-labeled natural and synthetic lignins administered orally to mice are absorbed through the digestive tract and excreted via urine, in addition to feces. Intravenous administration of lignins produced preferential accumulation of radioactivity in the liver and also in the stomach tissue and lung. It also induced an increase in the spleen weight (splenomegaly), suggesting that the immune system might be stimulated. Lignin significantly increased the heme oxygenase among several hepatic enzymes. Macroscopical examination of mice which were administered a lethal dose of lignin showed nasal and lung congestion leading to hemorrhage.

Absorption↗

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Production of hydrogen peroxide in cancerous tissue by intravenous administration of sodium 5,6-benzylidene-L-ascorbate.

We investigated whether the antitumor action of sodium 5,6-benzylidene-L-ascorbate (SBA) is mediated via oxidation-involved mechanism, in three different systems: 3'-methyl-4-dimethylaminoazobenzene (DAB)-induced rat hepatocellular carcinoma (in vivo), its homogenate (semi in vivo), and cultured cells (in vitro). Oral intake of DAB irreversibly produced hepatocellular carcinoma in rats, with a maximum incidence of carcinogenesis after 4 months. Intravenous administration of SBA induced vacuolar, eosinophilic degeneration and nuclear debris, producing greater amounts of ESR signal of ascorbate radical and hydrogen peroxide (H2O2)-derived chemiluminescence (CL) (H2O2-CL) in the cancerous tissue than in the normal tissue. When SBA was directly added to the homogenates, higher amounts of ascorbate radical and H2O2-CL were generated in cancerous tissues. When SBA was added to the RPMI1640 medium supplemented with 10% fetal bovine serum, methionine was oxidized to methionine sulfoxide and H2O2 was produced in amounts that sufficiently induce apoptotic cell death in human promyelocytic leukemic HL-60 cells. Cytotoxic activity of SBA was significantly reduced by catalase. These data suggest that antitumor activity of SBA in vivo might at least in part be due to H2O2, produced from SBA.

Animals↗

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Amino acid utilization during apoptosis in HL-60 cells.

Human promyelocytic leukemia (HL-60), human squamous carcinoma (HSC-2, HSC-4, NA) and rat pheochromocytoma (PC-12) cell lines consumed nonpolar (Leu, Ile, Val, Cys, Met, Phe), neutral polar (Gln, Ser, Thr, Tyr) and basic polar amino acids (Arg, Lys, His), whereas they produced nonpolar (Gly, Pro, Ala) and acidic polar amino acids (Glu). The consumption rate of Ser and Arg by HL-60 cells was significantly higher than that of other cell lines. During apoptosis of HL-60 cells induced by either sodium ascorbate, sodium 5,6-benzylidene-L-ascorbate (SBA) or dopamine, the consumption of nonpolar and polar amino acids (neutral or acidic) generally declined, except for Cys, Met and Arg, whereas the production of Gly and Glu was slightly increased. Since the intracellular concentration of cGMP was not significantly changed before and after ascorbate treatment, nitric oxide might not be involved in the ascorbate-induced apoptosis. The present data demonstrates that consumption rate of nonpolar and polar amino acid, whether neutral, acidic or basic, was reduced almost evenly during the apoptosis induction. This suggests that apoptosis-associated changes in the amino acid utilization might not be significantly affected by ATP depletion, which might be caused by mitochondrial dysfunction.

Adenosine Triphosphate↗

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Radical modulation activity of pine cone extracts of Pinus elliottii var. Elliottii.

The radical modulation activity of lignins prepared from the cone of Pinus elliottii var. Elliottii was investigated, using ESR spectroscopy. These lignins produced radical(s) under alkaline conditions, and the radical intensity was increased with increasing pH. Lower concentrations of lignins slightly reduced the radical intensity of sodium ascorbate, whereas higher concentrations of lignins enhanced both the radical intensity and cytotoxic activity of sodium ascorbate. Lignins effectively scavenged superoxide anion, produced by hypoxanthine-xanthine oxidase reaction. Elliottii lignins significantly inhibited the human immunodeficiency virus (HIV)-induced cytopathic effect, in similar fashions to other natural, commercial and synthetic lignins. Pretreatment of mice with lignins significantly protected them from the lethal infection with E. coli. Crude alkaline extracts of Elliottii pine cone displayed similar magnitude of activity with lignins. These data further supports the medicinal efficacy of plant extracts.

Animals↗

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Prevention of oral diseases by polyphenols (review).

This review summarizes the current data on the effects of natural products on various oral diseases, together with their basic biological activities. We have focused on polyphenols and their secondary metabolites, such as tannins, lignins and flavonoids, and their modulating factors, including saliva proline-rich proteins. These substances are found in a wide variety of plant sources such as vegetables, herbs, nuts and teas, and effectively reduce the incidence of carcinogenesis in the oral cavity, inhibit plaque growth and adsorption of oral bacteria, and inhibit the replication of various viruses. The mechanism of their action includes: the direct inactivation of the bacteria and viruses, inhibition of their replication enzymes, induction of apoptosis in tumor cells, stimulation of monocytes/macrophages to produce cytokines, and stimulation of myeloperoxidase-dependent iodination of neutrophiles. Polyphenols showed biphasic actions, acting as antioxidants at lower doses, but acting as prooxidants at higher doses. The development and progression of oral diseases might be modified not only by these natural products, but also by interaction with saliva, proline-rich proteins, antioxidants, metals and dental materials.

Animals↗

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Relationship between radical intensity and biological activity of cacao husk extracts.

The relationship between radical intensity and biological activity of cacao husk extracts was investigated. Electron spin resonance (ESR) spectroscopy demonstrated that the radical intensity of hexane, acetone, methanol and 70% methanol extracts increased with water-solubility. Several fractions of these husk extracts, separated by different column chromatographies, significantly inhibited the cytopathic effect of human immunodeficiency virus (HIV) infection in parallel with their radical intensity. However, their cytotoxic activity against human leukemic and carcinoma cell lines is not always correlated with their radical intensity. Water-soluble and lipophilic compounds might induce cytotoxic activity by different mechanisms.

Anti-HIV Agents↗

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Interaction between sodium 5,6-benzylidene-L-ascorbate and gallic acid.

The interaction between sodium 5,6-benzylidene-L-ascorbate (SBA) and gallic acid was investigated by two different parameters: radical intensity and cytotoxicity induction. These compounds produced ESR signals of radicals under alkaline conditions. The addition of increasing concentrations of SBA completely scavenged the gallate radical and replaced the latter with its ascorbate radical. On the other hand, gallic acid dose-dependently enhanced the radical intensity of SBA. Both of these two compounds dose-dependently reduced the viable cell number of human squamous carcinoma HSC-2 cells without inducing internucleosomal DNA cleavage. Electron micrographs of the dying cells demonstrate the irreversible degenerative changes especially in the cytoplasm of the cells. The cytotoxic activity of gallic acid was almost completely eliminated by catalase, whereas SBA was totally insensitive to catalase. When these two compounds were mixed together before adding to HSC-2 cells, the cytotoxic activity of gallic acid was significantly reduced by SBA, whereas that of SBA was not reduced by gallic acid. SBA dose-dependently reduced the gallate oxidation in the culture medium. The interaction between SBA and gallic acid may modify their individual biological activity.

Antineoplastic Agents↗

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Endonuclease activity and hydrogen peroxide-induced cytotoxicity in human glioblastoma and glioma cell lines.

Hydrogen peroxide (H2O2) induced internucleosomal DNA cleavage in human myelogenous leukemic cell lines (HL-60, ML-1, THP-1, U-937), but not in human glioblastoma (T98G, U87MG) and glioma (KG1C) cell lines. However, H2O2 produced apoptotic cells, characterized by cell shrinkage, nuclear fragmentation and chromatin condensation in glioblastoma and glioma cell lines. Autodigestion experiments revealed that the major endonucleases, present in all leukemic, glioblastoma and glioma cell lines, were divalent cation-independent endonuclease(s). The endonudease(s) present in the lysates of all these cells were activated at acidic, but not at neutral pH. The results suggest that the endonuclease activity might be differently regulated between leukemic and glioma cell lines.

Apoptosis↗

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Antitumor activity of benzo[a]phenothiazines.

We have previously reported on the diverse biological activities of benzo[a]phenothiazines, such as the induction of antitumor and antimutagenic activity in vivo, and differentiation and apoptosis in vitro. The relationship of radical generation and pi-spin density or dipole moment was investigated, using quantum-chemical calculation with UHF/PM3. These data suggest that the origin of radical generation by active benzo[a]phenothiazines, which affect such biological activities might be N-atom at position 12.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

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Chemical structure and tumor type specificity of "half-mustard type" phenothiazines.

The antiproliferative activity of six "half-mustard type" phenothiazines against a total of 54 tumor cell lines: 4 leukemia, 9 non-small-cell lung, 7 colon-, 5 CNS-, 8 melanoma, 6 ovarian-, 8 renal-, 1 prostate and 6 breast cancer was determined by NCI-Information Intensive-Approach. The C-2 position of phenothiazines were substituted with H, Cl and CF3 groups. The half-mustard and ring system was linked either by a propylene or a butylene bridge. Colon-cancer cell showed the highest sensitivity against "half-mustard type" phenothiazines, followed by leukemia, melanoma, prostate-, CNS-, breast-, lung-, renal and ovarian cancer cells. These data suggest the "cancer-type-specific" antitumor action of "half-mustard type" phenothiazines.

Antineoplastic Agents, Alkylating↗

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Establishment and characterization of human immature teratoma cell line (TES-1).

A new human immature teratoma cell line, TES-1, was established from a surgical specimen from a 12-year old male with third ventricular immature teratoma. TES-1 shows polygonal morphology rich in neurites, and proliferated as adherent monolayer, with an approximate population doubling time of 48 hours. Electron microscopic analysis revealed the presence of swollen rough endoplasmic reticulum, and prominent lipid droplets, lysosomes and microfilaments. The chromosome numbers were between 41 and 160 (mode 78), including abnormal karyotypes 1p-, 5q-, 12p+ and 17p+ (G-band analysis). Hetero-transplantation of TES-1 into BALB/c nude mice produced no visible tumors. Multipotential differentiation was not induced in TES-1 monolayer culture, but significant neuron specific enolase activity was expressed in both extracellular (by RIA method) and intracellular fractions (by immunohistochemical method), suggesting the differentiation toward neurocytes. This cell line provides a useful in vitro model for the pathophysiological analysis of immature teratoma.

Animals↗

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Electronic structure and cytotoxic activity of "half-mustard type" phenothiazines by MM3 and PM3 methods.

Among 54 cancer cell lines, colon-cancer cells were the most sensitive to six "half-mustard type" phenothiazines [7-12], followed by leukemia, melanoma, prostate-, CNS-, breast-, lung-, renal and ovarian cancer cells. The distribution of electrostatic potential (ESP) of "half-mustard type" phenothiazines [7-12] suggests that the ESP surface of urea site is important for the interaction between "half-mustard type" phenothiazines [7-12] and target cancer cell structures (or DNA base sequence). Actually, the urea site of "half-mustard type" phenothiazines displayed extensive variability in the energy of lone pair orbital and net atomic charges of N1, 0 and N3 atoms.

Algorithms↗

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Radical intensity and cytotoxicity of butylated hydroxyanisole and its orthobisphenol dimer.

The radical intensity of BHA (4-Hydroxy-3-t-butylanisole) and its dimer (3,3'-Di-t-butyl-5,5'-dimethoxy-1,1'-biphenyl-2,2'-diol, Bis-BHA) were compared with their cytotoxic activity. ESR spectroscopy showed that BHA produced characteristic five peaks of radicals under alkaline conditions (pH > 9.5). At higher pH, BHA radical rapidly disappeared, and progressively transformed into new radical species, as detected by the splitting of the ESR signal. BHA showed higher cytotoxic activity against salivary gland tumor cell line than against normal human gingival fibroblast. On the other hand, Bis-BHA did not produce any detectable amounts of radicals at wide ranges of pH, corresponding with its weaker cytotoxic activity as compared with BHA. BHA scavenged DPPH (1,1-Diphenyl-2-picrylhydrazyl) radical and superoxide anion, more efficiently than Bis-BHA. The present study demonstrated that BHA is more cytotoxic, produces higher amounts of radicals and more efficiently scavenges various radical species, as compared with Bis-BHA. This suggests the possible link between the cytotoxic activity and radical generation/scavenging activity in BHA-derived compounds.

Antioxidants↗