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PubMedDate not supplied

13CO2 excretion in breath of normal subjects and cirrhotic patients after 13C-aminopyrine oral load. Comparison with MEGX test in functional differentiation between chronic hepatitis and liver cirrhosis.

BACKGROUND/AIMS: Liver function can be evaluated using 13C breath tests that explore liver Cytochrome P450 activity. Aminopyrine is one of the first compounds used in liver function testing. Lidocaine metabolism to monoethylglycinexylidide is also a valid tool to assess liver function. Although liver Cytochrome P450 metabolizes both compounds, lidocaine metabolism is flow-dependent while aminopyrine metabolism does not depend on liver blood flow. METHODOLOGY: The 1st part of the study evaluated the appearance and disappearance rate of 13CO2 in the breath of both normal subjects and in cirrhotic patients, so as to establish optimal sampling times and to evaluate the amount of time needed before performing a subsequent breath test. The 2nd part of the study compared the aminopyrine breath test with the monoethylglycinexylidide test in patients with chronic hepatitis or cirrhosis. RESULTS: Complete 13CO2 disappearance was recorded 24 hours after the test in normal subjects, while it took 3 days to disappear from the breath of cirrhotic patients. Breath sampling at 60, 120 and 180 min were equally valid in differentiating chronic hepatitis from cirrhosis. The aminopyrine breath test and monoethylglycinexylidide test showed a good yet not close correlation. CONCLUSIONS: This study showed that in cirrhotic patients a 13C breath test can be performed 3 days after the previous one. In chronic hepatitis and cirrhotic patients, the aminopyrine breath test and the monoethylglycinexylidide test evaluated similar, but not identical, hepatic subfunctions, suggesting that multiple 13C breath test using different substrates could explore liver function better.

Adult↗
PubMed2003

Functional differentiation of hepatocyte-like spheroid structures from putative liver progenitor cells in three-dimensional peptide scaffolds.

We investigated the ability of a new type of biological material, the self-assembling peptide scaffold, to foster tissue-like function by a putative adult rat hepatocyte progenitor cell line, Lig-8. In conventional adherent petri-dish cultures, Lig-8 cells divide exponentially, express markers for definitive endoderm HNF3 beta and hepatocyte lineage, including CK8 and alpha-fetoprotein, but lack expression of mature hepatocyte markers. However, in the three-dimensional peptide scaffold cultures, Lig-8 exhibits non-exponential cell kinetics, acquires a spheroidal morphology, and produces progeny cells with mature hepatocyte properties. The differentiated progeny cells display expression of transcription factor C/EBP alpha and several other indicators that suggest hepatocyte maturation, including binucleation, up-regulation of albumin, and expression of cytochrome P450s CYP1A1, CYP1A2, and CYP2E1. Moreover, all three cytochrome p450 enzyme activities are induced using 3-methylcholanthrene in these spheroids. These results suggest that a designed biological material may provide a conducive microenvironment in which putative adult progenitor cells differentiate into functional hepatocyte-like spheroid clusters. This bioengineered scaffold system provides a better physiological approach to "progenitor cell differentiation" for future biomedical and pharmaceutics applications.

Animals↗
PubMed2001

Long-term expression of highly differentiated functions by isolated porcine hepatocytes perfused in a radial-flow bioreactor.

To overcome the limitations of standard hollow-fiber module in ensuring efficient cell perfusion and long-term expression of highly differentiated hepatocyte functions, we developed a novel bioreactor in which a three-dimensional hepatocyte culture system was perfused in radial-flow geometry. Isolated porcine hepatocytes were cultured for 2 weeks in recirculating serum-free tissue culture medium, in which NH4Cl and lidocaine were repeatedly added, and ammonia removal, urea synthesis, monoethylglycinexylide (MEGX) production, albumin secretion, Po2, Pco2, O2 consumption, and pH were measured thereafter. During the whole duration of the study, ammonia removal was paralleled by urea production, while MEGX concentration was constantly increased. Our results indicated that hepatocytes remained differentiated and metabolically active throughout the duration of the study. The radial-flow bioreactor allowed physiological contact between recirculating fluid and cells by equalizing the concentration of the perfusing components, including O2, throughout the module, suggesting a potential use of this configuration for extracorporeal liver support.

Albumins↗
PubMed1985

Acellular dental matrices promote functional differentiation of ameloblasts.

EDTA treatment of post-natal mouse molars made possible the isolation of cell-free dental matrices composed of basal lamina, predentin, dentin and enamel. Trypsin-isolated dental papillae and enamel organs from embryonic-mouse mandibular molars were combined with isolated matrices and cultured in vitro. In such recombinations, functional odontoblasts were never observed. On the other hand, competent preameloblasts in contact with the epithelial side of occlusal predentin overtly differentiated. Matrices treated with guanidine-EDTA or acetic acid were unable to promote the functional differentiation of ameloblasts. These data are discussed in terms of the epitheliomesenchymal interactions involved in odontogenesis.

Acetates↗
PubMed1996

Induction of morphological and functional differentiation of human promyelocytic leukemia cells (HL-60) by Tubeimoside 1.

Two functional parameters evaluated by nitroblue tetrazolium (NBT) dye reduction and zymosan particle phagocytosis and a morphological change assessed by the Wright-Giemsa stain of human promyelocytic leukemia cells (HL-60 cells) were used to determine the extent of HL-60 cell differentiation induced by tubeimoside 1. The results revealed that under the action of tubeimoside 1, HL-60 cells could be induced to differentiate to more mature cells with the functional characteristics of granulocytes. Therefore, tubeimoside 1 could be considered as a promising antileukemic agent for further animal trials.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Scoring noncovalent protein-ligand interactions: a continuous differentiable function tuned to compute binding affinities.

Exploitation of protein structures for potential drug leads by molecular docking is critically dependent on methods for scoring putative protein-ligand interactions. An ideal function for scoring must exhibit predictive accuracy and high computational speed, and must be tolerant of variations in the relative protein-ligand molecular alignment and conformation. This paper describes the development of an empirically derived scoring function, based on the binding affinities of protein-ligand complexes coupled with their crystallographically determined structures. The function's primary terms involve hydrophobic and polar complementarity, with additional terms for entropic and solvation effects. The issue of alignment/conformation dependence was solved by constructing a continuous differentiable nonlinear function with the requirement that maxima in ligand conformation/alignment space corresponded closely to crystallographically determined structures. The expected error in the predicted affinity based on cross-validation was 1.0 log unit. The function is sufficiently fast and accurate to serve as the objective function of a molecular-docking search engine. The function is particularly well suited to the docking problem, since it has spatially narrow maxima that are broadly accessible via gradient descent.

Bacterial Proteins↗
PubMed2006

Division of the male rat rhabdosphincter into structurally and functionally differentiated parts.

In order to understand the structure-function relationship in the male rat rhabdosphincter, the 3D structure of the striated muscle and associated dense connective tissue was reconstructed from representative serial sections cut from the proximal urethra harboring the muscle. The 3D structure was correlated with electromyography (EMG) of the rhabdosphincter, urodynamic parameters (bladder pressure and flow rate), and longitudinal contraction force of the proximal urethra. The muscular component of the rhabdosphincter consisted of a homogeneous population of the fast-twitch-type fibers. In the cranial part, striated muscle formed a complete ring encircling the urethra, deferent ducts, and ducts from seminal vesicles and prostatic lobes. Toward the middle part, the amount of densely packed connective tissue lacking type III collagen increased anteriorly and posteriorly and penetrated the muscular ring that became divided first posteriorly and then anteriorly into two symmetrical halves. In the caudal part, a thin midsagittal dense connective tissue septum remained posteriorly. EMG recordings suggested that the rhabdosphincter muscle was functionally divided into two parts. Unlike the cranial and middle parts, the caudal part did not show the first depolarization peak. It appears that rapid oscillatory oblique-to-circular muscular contractions proceeding in craniocaudal direction in the cranial and middle part draw the anterior wall supported by arch-like dense connective tissue closer to the posterior wall supported by a more rigid rhomboidal raphe. Longitudinal contractions of the urethra are possibly evoked from the proximal and caudal parts of rhabdosphincter. These could lead to simultaneous increase in urethral pressure ensuring rapid urine flow rate. The caudal part could augment the opening of urethral lumen during oscillatory voiding.

Actins↗
PubMed1999

From symptoms to social functioning: differential effects of antidepressant therapy.

Significant impairments in social functioning frequently occur simultaneously with depressive symptoms. The implications of such impairments extend beyond the depressed individual to their family, friends and society at large. Classical rating scales such as the Hamilton rating scale for depression primarily assess the core symptoms of depression. A range of rating scales are available, both self-reporting and administered by clinician; however, many have been criticised for their unspecified conceptual background and for being complex and time-consuming. While antidepressants in general appear to improve social functioning, no clear advantage for any single class of agent has been reported. Recently, a new self-report rating scale, the Social Adaptation Self-evaluation Scale, has been developed and used to compare the novel selective noradrenaline reuptake inhibitor, reboxetine, with the selective serotonin re-uptake inhibitor, fluoxetine. The noradrenergic agent, reboxetine, was shown to be significantly more effective in improving social functioning than the serotonergic agent, fluoxetine. These findings are consistent with previous observations that noradrenaline may preferentially improve vigilance, motivation and self-perception.

Adrenergic Uptake Inhibitors↗
PubMed1996

Structural and functional differentiation of sinusoidal endothelial cells during liver organogenesis in humans.

During fetal life, human liver sinusoids, which differentiate between 4 and 12 weeks of gestation from capillaries of the septum transversum, must support an important hematopoietic function and acquire the structural and functional characteristics of adult sinusoids. To gain insight into their differentiation process, we studied the expression of (1) markers of continuous endothelia, absent from adult sinusoidal endothelial cells (PECAM-1, CD34, and 1F10); (2) functional markers of adult sinusoidal endothelial calls (CD4, 1CAM-1, CD32, and CD14); and (3) extracellular matrix components (laminin, tenascin, fibronectin, and thrombospondin) in 37 fetuses of different gestational ages. We identified two successive differentiation events. (1) An early structural differentiation, occurring from 5 to 12 weeks of gestation, was characterized by the loss of continuous endothelial cell markers and a reduction in the perisinusoidal amount of laminin and in the deposition of tenascin, fibronectin, and thrombospondin; at the end of this process, fetal liver sinusoids present structural characteristics comparable to those of the sinuses in adult hematopoietic bone marrow. (2) A later functional differentiation was characterized by the acquisition of the markers of adult sinusoidal endothelial cells, initiating at 10 weeks of gestation and completed by 20 weeks of gestation; this process likely contributes to adapt liver sinusoids to the specific functions of the adult hepatic tissue.

Adult↗
PubMed2003

Functional differentiation of the placental syncytiotrophoblast: Effect of estrogen on chorionic somatomammotropin expression during early primate pregnancy.

Estrogen stimulates morphological and functional (i.e. steroidogenesis) differentiation of the primate placental trophoblast, and with advancing gestation there is an increase in estrogen and placental chorionic somatomammotropin (CS) mRNA and protein levels. To examine whether CS formation is regulated by estrogen, placental villous trophoblast CS was determined in baboons in which estradiol levels in uterine vein were increased 2- to 3-fold (P < 0.01) on d 60 of pregnancy (term = 184 d) by administration of aromatizable androstenedione on d 30-59 or estradiol benzoate on d 45-59 of gestation. Androstenedione and estradiol treatment resulted in a 75% decrease (P < 0.01) in placental whole villous CS-3 mRNA and CS protein levels, determined by Northern and Western blot analysis, on d 60, and a corresponding decrease in syncytiotrophoblast CS protein and maternal serum CS levels. In contrast, placental villous Delta(5)-3beta-hydroxysteroid dehydrogenase, 11 beta-hydroxysteroid dehydrogenase-2, and P-450 aromatase protein levels were unaltered by androstenedione or estradiol treatment. Collectively, these results suggest that, in elevated levels, estrogen suppressed CS formation by villous syncytiotrophoblast during the first one third of primate pregnancy. Therefore, estrogen has very different and specific actions on steroid and peptide hormone biosynthesis within the placental trophoblast, which we propose are important in regulating placental function and promoting fetal-placental development in the primate.

3-Hydroxysteroid Dehydrogenases↗
PubMed2002

Indicators of functional differentiation of the chick embryonic kidney.

Relevant indicators of the functional capability of the embryonic kidney were tested in the chick mesonephros chosen as an ideal model accessible to direct observation in vivo. Evidence of glomerular filtration (GF) was checked up by the arterial injection of 2% lissamine green (LG) followed by measurement of the LG passage time on days 5, 6 and 7. Presence of the electrogenic transport was investigated by determining the transepithelial potential difference (TPD) which distinguished proximal and distal tubules of the 6-day nephrons. GF and tubular reabsorption could be demonstrated from day 5 by the storage of trypan blue (TB) in proximal tubules after intra-amniotic administration of the dye. The distribution of tubule staining corresponded to the proximal-distal gradient of the nephron differentiation. Activities of embrane enzymes, alkaline phosphatase and 5'-nucleotidase, were detected from day 4. They preceded the ultrastructural maturation in the differentiating proximal tubule epithelia. A semiquantitative evaluation of enzyme activities by the method of measuring of the minimum incubation time (MIT) together with the TB storage, appeared reliable and relevant indicators of the functional properties of mesonephric nephrons, suitable for distinguishing between more and less advanced stages of the nephron development.

Animals↗
PubMed2001

Inhibition of heat shock protein 90 function by ansamycins causes the morphological and functional differentiation of breast cancer cells.

17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is an ansamycin antibiotic that binds to a conserved pocket in Hsp90 and induces the degradation of proteins that require this chaperone for conformational maturation. 17-AAG causes a retinoblastoma (RB)-dependent G1 block in cancer cells and is now in clinical trial. In breast cancer cells, G1 block is accompanied by differentiation and followed by apoptosis. The differentiation is characterized by specific changes in morphology and induction of milk fat proteins and lipid droplets. In cells lacking RB, neither G1 arrest nor differentiation occurs; instead, they undergo apoptosis in mitosis. Introduction of RB into these cells restores the differentiation response to 17-AAG. Inhibitors of the ras, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase pathways cause accumulation of milk fat proteins and induction of lipid droplets when associated with G1 arrest but do not cause morphological changes. Thus, regulation of Hsp90 function by 17-AAG in breast cancer cells induces RB-dependent morphological and functional mammary differentiation. G1 arrest is sufficient for some but not all aspects of the phenotype. Induction of differentiation may be responsible for some of the antitumor effects of this drug.

Antibiotics, Antineoplastic↗
PubMed1979

Functional differentiation of mouse T lymphocytes. GVHR-precursors: tissue origin and specificity of activity inducer.

For theoretical and practical reasons, it is important to find out whether the differentiation of T cell precursors to the functional lymphocytes can be induced under in vitro conditions. Using the local GVHR assay (based on the enlargement of the popliteal lymph node), the inducibility of the precursors of reactive cells was studied with bone marrow, thymus, spleen, and lymph node cell suspensions submitted to short-term incubation with cell-free extracts from calf thymus, spleen or brain. GVHR-precursors from bone marrow were inducible not only specifically (i.e., with thymus extract) but also--and even to a higher degree--with spleen or brain extract. Thymus and spleen cell suspensions (the latter also depleted of the reactive subpopulation by treatment with anti-Thy 1.2 serum and complement) were, on the other hand, inducible mainly specifically, whereas lymph node cells were refractory to induction. The inductive action of tissue extracts obviously depends on the tissue origin of T cell precursors; their effects on pre- and postthymic differentiation of T lymphocytes are discussed.

Animals↗
PubMed1984

Primary culture, cellular stress and differentiated function.

Isolation of specialized cell types for the analysis of tissue-specific gene function often results in loss of the differentiated phenotype. Examples of this type of phenotypic change following tissue disaggregation are reviewed together with possible explanations. Close similarities between the effects of cell isolation with those of other cellular stresses such as heat or anoxia point to common biochemical mechanisms being involved. This suggests that the study of freshly isolated cells will contribute significantly to out understanding of the nature of cellular stress and its consequences for the maintenance of phenotype and induction of tissue specific gene expression.

Animals↗
PubMed2006

The foetal Leydig cell-- differentiation, function and regulation.

The foetal Leydig cell population arises shortly after testicular differentiation at around 12.5 dpc in the mouse and 6 weeks in the human. These cells function, primarily, to produce androgens which are essential for masculinization of the foetus. The origin of the foetal Leydig cells remains uncertain but it has been suggested that adrenocortical cells and foetal Leydig cells may share a common origin in an adreno-genital primordium. Studies in the mouse are beginning to identify factors such as desert hedgehog and platelet-derived growth factor which are required for foetal Leydig cell development. Regulation of foetal Leydig cell function remains uncertain in most species. Unlike the adult population of Leydig cells, the foetal Leydig cells in the mouse do not require luteinizing hormone (LH) to stimulate androgen production. An intact pituitary does appear to be required, however, and adrenocorticotrophic hormone (ACTH) will stimulate foetal Leydig cell function directly suggesting that both LH and ACTH act to maintain Leydig cell function in vivo. In the human LH/hCG is required for foetal Leydig cell function although the cells may also be sensitive to ACTH.

Animals↗
PubMed1995

Ultrastructural and functional differentiation of hepatocytes under long-term culture conditions.

BACKGROUND: Studies on hepatocytes grown in different culture systems have shown that these cells rapidly dedifferentiate on a single support with liquid medium on top (single gel technique). However, in systems sandwiching them between two layers of extracellular matrix (double gel technique), the cells are able to regain and maintain typical light microscopical appearance and function. Their ultrastructural morphology is as yet unknown. METHODS: Isolated, adult rat hepatocytes were grown in both systems, and their fine structure (thin section electron microscopy) and the functional ability of albumin production (immunoassay) were studied and compared in both culture systems after 2, 7, and 14 days. RESULTS: The hepatocytes in conventional single gel culture did not completely regain their normal morphology and rapidly underwent progressive dedifferentiation. This was characterized by loss of cell polarization in terms of obliteration of the bile canaliculi-like intercellular expansions, loss of cell membrane differentiations, and reduction of organelles. Cytoskeletal components gradually increased, building up large filamentous zones underneath the plasma membrane. In double gel culture, the hepatocytes reachieved and maintained intact morphology and polarity over at least 14 days. The bile canaliculi were formed, preserved, or even enlarged and were associated with dense peribiliary bodies and Golgi fields. The plasma membrane facing both collagen layers bore numerous cytoplasmic microprojections like the sinusoidal surfaces of the hepatocytes in situ. Cell organelles, glycogen particles, and lipid droplets were always present. CONCLUSIONS: The hepatocyte is a cell type in which ultrastructural and functional differentiation are strongly interdependent. For these cells, the morphological microenvironment (i.e. the bipolar position of the extracellular matrix) may be as important or even more decisive for maintenance of normal cell differentiation than modifications of the composition of the matrix itself or addition of other cell types, as focused in other studies.

Albumins↗
PubMed2000

Transforming growth factor-beta1 promotes the morphological and functional differentiation of the myofibroblast.

The myofibroblast is responsible for the generation of contractile force associated with wound contraction and pathological contractures and is characterized by the presence of alpha-smooth muscle (alpha-sm) actin-containing stress fibers, vinculin-containing fibronexus adhesion complexes, and fibronectin fibrils containing the ED-A splice variant. Transforming growth factor-beta1 (TGF-beta1) can promote the expression of alpha-sm actin in myofibroblasts, but the functional significance of this increased expression is unclear. In this study, we demonstrate, using the stress-relaxed collagen lattice contraction assay, that TGF-beta1 promoted a dose-dependent increase in the generation of contractile force in myofibroblasts and a concomitant increase in the expression of alpha-sm actin. We also demonstrate that TGF-beta1 enhanced the formation of the structural elements important in myofibroblast contractile force generation and transmission, including stress fibers, vinculin-containing fibronexus adhesion complexes, and fibronectin fibrils, and that this enhancement occurred prior to, and independent of, alpha-sm actin expression. This differentiated myofibroblast phenotype was not stable. Removal of TGF-beta1 resulted in reduced expression of alpha-sm actin as well as a decreased assembly of stress fibers and vinculin-containing adhesion complexes; however, there was no reduction in fibronectin fibrils. We conclude that TGF-beta1 promotes the morphological and functional differentiation of the myofibroblast by first enhancing the formation of the structural elements characteristic of the myofibroblast followed by increased expression of alpha-sm actin and contractile force generation.

Actins↗