Deregulation of hepatocyte nuclear factor 4 (HNF4)as a marker of epithelial tumors progression.

Tissue-specific transcription factors forming the regulatory cascades which determine the specification and differentiation of epithelial cells during embryogenesis, play the central role in the control of functional and morphological properties of different cell types. Hepatocyte nuclear factors (HNFs) network is one of the most investigated tissue-specific regulatory systems which controls the specification and maintenance of differentiation of several epithelial cell types. Nuclear receptor HNF4α is one of the central elements of this regulatory network in the liver. We have found that deregulation of this gene is associated with rodent and human hepatocellular carcinoma (HCC) progression and induces the increase of proliferation rate, loss of epithelial morphology, dedifferentiation and metastasis. Restoration of HNF4α expression in dedifferentiated cells induced partial reversion of highly malignant phenotype both in vitro and in vivo. In human HCC samples HNF4α transcription was completely lost or significantly decreased in about 70% of HCCs, not associated with hepatitis B virus infection. Decrease of HNF4α isoforms expression correlated with poor prognosis. Thus we propose HNF4α is a candidate tumor suppressor for hepatic cells. Dysfunction of different HNFs was also reported in other epithelial tumors. We suppose that tissue-specific transcription factors which control the key steps of definite differentiation programs and are capable to receive and modulate extracellular signals can be considered as promising tumor suppressor candidates for their corresponding tissues.

Tissue-specific transcription factors in progression of epithelial tumors.

Dedifferentiation and epithelial-mesenchymal transition are important steps in epithelial tumor progression. A central role in the control of functional and morphological properties of different cell types is attributed to tissue-specific transcription factors which form regulatory cascades that define specification and differentiation of epithelial cells during embryonic development. The main principles of the action of such regulatory systems are reviewed on an example of a network of hepatocyte nuclear factors (HNFs) which play a key role in establishment and maintenance of hepatocytes--the major functional type of liver cells. HNFs, described as proteins binding to promoters of most hepatospecific genes, not only control expression of functional liver genes, but are also involved in regulation of proliferation, morphogenesis, and detoxification processes. One of the central components of the hepatospecific regulatory network is nuclear receptor HNF4alpha. Derangement of the expression of this gene is associated with progression of rodent and human hepatocellular carcinomas (HCCs) and contributes to increase of proliferation, loss of epithelial morphology, and dedifferentiation. Dysfunction of HNF4alpha during HCC progression can be either caused by structural changes of this gene or occurs due to modification of up-stream regulatory signaling pathways. Investigations preformed on a model system of the mouse one-step HCC progression have shown that the restoration of HNF4alpha function in dedifferentiated cells causes partial reversion of malignant phenotype both in vitro and in vivo. Derangement of HNFs function was also described in other tumors of epithelial origin. We suppose that tissue-specific factors that underlie the key steps in differentiation programs of certain tissues and are able to receive or modulate signals from the cell environment might be considered as promising candidates for the role of tumor suppressors in the tissue types where they normally play the most significant role.

Cosmogenic 22Na as an index of the residence time of water in freshwater basins: a review.

The goal of this review is to draw attention to an opportunity for the use of cosmogenic (22)Na for dating young surface and underground waters. After 1961 when a significant quantity of (22)Na was released into the environment as a result of nuclear weapon tests, its concentrations in river waters were greatly increased, and a return to natural (cosmogenic) levels took until the mid-1980s. The studies made during this non-steady-state period showed that the one-box model for freshwater basin correctly describes the experimental data. For the 19 studied basins of Russia, the Baltic States and Japan, a calculation based on this model gave values for the mean residence time of water in the range from 4 to 23 years. Now, only cosmogenic (22)Na is in the environment, and it is the single cosmogenic radionuclide at present, which can serve as a steady-state tracer for dating young waters (up to some decades).

Mesoscale engines by nonlinear friction.

A new approach to build mesoscopic-size engines that move translationally or rotationally and can perform useful functions such as the pulling of a cargo is presented. The approach is based on the transformation of internal vibrations of the moving object into directed motion, making use of the nonlinear properties of friction. This can be achieved by superimposing time-dependent external fields that break the spatial symmetry. The motion can be controlled and optimized by adjusting the system parameters.

Directed molecular transport in an oscillating symmetric channel.

A mechanism responsible for the directed transport and molecular separation in a symmetric channel is proposed. We found that under the action of spatial harmonic oscillations of the channel, the system exhibits a directed transport in either direction, presenting multiple current reversals as the amplitude and/or frequency of the oscillations are varied. The particles of different masses may be forced to move with different velocities in the same or in the opposite directions by properly adjusting driving parameters. The directed transport can be produced in both directions even in the absence of thermal noise; the latter can speed up or slow down the transport depending on the system parameters.

Lithium secretion in kidneys of amphibians and reptiles under hydrated conditions.

Renal lithium transport was studied at different hydration levels in five species of anuran amphibians (Bufo bufo, B. danatensis, B. viridis, Rana ridibunda, and R. temporaria), two species of urodeles (Triturus vulgaris and T. cristatus) and four species of reptiles (lizards Eremias multiocellata, Lacerta vivipara, Trapelus sanguinolentus, and Teratoscincus scincus). Under dehydration conditions, Li+ was reabsorbed in the kidneys of amphibians ans reptiles, but to a lesser degree than in mammalian kidneys: the ratio of lithium clearance (CLi) to glomerular filtration rate (GFR)--fractional lithium excretion--in dehydrated animals was in the range 0.5-0.8. The transition to the hydrated state resulted in a cessation of net renal lithium reabsorption. Under condition of high hydration, all the animals studied, except for urodeles, showed net renal secretion of Li+, i.e., CLi exceeded GFR. The ratio CLi/GFR was 1.2-1.3 in hydrated anurans and 1.7-2.3 in hydrated lizards. In urodeles, this ratio was approximately unity. It is suggested that renal lithium secretion in hydrated amphibians and reptiles reflects fluid secretion in the proximal tubule, which is additional to the glomerular filtration mechanism of fluid delivery to nephron under water loading.

Potassium channels of the lamprey erythrocyte membrane exhibit a high selectivity to K+ over Rb+: a comparative study of 86Rb and 41K transport.

In order to assess the specificity of potassium channels, we examined the K+ transport pathways in the lamprey red blood cells using 86Rb and stable isotope 41K as tracers measured by the mass spectrometric method. Upon replacing 4 mmol/l K+ with 4 mmol/l Rb+ in the incubation medium, the rate coefficient for unidirectional 86Rb influx (Kin) was significantly reduced from 1.48 +/- 0.10 h-1 to 0.82 +/- 0.05 h-1 (P < 0.001). Addition of 1 mmol/l Ba2+ to the incubation medium significantly decreased 86Rb influx in K(+)- (by 53%) and Rb(+)-media (by 26%). Thus, the reduction in the rate coefficient for 86Rb influx in Rb(+)-medium as compared to K(+)-medium was mainly due to the Ba(2+)-sensitive component (0.23 +/- 0.04 vs. 0.78 +/- 0.10 h-1, P < 0.001). The ouabain-sensitive component of 86Rb influx was also higher in K(+)-(Kin = 0.62 +/- 0.05 h-1) than in Rb(+)-medium (Kin = 0.54 +/- 0.05 h-1, P < 0.05). In the presence of 4 mmol/l 41KCl, the average value of the rate coefficient for the total 41K influx was 8.1 +/- 0.5 h-1. The rate coefficient for 41K influx was reduced to 0.82 +/- 0.13 h-1 in the presence of 1 mmol/l Ba2+. Under the conditions of our assays, the rate of 86Rb uptake via potassium channels of the lamprey red cells was only about 11% in K(+)-medium and only about 3% in Rb(+)-medium compared to 41K influx. These data clearly demonstrate a high selectivity of potassium channels for K+ over Rb+, as already reported for some potassium channels in a variety of cells and tissues.

[The dynamics of milk secretion in white mice and its consumption by progeny]. / Dinamika sekretsii moloka u belykh myshei i ego potreblenie potomstvom.

Only about 72 per cent of the litter manifested milk ingestion during every next nursing in white mice. The correlation between the dynamics of the milk ejection from the mammary gland and individual real milk intake by the litter, is discussed.

Endogenous lithium clearance as a probable measure of end-proximal fluid delivery in the amphibian kidneys: a study of renal water and Na+ reabsorption in the hydrated and dehydrated frog Rana temporaria.

In fully hydrated frogs (R. temporaria) a clearance of endogenous lithium (CLi) coincides with the glomerular filtration rate (CCoEDTA) which is on average 32 ml/kg/hr, i.e. fractional lithium excretion (FELi) is close to unity, and urine to plasma concentration ratios (U/P) of Li+ and 57Co-EDTA are about 1.4. On average, in severely dehydrated frogs CCoEDTA decreases to 6.2 ml/kg/hr, CLi to 2.4 ml/kg/hr, and (U/P)CoEDTA and (U/P)Li rise to 8.4 (max = 15.2) and 3.2 (max = 5.5), respectively. FELi makes about 0.4, i.e. in these animals, rather than in well hydrated ones, a noticeable lithium reabsorption in the kidney-urinary bladder complex is observed. Obtained data are discussed from the point of view that in amphibian kidneys (as in mammalian ones) the lithium clearance may serve as a measure of end-proximal fluid delivery and observed reabsorption of Li+ in the total kidney-urinary bladder complex in fact characterizes the reabsorption of Na+ and H2O in the proximal tubule.

Endogenous lithium determination in blood plasma and urine by isotope dilution mass spectrometry and preliminary isolation of lithium fraction using paper chromatography.

A version of isotope dilution mass spectrometric technique elaborated for measuring endogenous lithium concentrations in human blood plasma and urine (10(-7) M region) and applicable in clinical practice is described. A tracer solution of lithium (LiCl) enriched in 6Li (with abundances 6Li 92%, 7Li 8%) is added to a certain volume of human plasma (0.2-0.4 ml) or urine (0.05-0.1 ml) and dried under an infrared lamp. Thereupon a soluble part extracted from dried plasma with the aid of 0.1 N HCl is dried as well. Dry extracts from plasma and dried samples of urine are processed by 30% H2O2 and subsequently subjected to paper chromatography (with ethanol as a solvent). Such processing of samples is simple and short (about an hour, 3 min of chromatographic process inclusive), achieving a good separation from organic matrix and interfering macroelements. Contamination of sample in processing is about 2-5 pmol; routine control of contamination and account of their influence are accomplished by measuring two different volumes of each sample. Measurements are made with high precision: cyclic repeated scanning of 7Li and 6Li peaks have a standard deviation of 7Li/6Li ratio no more than 0.7%. The method described was used to determine endogenous lithium clearance of hypertensive patients and patients with transplanted kidney.

[Li+ as a Na+ analog in ion transport process in vertebrates]. / Li+ kak analog Na+ v nekotorykh protsessakh ionnogo transporta u pozvonochnykh.

Special features of Li+ transport in several organs ensuring ion homeostasis of vertebrates (in kidneys of fishes and mammals, in gills of teleost and rectal gland of elasmobranchs) are observed in comparison to Na+ transport in the same organs. Transport processes in extrarenal excretory organs--in gills of marine teleosts and in rectal gland of marine elasmobranchs--are distinguished by low lithium-sodium selectivity, i.e. in these processes Li+ behaves very much like Na+. On the contrary, renal excretion of these ions is accompanied by significant (more than ten times) increase of [Li]/[Na] ratio in urine in comparison with that of blood plasma. At the same time, there is no difference between Li+ and Na+ in process of glomerular filtration and their transfer across proximal tubule wall; discrimination takes place in distal parts of a nephron where Li+ is not involved in the process of Na+ reabsorption. Data on lithium-sodium selectivity of the kidneys and rectal gland were obtained by a direct measurement of Li+ and Na+ concentrations in body fluids. Estimations of lithium sodium-selectivity of gills of freshwater and marine teleosts were performed by means of the balance equation of Li+ and Na+ net fluxes in processes of exchange between the animal and its environment.

Secretion of endogenous lithium in teleost kidneys as a probable reflection of Na+ and water secretion in their renal proximal tubules.

Unlike mammals with renal reabsorption of lithium (Li+), in freshwater and, particularly, marine teleosts net secretion of this trace element by kidneys was discovered. The ratio of Li+ natural concentration (measured by mass spectrometric isotope dilution technique) in urine to that in blood plasma--(U/P)Li--lies in the range 2-6 in the freshwater species and between 5 and 14 in marine species, i.e. as a rule it is essentially higher than the inulin concentration index (U/P)In. It is supposed that the in vivo observed lithium net secretion in whole kidney reflects and quantitatively estimates Na+ and water secretion in renal proximal tubules of teleosts.

Lithium in marine elasmobranchs as a natural marker of rectal gland contribution in sodium balance.

Natural concentrations of lithium in blood plasma and urine of several species of elasmobranchs and teleosts from the Black Sea and in rectal gland fluid of the former were determined by mass-spectrometric isotope dilution techniques. Unlike the teleosts, the elasmobranchs showed a prominent shift of Li/Na ratio in blood plasma with respect to the surrounding water, the plasma Li/Na ratio being five times lower than that of sea-water. Li-Na selectivity was found to be high in the kidneys and negligible in the rectal gland. Differences in Li-Na selectivity between kidneys and rectal gland are used as a basis for the method of estimation of relative contributions of these excretory organs in sodium excretion. Permanent contributions of the kidneys and rectal gland in sodium excretion of the ray Dasyatis pastinaca were found to be nearly equal.

[Extraction of lithium ions from fresh water by Lampetra fluviatilis lampreys and Oncorhynchus nerka salmon in natural ecosystems]. / Izvlechenie ionov litiia iz presnoi vody minogoi Lampetra fluviatilis i lososem Oncorhynchus nerka v estestvennykh ékosistemakh.

Some theoretical criteria are discussed which allow, using the data on the dynamics of natural concentrations and the rate of excretion of elements (ions) in aquatic animals during prolonged starvation, to establish the presence or absence of direct uptake of these elements from water under natural conditions. During pre-spawning starvation of the lamprey Lampetra fluviatilis and salmon Oncorhynchus nerka, it was shown that they are capable to accumulate Li+, similarly to Na+, directly from the fresh water. Natural concentrations of Li+ in muscles, measured mass-spectrometrically using isotope dilution, vary in the lamprey within 0.3-0.6 muequiv./kg, and in spite of the rapid excretion of this ion by the kidneys, are not decreased within a 7-month starvation; in the salmon from the lake Dal'nee (Kamchatka) they vary within 0.1-0.2 muequiv./kg. The period of semi-exchange of Li+ in lampreys in fresh water is equal approximately to 1 day.