Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors. (65/89)


Cantharis in the early treatment of minor burns. (66/89)

The analgesic action of the homeopathic preparation Cantharis in the treatment of minor burns was assessed in a series of 34 patients. Under double blind conditions no statistically significant difference was found between Cantharis and a placebo.  (+info)

Dose response in the tetrazolium test for skin carcinogenicity. (67/89)

The tetrazolium test for skin carcinogenicity was performed with different doses of (i) a strong, complete carcinogen with moderate cytotoxicity, 20-methylcholanthrene; (ii) a weak carcinogen with strong cytotoxicity, the promoter 12-O-tetradecanoylphorbol-13-acetate; (iii) a strong toxic substance with very weak carcinogenicity for the skin, cantharidin; and (iv) X-rays. The dose-response relationship was determined, and the validity of the tetrazolium test was confirmed. However, substances strongly cytotoxic must be tested in small doses to avoid necrosis. The tetrazolium test should not be used on the skin to test substances carcinogenic for organs other than skin.  (+info)

Phosphatase inhibitors block in vivo binding of peptides to class I major histocompatibility complex molecules. (68/89)

Class I major histocompatibility complex (MHC) molecules are heterotrimers of heavy chains, beta 2-microglobulin, and 8-10 amino acid-long peptides. Assembly of class I MHC molecules into complexes which are stable and can be transported to the cell surface occurs soon after insertion of individual subunits into the endoplasmic reticulum (ER). To identify subcellular compartments required for class I MHC assembly, we studied class I biosynthesis in human cell lines treated with several inhibitors of intracellular transport. We found that HLA-B701 molecules do not assemble in CIR transfectants in which a block in protein transport from the ER is established by treatment with phosphatase inhibitors. In contrast, stable HLA-B701 complexes form in cells in which the ER becomes mixed with the Golgi after treatment with brefeldin A. Neither treatment impaired binding of HLA-B701 to the ER-resident protein calnexin, and unassembled heavy chains in phosphatase-inhibited cells showed prolonged association with calnexin. In addition, the mouse class I molecule H-2Db, which binds beta 2-microglobulin in human T2 cells in the absence of transporter of antigenic peptides, formed complexes in CIR cell transfectants treated with phosphatase inhibitors. Taken together, these data demonstrate that phosphatase inhibitors do not prevent assembly of class I heavy chain beta 2-microglobulin dimers, but instead interfere with peptide loading. These results are consistent with the possibility that class I MHC molecules are transported from their initial site of insertion into the rough ER before binding peptides, or alternatively that peptide loading mediated by transporter of antigenic peptides is blocked by phosphatase inhibitors.  (+info)

Induction of the polyamine-biosynthetic enzymes in mouse epidermis and their specificity for tumor promotion. (69/89)

The induction of ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase in mouse epidermis by various classes of tumor-promoting and nonpromoting compounds has been studied in order to determine the specificity of this response for tumor promotion. The effect of topical applications of a series of phorbol esters on these enzyme activities correlated well with their promoting abilities. Iodoacetic acid, anthralin, and Tween 60, all promoting compounds, also stimulated both of these enzyme activities after single and multiple applications. The hyperplastic agents acetic acid, cantharidin, and ethyl phenylpropriolate, however, had little effect on ornithine decarboxylase activity but a pronounced effect on epidermal S-adenosyl-L-methionine decarboxylase activity. The specificity of the ornithine decarboxylase response for tumor promotion was suggested by the results of the above experiments as well as the stimulatory effect of a completely carcinogenic dose of 7,12-dimethylbenz[a]anthracene; a lower initiating dose had no effect. In addition, epidermal tumors produced by a two-stage procedure showed consistently high levels of ornithine decarboxylase activity but variable levels of S-adenosyl-L-methionine decarboxylase activity.  (+info)

Pharmacodynamic activity of a cephalosporin, Ro 40-6890, in human skin blister fluid: antibiotic activity in concert with host defense mechanisms. (70/89)

The pharmacokinetics of an antimicrobial drug in human plasma and in vitro susceptibility testing of an antimicrobial drug do not necessarily predict its efficacy in vivo. Therefore, the combined activity of an antimicrobial drug and blood-derived polymorphonuclear leukocytes (PMN) against Staphylococcus aureus were investigated in vitro. In addition, a pharmacological model allowing analysis of the bactericidal activity of a drug-containing exudate against S. aureus ex vivo was developed. For this purpose, a phagocytic-bactericidal assay was miniaturized to a volume of 100 microliters in order to test the bactericidal activities of an antimicrobial drug with blood PMN in vitro and with skin blister fluid (CBF) ex vivo. Ro 40-6890, the active metabolite of the ester prodrug Ro 41-3399, was used as the test drug. Killing of S. aureus was clearly enhanced when Ro 41-6890 was combined in vitro with a suboptimal number of blood-derived PMN. In eight healthy volunteers, skin blisters were provoked by plasters containing cantharidin. Following a single oral dose of Ro 41-3399, CBF containing PMN was sampled at regular intervals and incubated ex vivo with S. aureus (5 x 10(5) CFU/ml) for 2, 4, 6, and 24 h at 37 degrees C. Concentrations of Ro 40-6890 were measured in CBF (CCBF) and plasma. Ro 40-6890 distributed well from plasma into CBF. When CCBF was below the MIC, an enhanced effect of Ro 40-6890 and host defense factors present in CBF against S. aureus was observed. In conclusion, the present model can provide additional information on human plasma drug concentrations and MICs established in vitro.  (+info)

Cantharidin, another natural toxin that inhibits the activity of serine/threonine protein phosphatases types 1 and 2A. (71/89)

Cantharidin, a natural toxicant of blister beetles, is a strong inhibitor of protein phosphatases types 1 (PP1) and 2A (PP2A). Like okadaic acid, cantharidin inhibits the activity of the purified catalytic subunit of PP2A (IC50 = 0.16 microM) at a lower concentration than that of PP1 (IC50 = 1.7 microM) and only inhibits the activity of protein phosphatase type 2B (PP2B) at high concentrations. Dose-inhibition studies conducted with whole cell homogenates indicate that cantharidin also inhibits the native forms of these enzymes. Thus, cantharidin, which is economical and readily available, may be useful as an additional probe for studying the functions of serine/threonine protein phosphatases.  (+info)

Inhibition of protein phosphatase 1 stimulates secretion of Alzheimer amyloid precursor protein. (72/89)

BACKGROUND: Aberrant metabolism of the Alzheimer amyloid precursor protein (APP) or its amyloidogenic A beta fragment is thought to be centrally involved in Alzheimer's disease. Nonamyloidogenic processing of APP involves its cleavage within the A beta domain by a protease, termed alpha-secretase, and release of the large extracellular domain, termed APPS. Secretion of APPS can be stimulated by phorbol esters, activators of protein kinase C, with concurrent inhibition of A beta production. While the role of protein kinases of APP metabolism has been investigated, considerably less effort has been devoted to elucidating the role played by protein phosphatases. Okadaic acid, a protein phosphatase inhibitor, has been shown to stimulate secretion of APPS, but the identity of the phosphatase involved has not been investigated. MATERIALS AND METHODS: The secretion of APPS from COS-1 cells was measured in the absence or presence of various doses of serine/threonine-specific phosphatase inhibitors. Quantitation of the derived IC50 values was used to determine the identity of the phosphatase involved in the control of APP secretion. RESULTS: The availability of protein phosphatase inhibitors with different relative potencies against the different types of serine/threonine-specific protein phosphatase allowed us to examine which of the four known types of protein phosphatase might be involved in the regulation of APP secretion. Both okadaic acid and calyculin A stimulated the secretion of APP from COS-1 cells in a dose-dependent manner. The half-maximal dose for stimulation of APP secretion was approximately 100-fold higher with okadaic acid than with calyculin A. CONCLUSIONS: The nearly 100-fold difference in the observed IC50 values for okadaic acid and calyculin A implicates a type 1 protein phosphatase in the control of APPS production. Protein phosphatase 1 (PP1) is known to be highly expressed in adult mammalian brain, both in neurons and glia. The identification of a specific phosphatase type in the control of APP secretion opens new avenues to the development of rational therapeutic intervention strategies aimed at the prevention and/or treatment of Alzheimer's Disease.  (+info)