Sodium deoxycholate promotes the absorption of heparin administered orally, probably by acting on gastrointestinal mucosa, in rats

Sodium deoxycholate (DOC), selected as a promoter of gastrointestinal absorption of heparin, was administered orally to rats, followed, at increasing intervals, by heparin. Maximal plasma clearing activity (PC) was obtained with a 60-min interval, though PC was still elicited after 24 h, suggesting that DOC acts on the gastrointestinal mucosa. Inhibition of blood coagulation was also observed after oral heparin. The suggestion that DOC increases heparin absorption is supported by increased plasma levels of heparin. No signs of several gastrointestinal damage were seen.     

Comparison of a natural heparinoid with sodium and calcium heparin for their effect on the inhibitor of activated factor X

Summary The reaction between activated factor X (Xa) and its natural inhibitor (XaI) was accelerated in vitro by both sodium heparin and an heparinoid, which was about 3 times less potent than heparin. The s. c. administration in humans of 5,000 units of sodium and calcium heparin was followed by the detection of a plasma activity potentiating XaI. In the majority of subjects, the heparinoid was not effective. These observations indicate that the use of heparinoids should not be considered as an alternative to heparin in the prevention of thromboembolism.     

Comparison of a natural heparinoid with sodium and calcium heparin for their effect on the inhibitor of activated factor X.

The reaction between activated factor X (Xa) and its natural inhibitor (XaI) was accelerated in vitro by both sodium heparin and an heparinoid, which was about 3 times less potent than heparin. The s. c. administration in humans of 5,000 units of sodium and calcium heparin was followed by the detection of a plasma activity potentiating XaI. In the majority of subjects, the heparinoid was not effective. These observations indicate that the use of heparinoids should not be considered as an alternative to heparin in the prevention of thromboembolism.     

Plasma enteroglucagon, peptide YY and gastrin in rats deprived of luminal nutrition, and after urogastrone-EGF administration. A proliferative role for PYY in the intestinal epithelium?

Intestinal tissue mass was significantly reduced throughout the gastrointestinal tract (p less than 0.001) of intravenously fed (TPN) rats. Urogastrone-epidermal growth factor, (URO-EGF), reversed these changes. Although plasma enteroglucagon and gastrin levels showed a small increase with URO-EGF, this was far less than the gut tissue weight change, suggesting that it was unlikely that they were involved in modulating the proliferative response of the intestine to URO-EGF. Peptide tyrosine tyrosine (PYY) levels were however significantly increased by URO-EGF, indicating that PYY may possibly have a role in the modulation of intestinal cell proliferation.     

Heparin inhibition of the antithrombin activity of alpha-2-macroglobulin]

The interaction between thrombin and alpha-2-macroglobulin was studied on human purified materials, either in the presence or in the absence of heparin, by kinetic analysis of thrombin inhibition and polyacrylamide gel electrophoresis. In the absence of heparin, binding of thrombin to alpha-2-macroglobulin, shown by electrophoresis, leads to the loss of the coagulant property of the enzyme. In the presence of heparin the rate of inhibition of thrombin clotting activity by alpha-2-macroglobulin is strongly decreased. Heparin binds to thrombin, impairing the formation of thrombin-alpha-2-macroglobulin complex. These data show that heparin paradoxically protects thrombin from inhibition by alpha-2-macroglobulin whereas it increases the enzyme inhibition by antithrombin III. Such a phenomenon could be of practical interest for treatment of thrombosis in patients with high plasma level of alpha-2-macroglobulin and low level of antithrombin III, such as occurs in the nephrotic syndrome.     

Circadian rhythm of plasma corticosterone in vagotomized rats

Summary In vagotomized rats, 2 weeks after surgery, the amplitude of the circadian rhythm of plasma corticosterone was extremely low, indicating that gastrointestinal activity may be in part involved in the hypothalamo-hypophyseal circadian rhythmicity.     

Selenoprotein P

Selenoprotein P (SeP) is an extracellular, monomeric glycoprotein containing up to 10 selenocysteine residues in the polypeptide chain. It is ubiquitously expressed in mammalian tissues, and in human plasma it accounts for at least 40% of the total selenium concentration. SeP binds to heparin and cell membranes, and is associated with endothelial cells. SeP in human plasma protects against peroxynitrite-mediated oxidation and reduces phospholipid hydroperoxide in vitro, in accordance with the presumption that it has a function as an extracellular oxidant defense. Immunochemical assays have demonstrated that its concentration in plasma varies much with selenium intake, but other factors also have an influence.     

Direkte Hemmwirkung des Heparins auf die Insulinsekretion

Summary The injection of heparin into the A. pancreaticoduodenalis of anaesthetized dogs produces an immediate decrease of the IRI-concentration in the pancreatic and peripheral venous plasma. This decrease could not be correlated with any alteration of blood sugar or FFA. A direct inhibitory action of heparin on the pancreatic B-cell is suggested.     

Absorption of double labeled (glycerol 3H-linoleic acid 14C) native bile by phosphatidylcholines]

Double-labeled bile ([U. 3H glycerol] [1. 14C linoleic acid])--in which about 70% of labeling 14C and 80% of labeling 3H of total lipids were borne by phosphatidylcholines (PC), (isotopic ratio of these PC was equal to 1)--was introduced into the duodenum of test Rats, some of them with a bile fistula. As low amounts of the hydrolysis products of biliary PC were found in the intestinal lumen, a higher hydrolysis must occur further (brush border, enterocyte ?) because, in the mucosa, the highest labeling 14C was present as triglycerides and PC have an isotopic ratio 3H/14C higher than 1. As in the lumen the isotopic ratio 3H/14C of PC was higher than 1 and increased with the time elapsed, this finding suggests that mucosal PC were added to biliary PC (secretion or desquamation ?) unless these modifications were due to luminal micro-organisms. As test Rat bile was poorly labeled a very weak enterohepatic circulation of biliary diunsaturated PC may exist.     

Endogenous protein C is essential for the functional integrity of human endothelial cells

Circulating protein C (PC) plays a vital role as an anti-coagulant and anti-inflammatory mediator. We show here that human endothelial cells produce PC that acts through novel mediators to enhance their own functional integrity. When endogenous PC or its receptor, endothelial protein C receptor (EPCR), was suppressed by small interfering (si) RNA, human umbilical cord endothelial cell (HUVEC) proliferation was decreased and apoptosis elevated. Interestingly, PC or EPCR siRNA significantly increased HUVEC permeability, which is likely via reduction of the angiopoietin (Ang)1/Ang2 ratio and inhibition of the peripheral localization of the tight junction protein, zona occludins-1. In addition, PC or EPCR siRNA inhibited type IV collagen and matrix metalloproteinase-2, providing the first evidence that PC contributes to vascular basement membrane formation. These newly described actions of endogenous PC act to stabilize endothelial cells and enhance barrier function, to potentially promote the functional integrity of blood vessels.     

The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates

While the production of melatonin in higher vertebrates occurs in other organs and tissues besides the pineal, the contribution of extrapineal sites of melatonin synthesis such as the retina, the Harderian glands and the gut to circulating melatonin levels is still a matter of debate. The amount of melatonin found in the gastrointestinal tract is much higher than in any other organ including the pineal and the gut appears to make a significant contribution to circulating melatonin at least under certain conditions. The gut has been identified to be the major source of the elevated plasma concentrations of melatonin seen after tryptophan administration and of the changes of circulating melatonin level induced by the feeding regime. Whereas the circadian and circannual fluctuations of the concentration of melatonin in the blood seem to be triggered by changes of the photoenvironment and its effect of pineal melatonin formation, basal daytime melatonin levels and the extent of their elevation at nighttime appear to be additionally controlled by nutritional factors, such as the amount and the composition of ingested food and therefore availability of tryptophan as a rate-limiting precursor of melatonin formation by the enterochromaffin cells of the gastrointestinal tract.     

The therapeutic potential of GPR43: a novel role in modulating metabolic health

GPR43 is a receptor for short-chain fatty acids. Preliminary data suggest a putative role for GPR43 in regulating systemic health via processes including inflammation, carcinogenesis, gastrointestinal function, and adipogenesis. GPR43 is involved in secretion of gastrointestinal peptides, which regulate appetite and gastrointestinal motility. This suggests GPR43 may have a role in weight control. Moreover, GPR43 regulates plasma lipid profile and inflammatory processes, which further indicates that GPR43 could have the ability to modulate the etiology and pathogenesis of metabolic diseases such as obesity, type 2 diabetes mellitus, and cardiovascular disease. This review summarizes the current evidence regarding the ability of GPR43 to mediate both systemic and tissue specific functions and how GPR43 may be modulated in the treatment of metabolic disease.     

Relationship of phosphatidylcholine to hydrophobic surfactant on rat intestinal chylomicron secretion

Hydrophobic surfactants such as Poloxalene inhibit triglyceride secretion into lymph by enterocytes. The inhibitory effect of these agents on triglyceride secretion is reversed when lipid presented for absorption is exclusively in the form of phosphatidylcholine (PC) and not triglyceride. The present investigation performed in conscious mesenteric lymph fistula rats was designed to determine whether various mixtures of triglyceride and PC given intraduodenally with Poloxalene would also reverse the inhibitory effect of Poloxalene on triglyceride secretion into lymph. A 50–50 mixture of triolein (TO) and PC resulted in normal triglyceride secretion into lymph. However, when the mixture of lipids was 75-25, TO to PC, results for triglyceride recovery in lymph were considerably reduced. The transport rate for triglyceride into lymph was not as depressed, however, as observed for Poloxalene treated rats given lipid for absorption basically in the triglyceride form. Substitution of phosphatidylethanolamine for PC had no beneficial effect on triglyceride secretion in Poloxalene treated rats. It is concluded that PC can reverse the inhibitory effect of Poloxalene on triglyceride secretion into lymph even when considerable amounts of triglyceride along with PC are presented for absorption.     

Use of three specific radioimmunoassays in measuring neurohypophysial hormone content and plasma concentrations of vasopressin, oxytocin and DDAVP in rats after prolonged infusion of DDAVP

Specific radioimmunoassays (RIA) were employed for measuring plasma and neurohypophysial concentrations of oxytocin (OT) and vasopressin (AVP) after administration of 1-deamino-8-D-Arg-vasopressin (DDAVP). DDAVP concentrations were measured by a newly-developed specific RIA. Through the use of minipumps, DDAVP was infused i.p. over a period of 3 days in normally hydrated rats. Despite decreased urine production and increased urine osmolality no changes could be observed in neurohypophysial and plasma hormone concentrations.     

Long-term incubation with mifepristone (MLTI) increases the spine density in developing Purkinje cells: new insights into progesterone receptor mechanisms

Cerebellar Purkinje cells (PC) physiologically reveal an age-dependent expression of progesterone with high endogenous concentrations during the neonatal period. Even if progesterone has been previously shown to induce spinogenesis, dendritogenesis and synaptogenesis in immature PC, data about the effects of progesterone on mature PC are missing, even though they could be of significant therapeutic interest. The current study demonstrates for the first time a progesterone effect, depending on the developmental age of PC. Comparable with the physiological course of the progesterone concentration, experimental treatment with progesterone for 24 h achieves the highest effects on the dendritic tree during the early neonate, inducing an highly significant increase in dendritic length, spine number and spine area, while spine density in mature PC could not be further stimulated by progesterone incubation. Observed progesterone effects are certainly mediated by classical progesterone receptors, as spine area and number were comparable to controls when progesterone incubation was combined with mifepristone (incubation for 24 h), an antagonist of progesterone receptors A and B (PR-A/PR-B). In contrast, an increase in the spine number and area of both immature and mature PC was detected when slice cultures were incubated with mifepristone for more than 72 h (mifepristone long-time incubation, MLTI). By including time-lapse microscopy, electron microscopic techniques, PCR, western blot, and MALDI IMS receptor analysis, as well as specific antagonists like trilostane and AG 205, we were able to detect the underlying mechanism of this diverging mifepristone effect. Thus, our results provide new insights into the function and signaling mechanisms of the recently described progesterone receptor membrane component 1 (PGRMC1) in PC. It is highly suitable that progesterone does not just induce effects by the well-known genomic mechanisms of the classical progesterone receptors but also acts through PGRMC1 mediated non-genomic mechanisms. Thus, our results provide first proofs for a previously discussed progesterone-dependent induction of neurosteroidogenesis in PC by interaction with PGRMC1. But while genomic progesterone effects mediated through classical PR-A and PR-B seem to be restricted to the neonatal period of PC, PGRMC1 also transmits signals by non-genomic mechanisms like regulation of the neurosteroidogenesis in mature PC. Thus, PGRMC1 might be an interesting target for future clinical studies and therapeutic interventions.     

Plasma lipid-bound sialic acid alterations in neoplastic diseases

Plasma lipid-bound sialic acid (LSA) was assayed in normal volunteers, patients with non-malignant diseases, and a variety of cancer patients. Mean plasma LSA in 50 normal volunteers, 16 patients with non-malignant diseases, 54 breast cancer, 17 lung cancer, 15 colon cancer, 7 ovarian cancer, 5 prostate cancer, 4 leukemia, 4 gastrointestinal, 3 thyroid cancer, 3 pancreas cancer and 2 adrenal cancer patients were 17.7, 23.2, 58, 85, 56.7, 46.2, 56.7, 53.3, 31.1, 33.2 and 119.5 mg/dl, respectively. None of the normal volunteers had elevated plasma LSA values. Plasma LSA level was not significantly different in male and female volunteers. Two out of 114 different cancer patients had plasma LSA levels within normal range exhibiting 98.2% sensitivity of the assay. Plasma LSA, which is relatively simple to assay, may be used as a tumor marker in wide variety of neoplastic diseases.     

Effect of alkali cations on the interaction between detergents and erythrocyte membranes

Resumen Los distintos cationes alcalinos monovalentes (145 mM) y divalentes (100 mM) modifican marcadamente el grado de hemólisis de eritrocitos humanos provocado por Triton X-100 y por desoxicolato de Na (DOC). La serie de actividad con cationes monovalentes en hemólisis por Triton es K>Rb=Cs>NaLi, y por DOC es Li>Rb=Cs>K>Na. Por el contrario, el grado de solubilización de membranas eritrocitarias producido por Triton o DOC es independiente de los distintos cationes alcalinos.     

Multiplication of human-derived Pneumocystis carinii in severe combined immunodeficient (SCID) mice.

Clinically healthy SCID mice were infected intratracheally with Pneumocystis carinii (PC) of human origin. The data obtained provides unambiguous evidence that progressive multiplication of PC organisms of human origin takes place in the lungs of experimentally infected animals. SCID mice that were infected with human-derived PC also revealed a markedly greater number of mouse PC organisms in their lungs than the controls. All the SCID recipients of human PC died by day 65 post infection, whereas the controls, housed under identical conditions, started dying significantly later due to severe mouse pneumocystosis. This animal model could be used for the maintenance and propagation of human PC, and for evaluating strategies for treating human pneumocystosis.     

Multiplication of human-derivedPneumocystis carinii in severe combined immunodeficient (SCID) mice

clinically healthy SCID mice were infected intratracheally withPneumocystis carinii (PC) of human origin. The data obtained provides unambiguous evidence that progressive multiplication of PC organisms of human origin takes place in the lungs of experimentally infected animals. SCID mice that were infected with human-derived PC also revealed a markedly greater number of mouse PC organisms in their lungs than the controls. All the SCID recipients of human PC died by day 65 post infection, whereas the controls, housed under identical conditions, started dying significantly later due to severe mouse pneumocystosis. This animal model could be used for the maintenance and propagation of human PC, and for evaluating strategies for treating human pneumocystosis.