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Biomedical subjects

A Krautheim

Publications and source records attributed to A Krautheim.

7 recordsLinked to original sources
PubMed2000

Michael adducts of ascorbic acid as inhibitors of protein phosphatase 2A and inducers of apoptosis.

Michael adducts of ascorbic acid with alpha,beta-unsaturated carbonyl compounds have been shown to be potent inhibitors of protein phosphatase 1 (PP1) without affecting cell viability at the respective concentrations. Here we were able to show that higher concentrations can partially inhibit PP2A activity and concomitantly induce apoptotic cell death. A nitrostyrene adduct of ascorbic acid proved to be a more potent and effective inhibitor of PP2A as well as a stronger inducer of apoptosis. These adducts only slightly lost their cytotoxic potential in multidrug resistant cells that were 10-fold less sensitive to apoptosis induction by okadaic acid and vinblastine.

Animals↗
PubMed2000

Hamster pancreatic beta cell lines with altered sensitivity towards apoptotic signalling by phosphatase inhibitors.

Specific inhibitors of serine/threonine phosphatases like okadaic acid can induce apoptotic cell death in the pancreatic beta cell line HIT. Cultivation in stepwise increased concentrations of okadaic acid enabled the isolation of HIT100R cells which proliferate at 100 nM okadaic acid (8 - 10 times the initially lethal concentration). These two cell lines were used to characterize the events triggered by okadaic acid that led to apoptosis. Biochemical markers, e.g. cytochrome c release from mitochondria and increase of caspase-3-like activity, revealed that induction of apoptosis by 100 nM okadaic acid in parental HIT cells started with the release of cytochrome c. In HIT100R cells 500 nM okadaic acid were necessary to induce alterations comparable to those observed with 100 nM okadaic acid in non-resistant HIT cells. In contrast to okadaic acid, the potency of the structurally different phosphatase inhibitor cantharidic acid to induce cytochrome c release, increase of caspase-3-like activity and DNA fragmentation was comparable in HIT and HIT100R cells. Thus, no cross-resistance between these phosphatase inhibitors seemed to exist. Phosphatase activity in extracts from HIT and HIT100R cells did not differ in its total amount or in its sensitivity for okadaic acid. Since higher concentrations of okadaic acid were needed to induce apoptosis in HIT100R cells, a compromised intracellular accumulation of the toxin appeared likely. Functional and structural analysis revealed that this was achieved by the development of the multidrug resistance phenotype in HIT100R cells. The underlying mechanism appeared to be the enhanced expression of the pgp1 but not the pgp2 gene.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Interaction between CCK and a preload on reduction of food intake is mediated by CCK-A receptors in humans.

Cholecystokinin (CCK) interacts with neural signals to induce satiety in several species, but the mechanisms are unclear. We therefore tested the hypothesis that alimentary CCK (CCK-A) receptors mediate the interaction of CCK with an appetizer on food intake in humans. CCK octapeptide (CCK-8, 0.75 microgram infused over 10 min) or saline (placebo) with concomitant infusions of saline (placebo) or loxiglumide, a specific CCK-A antagonist, was infused into 16 healthy men with use of a double-blind, four-period design. All subjects received a standard 400-ml appetizer (amounting to 154 kcal) but were free to eat and drink thereafter as much as they wished. The effect of these infusions on feelings of hunger and satiety and on food intake was quantified. CCK-8 induced a reduction in calorie intake (P < 0.05) compared with saline. Furthermore, a decrease in hunger feelings (P < 0.05, saline-CCK-8 vs. all other treatments) and an increase in fullness were observed. These effects were antagonized for hunger and fullness by loxiglumide. We conclude that CCK-8 interacts with an appetizer to modulate satiety in humans. These effects are mediated by CCK-A receptors.

Adult↗
PubMed1999

Phosphatase inhibitors induce defective hormone secretion in insulin-secreting cells and entry into apoptosis.

A long-term (> or =24 h) exposure of insulin-secreting HIT T15 cells to the phosphatase inhibitor, okadaic acid (OA), at concentrations inhibiting serine/threonine phosphatases 1 (PP1) and 2A (PP2A) reduced proliferation and insulin secretion. The reduced proliferation was related to the induction of apoptosis as evidenced by morphological criteria and the occurrence of internucleosomal DNA fragmentation after 15 h in 50 nM OA. The compromised insulin secretion was not simply a consequence of a lowered hormone content and cell growth, but comprised also a complete suppression of secretion stimulated by K+ depolarisation and forskolin. K+ depolarisation of HIT cells cultured for 24 h in 50 nM OA resulted in a nearly unimpaired influx of Ca2+, but did not induce secretion. These observations suggest that the secretory defect may be localised distal to Ca2+ influx in stimulus secretion coupling of insulin-secreting cells.

Apoptosis↗
PubMed1999

Codon 215 mutations in human immunodeficiency virus-infected pregnant women. Swiss Collaborative 'HIV and Pregnancy' Study.

In 1994, the Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 demonstrated a two-thirds reduction of perinatal human immunodeficiency virus (HIV) type 1 transmission with zidovudine chemoprophylaxis. However, zidovudine alone does not fully suppress HIV replication, and chemoprophylaxis with zidovudine alone might select for zidovudine-resistant viral variants, decreasing the efficacy of zidovudine prophylaxis and affecting future responses to combined antiretroviral regimens. Sixty-two HIV-infected pregnant women consecutively enrolled in the ongoing Swiss HIV and Pregnancy Study were prospectively evaluated for the presence or development of zidovudine resistance by analysis of codon 215 of the reverse transcriptase gene. Six women (9.6%) harbored a codon T215Y/F mutation, which is associated with high-level resistance to zidovudine. Postnatal evaluation was completed in all children of mothers harboring the mutation. None was HIV-infected. The observed prevalence of codon 215 mutations of 9.6% raises important concerns regarding the future use of the PACTG 076 regimen.

Amino Acid Substitution↗