Ribonucleotide reductase--a "target" of the action of nitrosomethylurea]

The antitumor and toxic effects of methylnitrosourea (MNU) are determined through its metabolic pathways. In organism MNU is subject to hydrolytic decomposition and denitrosation. It has been shown in vivo studies that MNU abdominal injections of therapeutic doses caused the inhibition of ribonucleotide reductase in mouse spleen, and therefore the DNA synthesis depress. The effect may apparently contribute to antitumor property of MNU. It has been estimated that destruction of M2 subunit of the enzyme is occurred. The relation between the loss of ribonucleotide reductase activity and the inhibition of protein synthesis was discussed. Besides, the cancerogenic and mutagenic properties of MNU were discussed as a result of imbalance of DNA precursor pools. Changes in contents of Fe(3+)-transferrin, ceruloplasmin, methemoglobin in blood and spleen of animals after MNU injections have been found. The changes were reversible after single MNU injection and became irreversible after multiple injections.     

Electrotropic acetylcholine action on the mammalian auricle by means of the "phase plane" trajectories of the action potential

A single sucrose gap techniques has been used to study action potentials and phase plane trajectories of them in atrial trabeculae of the rabbit. Using polynomial representations of current-voltage relationships a model of membrane action potential of atrial myocardial fibres is described and allows an interpretation of recording data from the phase plane trajectories. Our findings show: 1. Increasing extracellular calcium concentration increases a potassium conductivity of the atrial membrane. 2. An anomalous rectification concerning repolarizing currents in atrial fibres decreases with increasing extracellular calcium. 3. Acetylcholine (3.10(-4) g.cm-3) abolishes the anomalous rectification. These results are discussed in relation to previous electrophysiological studies of negative electrotropic effects of acetylcholine in cardiac muscle.     

A quantitative assessment of the "tendon" action of two-joint muscles]

Two-joint muscles are able to transmit mechanical energy between the links of the body having no common joint ("tendon action" of the muscles). It is proposed to calculate difference between control moment power in a joint and the sum of powers developed by all muscles serving this joint in order to determine the direction and rate of mechanical energy transfer through the two-joint muscles. It was shown that in the shock-absorbing phase of support in running two-joint muscles the energy transfers from distal to proximal links (from foot to thigh, and from shank to pelvis), in take-off phase-from proximal links to distal ones (from pelvis to shank, and from thigh to foot).     

The "two-headed" peptide inhibitors of interleukin-1 action

Two peptide fragments of IL-1 family proteins, ITGSE and VTKFYF compete with IL-1 for the cellular receptor. We synthesized a series of peptides composed of the sequences ITGSE and VTKFYK bound directly to each other or connected by such linkers as (Gly)(n), L- and D-Pro residues, Glu and Lys residues (with peptide bond formed by main amino and carboxy groups or by side chain groups), and beta-alanine and its homologues. Peptide IX with a gamma-Glu linker was the most potent inhibitor of IL-1 action. It was twice as potent as both of the peptides indicated.     

Dynamin: possible mechanism of "Pinchase" action.

Dynamin is a GTPase playing an essential role in ubiquitous intra cellular processes involving separation of vesicles from plasma membranes and membranes of cellular compartments. Recent experimental progress (. Cell. 93:1021-1029;. Cell. 94:131-141) has made it possible to attempt to understand the action of dynamin in physical terms. Dynamin molecules are shown to bind to a lipid membrane, to self-assemble into a helicoidal structure constricting the membrane into a tubule, and, as a result of GTP hydrolysis, to mediate fission of this tubule (). In a similar way, dynamin is supposed to mediate fission of a neck connecting an endocytic bud and the plasma membrane, i.e., to complete endocytosis. We suggest a mechanism of this "pinchase" action of dynamin. We propose that, as a result of GTP hydrolysis, dynamin undergoes a conformational change manifested in growth of the pitch of the dynamin helix. We show that this gives rise to a dramatic change of shape of the tubular membrane constricted inside the helix, resulting in a local tightening of the tubule, which is supposed to promote its fission. We treat this model in terms of competing elasticities of the dynamin helix and the tubular membrane and discuss the predictions of the model in relation to the previous views on the mechanism of dynamin action.     

Control of the action of phospholipases A by "vertical compression" of the substrate monolayer

Monolayers of rac-1,2-didodecanoyl-sn-glycero-3-phosphoglycerol at an air-water interface were "vertically compressed" by substituting an alkylated glass plate for air while maintaining a constant surface pressure of 15 mN m-1. At this surface pressure the overlaying of the lipid film by the alkylated surface resulted in an average increase of 16 A2/molecule in the mean molecular area of those phospholipid molecules residing at the interface between water and the alkylated glass. Subsequently, the activities of phospholipases A1 and A2 toward the monolayers were measured both in the presence and in the absence of the support. While phospholipase A1 activity was increased 4-fold by the support, the activity of phospholipase A2 was reduced to 15% of the activity measured in the absence of the alkylated surface. These findings indicate that such a "vertical compression" of the monolayer is likely to induce a conformational change in the phospholipid molecules, which in turn would cause the above reciprocal changes in the activities of phospholipases A1 and A2. A molecular model accounting to these findings is presented.     

The "cryptic" mechanism of action of glucagon-like peptide-2

Glucagon-like peptide-2 (GLP-2) is a peptide hormone with multiple beneficial effects on the intestine, including expansion of the mucosal surface area through stimulation of crypt cell proliferation, as well as enhancement of nutrient digestion and absorption. Recent advances in clinical trials involving GLP-2 necessitate elucidation of the exact signaling pathways by which GLP-2 acts. In particular, the GLP-2 receptor has been localized to several intestinal cell types that do not include the proliferating crypt cells, and the actions of GLP-2 have thus been linked to a complex network of indirect mediators that induce diverse signaling pathways. The intestinotropic actions of GLP-2 on the colon have been shown to be mediated through the actions of keratinocyte growth factor and insulin-like growth factor (IGF)-2, whereas small intestinal growth has been linked to IGF-1, IGF-2, and ErbB ligands, as well as the IGF-1 receptor and ErbB. The cellular source of these mediators remains unclear, but it likely includes the intestinal subepithelial myofibroblasts. Conversely, the anti-inflammatory and blood flow effects of GLP-2 are dependent on vasoactive intestinal polypeptide released from submucosal enteric neurons and nitric oxide, respectively. Finally, recent studies have suggested that GLP-2 not only modulates intestinal stem cell behavior but may also promote carcinogenesis in models of sporadic colon cancer. Further consideration of the molecular cross-talk and downstream signaling pathways mediating the intestinotropic effects of GLP-2 is clearly warranted.