Biomedical subjects

Andreas Becker

Publications and source records attributed to Andreas Becker.

25 records · Page 2Linked to original sources

PubMed2004

Effects of aesthetic abdominoplasty on abdominal wall perfusion: a quantitative evaluation.

Abdominoplasty procedures involve a high risk of early complications, including hematomas, seromas, necrosis, and wound-healing problems. Their rationale is evident from the vascular anatomy of the abdominal wall, as traditional abdominoplasty includes a division of the main perforating vessels. No studies exist to quantitatively assess the consequences of abdominoplasty on the perfusion of the random pattern abdominal flap. To address this issue and quantify the influence of classic abdominoplasty on the perfusion of the abdominal skin, the authors performed a prospective clinical trial including 15 low-risk patients undergoing abdominoplasty for aesthetic purposes. Perfusion of the abdominal flap was measured intraoperatively using the technique of dynamic laser-fluorescence-videoangiography. In the region between the umbilicus and the transverse scar (zone 1), the increment of fluorescence (the slope of the intensity curve during inflow of the indocyanine green) was recorded and compared with the intensity curve of normal tissue that was not involved in surgery (thoracic wall). The results of the intraoperative indocyanine green perfusography showed a significant impairment of the vascular supply of zone 1 in all patients. The mean perfusion index in this region was 17.2 percent (range, 5 to 32 percent) of the perfusion of the surrounding skin that was not involved in surgery. The complication rate was 33 percent (five patients) and included two cases of hematoma and three cases of scar dehiscence with skin and/or fat necrosis. These data indicate that conventional abdominoplasty including extended undermining and division of the superficial and the deep arterial systems causes profound devascularization of the abdominal flap. This might explain the high incidence of complications following this procedure.

Abdomen↗

PubMed2003

X-ray structure of glutathione S-transferase from the malarial parasite Plasmodium falciparum.

GSTs catalyze the conjugation of glutathione with a wide variety of hydrophobic compounds, generally resulting in nontoxic products that can be readily eliminated. In contrast to many other organisms, the malarial parasite Plasmodium falciparum possesses only one GST isoenzyme (PfGST). This GST is highly abundant in the parasite, its activity was found to be increased in chloroquine-resistant cells, and it has been shown to act as a ligandin for parasitotoxic hemin. Thus, the enzyme represents a promising target for antimalarial drug development. We now have solved the crystal structure of PfGST at a resolution of 1.9 A. The homodimeric protein of 26 kDa per subunit represents a GST form that cannot be assigned to any of the known GST classes. In comparison to other GSTs, and, in particular, to the human isoforms, PfGST possesses a shorter C-terminal section resulting in a more solvent-accessible binding site for the hydrophobic and amphiphilic substrates. The structure furthermore reveals features in this region that could be exploited for the design of specific PfGST inhibitors.

Animals↗

PubMed2003

Comparison of proteomic and genomic analyses of the human breast cancer cell line T47D and the antiestrogen-resistant derivative T47D-r.

In search of novel mechanisms leading to the development of antiestrogen-resistance in human breast tumors, we analyzed differences in the gene and protein expression pattern of the human breast carcinoma cell line T47D and its derivative T47D-r, which is resistant toward the pure antiestrogen ZM 182780 (Faslodex trade mark, fulvestrant). Affymetrix DNA chip hybridizations on the commercially available HuGeneFL and Hu95A arrays were carried out in parallel to the proteomics analysis where the total cellular protein content of T47D or T47D-r was separated on two-dimensional gels. Thirty-eight proteins were found to be reproducibly up- or down-regulated more than 2-fold in T47D-r versus T47D in the proteomics analysis. Comparison with differential mRNA analysis revealed that 19 of these were up- or down-regulated in parallel with the corresponding mRNA molecules, among which are the protease cathepsin D, the GTPases Rab11a and MxA, and the secreted protein hAG-2. For 11 proteins, the corresponding mRNA was not found to be differentially expressed, and for eight proteins an inverse regulation was found at the mRNA level. In summary, mRNA expression data, when combined with proteomic information, provide a more detailed picture of how breast cancer cells are altered in their antiestrogen-resistant compared with the antiestrogen-sensitive state.

Breast Neoplasms↗

PubMed2003

A structural model for actin-induced nucleotide release in myosin.

Myosins are molecular motor proteins that harness the chemical energy stored in ATP to produce directed force along actin filaments. Complex communication pathways link the catalytic nucleotide-binding region, the structures responsible for force amplification and the actin-binding domain of myosin. We have crystallized the nucleotide-free motor domain of myosin II in a new conformation in which switch I and switch II, conserved loop structures involved in nucleotide binding, have moved away from the nucleotide-binding pocket. These movements are linked to rearrangements of the actin-binding region, which illuminate a previously unobserved communication pathway between the nucleotide-binding pocket and the actin-binding region, explain the reciprocal relationship between actin and nucleotide affinity and suggest a new mechanism for product release in myosin family motors.

Actins↗

PubMed2002

X-ray structure of pyruvate formate-lyase in complex with pyruvate and CoA. How the enzyme uses the Cys-418 thiyl radical for pyruvate cleavage.

The glycyl radical enzyme pyruvate formate-lyase (PFL) synthesizes acetyl-CoA and formate from pyruvate and CoA. With the crystal structure of the non-radical form of PFL in complex with its two substrates, we have trapped the moment prior to pyruvate cleavage. The structure reveals how the active site aligns the scissile bond of pyruvate for radical attack, prevents non-radical side reactions of the pyruvate, and confines radical migration. The structure shows CoA in a syn conformation awaiting pyruvate cleavage. By changing to an anti conformation, without affecting the adenine binding mode of CoA, the thiol of CoA could pick up the acetyl group resulting from pyruvate cleavage.

Acetyltransferases↗

PubMed2002

Stimulation of beta-adrenoceptors activates astrocytes and provides neuroprotection.

Our previous studies established that induction of growth factor synthesis and neuroprotection by the beta(2)-adrenoceptor agonist clenbuterol in vitro and in vivo was associated with the activation of astrocytes, the major source of trophic factors in the brain. In the present study, we further investigated the specificity of beta(2)-adrenoceptor-mediated effects on astrocyte activation and neuroprotection. In mixed hippocampal cultures neuroprotection against glutamate-induced cell death by clenbuterol (1 microM) was blocked by the beta(1/2)-adrenoceptor antagonist propranolol and the specific beta(2)-adrenoceptor antagonists 1-[2,3-(Dihydro-7-methyl-1H-inden-4-yl)-oxy]-3-[(1-methylethyl)-amino]-2-butanol (ICI 118,551, 10 microM) and butoxamine (10 microM), while the beta(1)-adrenoceptor-selective antagonist metoprolol (10 microM) showed no effect. The beta(2)-adrenoceptor agonists clenbuterol (1-100 microM) and salmeterol (0.01-1 microM) induced profound morphological changes of cultured astrocytes which transformed into activated astroglia with pronounced dendrite-like processes. This phenomenon was blocked by butoxamine (1 mM) and propranolol (10 microM), but not by metoprolol (10 microM). However, similar morphological changes in astrocytes were also observed after stimulation of beta(1)-adrenoceptors by dobutamine (1-10 microM) and norepinephrine (1-10 microM). This effect was blocked by propranolol (10 microM) and metoprolol (10 microM) but not by butoxamine (1 mM), suggesting that stimulation of either beta(1)- or beta(2)-adrenoceptors was sufficient to induce activation of astrocytes. In addition, beta(1)-adrenoceptor stimulation by dobutamine (1-10 microM) protected hippocampal neurons against glutamate toxicity. In a model of focal cerebral ischemia in mice the cerebroprotective effect of clenbuterol (0.3 mg/kg) was blocked by propranolol (5 mg/kg) and butoxamine (5 mg/kg). Interestingly, the infarct size was reduced after co-treatment with clenbuterol (0.3 mg/kg) and metoprolol (5 mg/kg) as compared to clenbuterol treatment (0.3 mg/kg) alone. In conclusion, activation of astrocytes and neuroprotection can be achieved by stimulation of either beta(1)- or beta(2)-adrenoceptors in vitro, whereas in vivo neuroprotection is preferentially mediated through beta(2)-adrenoceptors.

Adrenergic beta-Agonists↗

PubMedDate not supplied

A complete substitutional analysis of VIP for better tumor imaging properties.

Since numerous tumor cells overexpress the vasoactive intestinal peptide (VIP) receptor subtype 1 (VPAC(1)), VIP-dye conjugates would be useful as contrast agents for in vivo imaging. However, proteolytic degradation of VIP in vivo limits their diagnostic use and highlights the need for structurally optimized VIP derivatives with improved pharmacokinetics. Here, we applied parallel nano-synthesis of cleavable peptides on cellulose membranes to perform a complete VIP substitutional analysis. The resulting 504 different VIP-dye analogs were tested for cell binding by flow cytometry. They provided a detailed analysis of amino acid positions essential for binding to VPAC(1) overexpressing cells. A generalized VIP-dye binding motif derived from the substitutional analysis results served as a reference point for further optimization. An [Arg8]-VIP-dye analog showed increased stability towards proteolytic degradation, good tumor-to-tissue contrast in mice and a longer half-life in vivo.

Amino Acid Sequence↗