bluuebunny/crossref_metadata_2025 huggingface dataset:
Control of rate and extent of the proliferative response after partial hepatectomy
Authors: Lambotte Luc , Saliez Alain , Triest Sandrine , Tagliaferri Eugenio M. , Barker Andrew P. , Baranski Andrzej G.
Published: December 2017

To examine the role of the early changes occurring in the liver within the first hours after a partial hepatectomy and in an attempt to demonstrate the involvement of subsequent regulatory mechanisms, the size of the remnant liver was modified at various times and by different surgical techniques. Male Wistar rats were submitted to a two-thirds “temporary partial hepatectomy” produced by a 3-h occlusion of the pedicle of the anterior lobes protected by local hypothermia. Various indexes of cell proliferation ([3H]thymidine uptake and 5-bromo-2′-deoxyuridine and proliferating cell nuclear antigen labeling) were not increased despite a c- myc expression as high as that observed after a two-thirds partial hepatectomy. The temporary partial hepatectomy and a sham operation induced modifications of the hepatocytes, allowing rapid DNA synthesis after a subsequent two-thirds partial hepatectomy. After this initial nonspecific response, the extent of the regenerative response is determined according to the size of the liver mass present approximately from the 10th to the 18th hour after the initial stimulus. For instance, when a one-third partial hepatectomy was converted into a two-thirds partial hepatectomy at the 10th hour, the DNA synthesis at the 24th hour reached the value observed after a straightforward two-thirds partial hepatectomy. Inversely, the regenerative response was significantly reduced when additional liver lobes were connected to neck vessels between the 14th and the 18th hour after a two-thirds partial hepatectomy. In conclusion, the actual liver mass present during the period corresponding to mid- to late G1appears to control the magnitude of the proliferative response, which is not the simple consequence of the early changes following a partial hepatectomy.
Role of maxi-K+ channels in endothelin-induced vasoconstriction of mesenteric and submucosal arterioles
Authors: Hill Ceredwyn E. , Kirton Adam , Wu Douglas D. , Vanner Stephen J.
Published: December 2017

The action of endothelin in small intestinal resistance vessels of the guinea pig was studied by examining submucosal arteriole vasoactivity in vitro and electrical properties of mesenteric arteriole smooth muscle cells. Endothelin-1 (ET-1) constricted submucosal arterioles with a half-maximal effective concentration of 170 pM. ET-3 caused detectable constriction with a minimum of 20 nM. The ET-1 response was prolonged, with a time to 90% relaxation of 41 ± 2.8 min after washout. The ETA antagonist BQ-123 (200 nM) decreased the sensitivity to ET-1 ∼40-fold. Arterioles preconstricted with prostaglandin F2α did not relax when superfused with ET-1, ET-3, or an ETB agonist, IRL-1620, and pretreatment with the nitric oxide synthase inhibitor N G-monomethyl-l-arginine was ineffective in countering ET-1-induced constriction, indicating the absence of functional ETBreceptors. Resting membrane potential in isolated cells was characterized by transient hyperpolarizing spikes (THs). ET-1 (20 nM) increased TH frequency and caused the emergence of a larger amplitude population. Under voltage clamp, spontaneous transient outward currents (STOCs) were seen that reversed at the K+ equilibrium potential. ET-1 increased STOC frequency and amplitude. Iberiotoxin (IBTX; 200 nM), a maxi-K+ channel antagonist, blocked the ET-1-induced THs and reduced STOC activity. IBTX or tetraethylammonium increased the rate and extent of ET-1-induced arteriole constriction. We suggest that ET-1-induced vasoactivity of ileal resistance arterioles involves ETA receptor-mediated early activation of maxi-K+ channels that serves to counter strong constriction.
Differential activation of the Stat signaling pathway in the liver after burn injury
Authors: Wang Shan , Wolf Steven E. , Evers B. Mark
Published: December 2017

The liver plays a crucial role in the acute phase response after injury; mechanisms responsible for transducing inflammatory signals to the nucleus to initiate this response are not known. The purpose of this study was to examine the induction of the novel Stat (signal transducer and activator of transcription) pathway in the liver after burn injury. Rats were subjected to either a 60% burn or sham treatment; livers were removed over a time course and extracted for nuclear protein. We found that Stat3, but not Stat5, binding was predominantly increased in the liver after burn injury as assessed by gel mobility and “supershift” analyses. Moreover, Stat3 nuclear protein levels were increased 6- to 14-fold in the livers of burned rats compared with those of sham rats. Stat3 phosphorylation was rapidly induced after burn injury; the subsequent increase of Stat3 binding was completely blocked by preincubation with the antiphosphotyrosine antibody (4G10). We conclude that a differential and early induction of Stat3 binding activity occurs in the liver after burn injury; this induction is mediated by an increase in phosphorylation. These findings suggest an important role for Stat3 in transducing inflammatory signals to the nucleus of liver cells after a systemic burn injury.
Novel insights into histamine H2receptor biology
Authors: Del Valle John , Gantz Ira
Published: December 2017

Histamine exerts multiple biological actions through one of three receptor subtypes (H1, H2, and H3). This review focuses on new developments regarding the structure and function of the H2receptor. In addition to the important role this receptor plays in stimulating gastric acid secretion, recent studies have demonstrated that it is also involved in regulating gastrointestinal motility and intestinal secretion. The potential role of the H2receptor in regulating cell growth and differentiation has also been added to the list of actions this biogenic amine may exert in both normal and transformed tissues. Molecular cloning of the gene indicates that it has the structural characteristics of a heptahelical G protein-linked receptor. Site-directed mutagenesis studies of this receptor reveal the presence of key amino acids within the third and fifth transmembrane domains that are critical for ligand recognition. Molecular approaches have also shed light on the structural components of the H2receptor important in regulating desensitization and internalization. Although the H2receptor was classically thought to couple to the adenylate cyclase pathway, recent work with the cloned receptor indicates that it can also activate the phosphoinositide signaling cascade through an independent G protein-dependent mechanism. The novel observation that histamine may stimulate c- fos gene expression lends further support to the possible role of this receptor in regulating cell growth and differentiation.
Adrenergic modulation of human colonic motor and sensory function
Authors: Bharucha Adil E. , Camilleri Michael , Zinsmeister Alan R. , Hanson Russell B.
Published: December 2017

The effects of pharmacological modulation of adrenergic receptors on colonic motor and sensory function are unclear. We studied 40 healthy volunteers in a single-blind design; 12 received saline, and the remaining 28 received either clonidine, yohimbine, phenylephrine, or ritodrine. A barostat-manometric assembly in the left colon recorded drug effects on fasting and postprandial motor function, compliance, and sensation in response to standardized phasic balloon distensions delivered in random order. Clonidine reduced and yohimbine increased fasting, but not postprandial tone, by 63.2 ± 22.3% and 24.8 ± 8.8% (SE), respectively. Clonidine tended to reduce fasting phasic activity in the descending and sigmoid colon. A power exponential model provided the best fit to the compliance curve. Clonidine significantly increased colonic compliance. Clonidine reduced and yohimbine increased colonic perception of pain but not gas sensation during distension. Phenylephrine and ritodrine did not influence colonic motor or sensory function in the present studies. Thus α2-receptors modulate fasting colonic tone and compliance and alter perception of pain but not gas during mechanical stimulation of the colon.
Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas, and intestine
Authors: Jones Blake A. , Gores Gregory J.
Published: December 2017

Cell death of gastrointestinal epithelial cells occurs by a process referred to as apoptosis. In this review, we succinctly define apoptosis and summarize the role of apoptosis in the physiology and pathophysiology of epithelial cells in the liver, pancreas, and small and large intestine. The physiological mediators regulating apoptosis in gastrointestinal epithelial cells, when known, are discussed. Selected pathophysiological consequences of excessive apoptosis and inhibition of apoptosis are used to illustrate the significance of apoptosis in disease processes. These examples demonstrate that excessive apoptosis may result in epithelial cell atrophy, injury, and dysfunction, whereas inhibition of apoptosis results in hyperplasia and promotes malignant transformation. The specific cellular mechanisms responsible for dysregulation of epithelial cell apoptosis during pathophysiological disturbances are emphasized. Potential future areas of physiological research regarding apoptosis in gastrointestinal epithelia are highlighted when appropriate.
Adenosine kinase inhibitor GP515 attenuates hepatic leukocyte adhesion after hemorrhagic hypotension
Authors: Bauer Clemens , Bouma Maarten G. , Herrmann Isa , Van Den Wildenberg Frans A. J. M. , Firestein Gary S. , Marzi Ingo , Buurman Wim A.
Published: December 2017

Adhesion of leukocytes to the vascular endothelium hallmarks a key event in neutrophil-mediated organ injury after ischemia-reperfusion. The autacoid adenosine has been shown to inhibit activated neutrophil function and to interfere with leukocyte-endothelial adherence. Its therapeutic use in ischemia-reperfusion, however, has been limited by severe cardiovascular side effects. We therefore investigated the effects of the adenosine kinase inhibitor GP515 in vivo on hepatic leukocyte-endothelial interactions in a rat model of hemorrhagic hypotension and resuscitation, using intravital microscopy. Rats were pretreated with either GP515 (0.25 mg/kg) or saline in a randomized and blinded manner and subjected to pressure-controlled hemorrhagic hypotension at a mean arterial pressure of 40 mmHg for 60 min followed by 5 h of resuscitation. Five hours after resuscitation in saline-treated animals, firm leukocyte-sinusoidal adhesion was strongly enhanced in the periportal and midzonal sublobular regions, and sinusoidal diameters were also markedly reduced. Compared with saline treatment, GP515 significantly attenuated shock and resuscitation-induced leukocyte adhesion in both sublobular regions. Moreover, although GP515 did not significantly affect macrohemodynamical and hematological parameters, it enlarged narrowed sinusoidal diameters and tended to improve sinusoidal blood flow. We propose that the adenosine-regulating agent GP515 has a therapeutic potential to attenuate ischemia-reperfusion-induced inflammation by capitalizing on the beneficial anti-inflammatory effects of endogenous adenosine.
Hepatic uptake of hippurate: a multiple-indicator dilution, perfused rat liver study
Authors: Yoshimura Tsutomu , Schwab Andreas J. , Tao Lei , Barker Ford , Pang K. Sandy
Published: December 2017

The hepatic transport of hippuric acid (HA), a glycine-conjugated metabolite of benzoic acid that exhibits only modest plasma albumin binding (binding association constant of 2.1 × 103M−1), was studied in the single-pass perfused rat liver (12 ml/min), using the multiple indicator dilution (MID) technique. The venous recovery of [3H]HA on portal venous injection of a MID dose containing a mixture of a set of noneliminated reference indicators and [3H]HA revealed a survival fraction of unity, corroborating the lack of disappearance of bulk HA from plasma. When the outflow recovery was fitted to the barrier-limited model of Goresky et al. (C. A. Goresky, G. G. Bach, and B. E. Nadeau. J. Clin. Invest. 52: 991–1009, 1973), the derived influx ( PinS ) and efflux ( PoutS ) permeability-surface area products were found to be dependent on the concentration of HA (1–930 μM); PinS and PoutS were ∼3.5 times the plasma flow rate at low HA concentration, but decreased with increasing HA concentration. All values, however, greatly exceeded the expected contribution from passive diffusion, because the equilibrium distribution ratio of chloroform to buffer for HA was extremely low (0.0001 at pH 7.4). The tissue equilibrium partition coefficient ( Pin/ Pout, or ratio of influx to efflux rate constants, k1/ k−1) was less than unity and decreased with concentration. The optimized apparent Michaelis-Menten constant and maximal velocity were 182 ± 60 μM and 12 ± 4 nmol ⋅ s−1⋅ g−1, respectively, for influx and 390 ± 190 μM and 29 ± 13 nmol ⋅ s−1⋅ g−1, respectively, for efflux. In the presence ofl-lactate (20 mM), however, PinS for the uptake of HA (174 ± 3 μM) was reduced. Benzoic acid (10–873 μM) was also effective in reducing hepatic uptake of HA (5.3 ± 0.9 μM). These interactions suggest that MCT2, the monocarboxylate transporter that mediates the hepatic uptake of lactate and other monocarboxylic acids, may be involved in HA transport.
Effects of pacing parameters on entrainment of gastric slow waves in patients with gastroparesis
Authors: Lin Z. Y. , McCallum R. W. , Schirmer B. D. , Chen J. D. Z.
Published: December 2017

The aim of this study was to investigate the effect of pacing parameters on the entrainment of gastric slow waves in patients with gastroparesis. Four pairs of cardiac pacing wires were placed on the serosal surface of the stomach in 13 patients with gastroparesis. After a baseline recording for 30 min, gastric pacing was performed in a number of sessions with different effective parameters, each lasting for 30 min. The following parameters were found to be effective for the entrainment of the gastric slow wave: a pacing frequency 10% higher than the intrinsic gastric slow wave frequency (IGF), 300 ms pulse width, and 4 mA pacing amplitude. A reduction of pacing amplitude from 4 to 2 mA and 1 mA reduced the percentage of entrainment of the gastric slow wave to 79 ± 10% and 50 ± 11%, respectively. Pacing with a pulse width of 30 or 3 ms was not able to entrain the gastric slow wave in any of the patients. An ectopic pacemaker of tachygastria found in three patients was reversed with gastric pacing. It was concluded that gastric pacing at a frequency up to 10% higher than the IGF and with an amplitude of 4 mA and a pulse width of 300 ms is able to completely entrain the gastric slow wave and normalize gastric dysrhythmias in patients with gastroparesis.
Disruption of intestinal barrier function associated with experimental colitis: possible role of mast cells
Authors: Stein Jürgen , Ries Jürgen , Barrett Kim E.
Published: December 2017

The objective was to characterize changes in barrier and transport function in an experimental model of colitis, and to determine whether mast cells contribute to these changes. Colitis was induced in rats with intracolonic 2,4,6-trinitrobenzenesulfonic acid (TNBS, 30 mg) in 50% ethanol. Controls received 0.9% saline or the ethanol vehicle alone. In vivo loop perfusion was used to assess colonic water flux (in μl ⋅ cm−1⋅ h−1) and lumen-to-blood51Cr-labeled EDTA clearance (% administered dose) after TNBS. Myeloperoxidase (MPO) was used as an index of granulocyte influx. TNBS or its vehicle caused a marked decrease in water absorption and an increase in permeability at 4 h after administration compared with saline. Neither dexamethasone (anti-inflammatory control) nor doxantrazole (mast cell stabilizer) was able to attenuate these early changes likely caused by the vehicle. In contrast, at later times, TNBS (but not its vehicle) also increased51Cr-EDTA permeability and decreased water absorption; both effects were significantly attenuated by dexamethasone or doxantrazole. These drugs also significantly reduced TNBS-induced MPO accumulation and release of rat mast cell protease II. We conclude that experimental colitis is associated with severe defects in intestinal transport and barrier functions and that mast cells may contribute to the pathogenesis of these changes.
Luminal fructose modulates fructose transport and GLUT-5 expression in small intestine of weaning rats
Authors: Shu Rong , David Elmer S. , Ferraris Ronaldo P.
Published: December 2017

In neonatal rats, precocious introduction of dietary fructose significantly enhances brush-border fructose transport rates and GLUT-5 mRNA levels during early weaning. In this study, these rates and levels were more than two times higher in the anastomosed intestine compared with those in the bypassed loop of weaning pups that underwent Thiry-Vella surgery and consumed high-fructose (HF) diets. In Thiry-Vella pups fed fructose-free (NF) diets, uptake rates and mRNA levels in the anastomosed intestine were very low and similar to those in the bypassed loop. In sham-operated littermates, transport rates and mRNA levels were similar between intestinal regions that corresponded to anastomosed and bypassed loops in Thiry-Vella pups and were two to three times greater in pups fed HF than in those fed NF diet. In contrast, rates of brush-border glucose transport and levels of SGLT-1 and of GLUT-2 mRNA were independent of diet and were similar between bypassed and anastomosed regions. Changes in GLUT-5 expression did not follow a distinct diurnal rhythm. When pups were fed HF diet after 12 h of starvation to empty the intestinal lumen, fructose transport rates increased with feeding duration and reached a plateau 12–24 h after feeding; in contrast, GLUT-5 mRNA levels were highest within 4 h after arrival of chyme in the jejunum and then decreased gradually and returned to baseline levels 24 h later. In littermates fed NF diet, mRNA levels and uptake rates were each independent of feeding duration. Luminal, and not endocrine, signals regulate GLUT-5 expression in weaning pups.
Mechanism of galanin-induced contraction of longitudinal smooth muscle of the rat jejunum
Authors: Ahtaridis Simon A. , Katoch Surender S. , Moreland Robert S.
Published: December 2017

Intact and α-toxin-permeabilized longitudinal smooth muscle were mounted for measurement of force and myosin light chain phosphorylation. Galanin contracted intact jejunum with a half-maximum effective concentration of 9.2 ± 0.1 nM. Neither atropine, hexamethonium, guanethidine, nor tetrodotoxin affected the contraction. The contraction was also unaffected by depletion of intracellular Ca2+or by addition of thapsigargin; removal of extracellular Ca2+or addition of nifedipine abolished the contraction. Galanin increased myosin light chain phosphorylation levels concomitantly with force. During continued tissue stimulation, force fell to suprabasal values, whereas myosin light chain phosphorylation levels remained elevated. Galanin increased Ca2+sensitivity of contraction in α-toxin-permeabilized tissues, and this was reversed by either guanosine 5′- O-(2-thiodiphosphate) or pertussis toxin. These results suggest that galanin-induced contraction of longitudinal jejunal smooth muscle is dependent on a pertussis toxin-sensitive G protein that is apparently not coupled to the release of intracellular Ca2+but to the influx of extracellular Ca2+and involves an initial myofilament Ca2+sensitization followed by Ca2+desensitization.
Proximal and distal esophageal contractions have similar manometric features
Authors: Peghini Paolo L. , Pursnani Kishore G. , Gideon Matthew R. , Castell June A. , Nierman Jennifer , Castell Donald O.
Published: December 2017

The human esophagus is composed of striated muscle proximally and of smooth muscle distally with a transition zone between the two. Striated muscle contracts much faster than smooth muscle. The change in pressure over time (dP/d t) of the contraction amplitude should therefore be higher in proximal than in distal esophagus, reflecting the presence of striated muscle proximally. There were 34 normal esophageal manometries of patients analyzed for swallow amplitude and dP/d t in the pharynx and esophagus. An additional 11 healthy controls were similarly studied. Amplitudes in pharynx and proximal and distal esophagus were not different. The midesophagus had a pressure trough ( P < 0.001). The dP/d t in the pharynx was much higher than that in the esophagus ( P < 0.001). The dP/d t of proximal and distal esophagus were of the same order of magnitude. The manometric behavior of the striated muscle portion of the proximal esophagus differs from that seen in the pharynx and shows similar characteristics to distal esophageal smooth muscle.
CCK-, secretin-, and cholinergic-independent pancreatic fluid hypersecretion in protease inhibitor-treated rats
Authors: Yamamoto Mitsuyoshi , Shirohara Hisashi , Otsuki Makoto
Published: December 2017

Plasma cholecystokinin (CCK) levels in fed rats increased from 2.59 ± 0.13 pmol/l to the peak of 27.6 ± 4.1 pmol/l at 1 h after a single oral administration of synthetic protease inhibitor (PI; ethyl N-allyl- N-{( E)-2-methyl-3-[4-(4-amidino-phenoxycarbonyl)phenyl]propenoyl}amino acetate methansulfonate; 20 mg/kg body wt), but then returned to the preloading value at 12 h after administration. The pancreatic fluid secretion, rich in chloride but poor in bicarbonate, was significantly elevated at 6–12 h postfeeding (100.9 ± 8.2 vs. 27.3 ± 2.3 μl/30 min in control rats, P < 0.01). Loxiglumide (50 mg ⋅ kg body wt−1⋅ h−1), atropine (100 μg ⋅ kg body wt−1⋅ h−1), or antisecretin serum (100 μl/rat) at 12 h postfeeding did not modify the fluid hypersecretion. Loxiglumide, when given together with PI, completely abolished fluid hypersecretion, but it could not inhibit hypersecretion when applied 3 h after PI treatment. Labeling with 5-bromo-2′-deoxyuridine showed active proliferation of acinar cells at 3 h after PI treatment (3.56 ± 0.29% vs. 0.46 ± 0.08% in control, P < 0.001), but not in rats given loxiglumide together with PI. In rats that fasted from 12 h before to 12 h after PI feeding, neither pancreatic fluid hypersecretion nor active proliferation of acinar cells was observed. These results suggest that pancreatic fluid hypersecretion in fed rats at 6–12 h after PI treatment is caused not by CCK-, secretin-, or cholinergic-dependent mechanisms but probably by acinar cell proliferation.
Significant cholinergic role in secretin-stimulated exocrine secretion in isolated rat pancreas
Authors: Park Hyung Seo , Lee Yun Lyul , Kwon Hyeok Yil , Chey William Y. , Park Hyoung Jin
Published: December 2017

Effects of intrapancreatic cholinergic activation by electrical field stimulation (EFS) on secretin-stimulated pancreatic exocrine secretion were investigated in the totally isolated perfused rat pancreas. EFS at 15 V, 2 ms, and 8 Hz for 45 min markedly increased spontaneous pancreatic secretion. This increase was completely inhibited by tetrodotoxin (1 μM) but not by hexamethonium (100 μM). Atropine (2 μM) significantly reduced the EFS-evoked volume flow and amylase output by 52% and 80%, respectively. EFS further increased the secretin (12 pM)-stimulated pancreatic secretion of fluid and amylase. The increases of the two parameters were significantly suppressed by atropine by 28% and 72%, respectively. Interestingly, EFS significantly increased concentrations of somatostatin-like immunoreactivity in portal venous effluents. When pertussis toxin (200 ng/ml) or rabbit antisomatostatin serum (0.1 ml/10 ml; titer of 1:50,000) was intra-arterially administered, EFS further increased the secretin-stimulated pancreatic secretion. In conclusion, the activation of intrapancreatic cholinergic neurons potentiated the secretin action on pancreatic exocrine secretion in the rat. This potentiating effect was significantly reduced by local somatostatin released during EFS that activated intrapancreatic cholinergic tone.
PGE2 hyperpolarizes gallbladder neurons and inhibits synaptic potentials in gallbladder ganglia
Authors: Jennings Lee J. , Mawe Gary M.
Published: December 2017

Gallbladder prostaglandin E2(PGE2) levels are significantly elevated in pathophysiological conditions, resulting in changes in gallbladder motility or secretion that may involve actions of the prostanoid in intramural ganglia. This study was undertaken to examine the effects of PGE2 on neurons of the intramural ganglia of the guinea pig gallbladder. Application of PGE2 by microejection or superfusion elicited a complex triphasic change in the resting membrane potential (RMP). For example, application of PGE2 by microejection (100 μM) resulted in a brief hyperpolarization (mean duration 11.1 ± 1.3 s), followed by a mid-phase repolarization toward or above RMP (mean duration 50.7 ± 8.1 s), and finally a long-lasting hyperpolarization (mean duration 157.3 ± 36.7 s). Associated with these PGE2-evoked alterations in RMP were changes in input resistance measured via injection of hyperpolarizing current pulses. An examination of the action potential afterhyperpolarization (AHP) during the PGE2-evoked response revealed an attenuation of both the amplitude and duration of the AHP. However, only a slight increase in excitability of gallbladder neurons in the presence of PGE2 was evident in response to depolarizing current pulses, and PGE2 did not cause the cells to fire spontaneous action potentials. Application of PGE2 reduced the amplitudes of both fast and slow excitatory synaptic potentials. These results suggest that increased prostaglandin production may decrease ganglionic output and therefore contribute to gallbladder stasis.
Mammalian bombesin receptors are coupled to multiple signal transduction pathways in pancreatic acini
Authors: Nishino Hirokazu , Tsunoda Yasuhiro , Owyang Chung
Published: December 2017

We investigated the structural requirements for bombesin (BB)-like peptides to stimulate amylase secretion in rat pancreatic acini and examined the responsible intracellular signal transduction pathways. The tetradecapeptide BB-(1—14) was a full agonist, whereas the heptapeptide BB-(8—14) did not evoke amylase secretion. The mammalian BB analog neuromedin C decapeptide [NMC-(5—14)] was as potent as BB-(1—14) in stimulating amylase secretion, suggesting that Gly5-Asn6-His7(or Gln7) of the COOH-terminal decapeptide are essential amino acids for full biological activity. BB and NMC equipotently stimulatedd- myo-inositol 1,4,5-trisphosphate production, which was inhibited by the phospholipase C (PLC) inhibitor U-73122. BB and NMC also stimulated protein tyrosine kinase (PTK) activities. The half-maximal effective concentration (EC50) for NMC-activated PTK was 2 log units less than the EC50for BB-activated PTK. NMC was 10–34 times more potent than BB in increasing leukotriene C4(an index of arachidonic acid production). The production of leukotriene C4was inhibited by the phospholipase A2(PLA2) inhibitor ONO-RS-082. NMC is structurally homologous to BB-(5—14) except that Gln7in BB is replaced by His7in NMC. Therefore, substitution of Gln7for His7may alter the signal transduction systems to include the PTK and PLA2pathways. U-73122 inhibited Ca2+spiking and amylase secretion induced by NMC and BB. However, the PTK inhibitor genistein and the PLA2inhibitor ONO-RS-082 inhibited secretion induced by NMC but not that induced by BB. In contrast to nonmammalian BB receptors, which primarily use the PLC pathway, the rat BB receptor is linked to three different signal transduction systems: PLC, PTK, and PLA2pathways.
Impaired gastric acid secretion in gastrin-deficient mice
Authors: Friis-Hansen Lennart , Sundler Frank , Li Ying , Gillespie Patrick J. , Saunders Thomas L. , Greenson Joel K. , Owyang Chung , Rehfeld Jens F. , Samuelson Linda C.
Published: December 2017

To further understand the role of the peptide hormone gastrin in the development and function of the stomach, we have generated gastrin-deficient mice by gene targeting in embryonic stem cells. Mutant mice were viable and fertile, without obvious visible abnormalities. However, gastric function was severely affected by the loss of gastrin. Basal gastric acid secretion was abolished and could not be induced by histamine, carbachol, or gastrin. Histological analysis revealed alterations in the two cell types primarily involved in acid secretion, parietal and enterochromaffin-like (ECL) cells. Parietal cells were reduced in number with an accumulation of immature cells lacking H+-K+-adenosinetriphosphatase (H+-K+-ATPase). ECL cells were positioned closer to the base of the gastric glands, with markedly lower expression of histidine decarboxylase. Gastrin administration for 6 days reversed the effects of the gastrin deficiency, leading to an increase in the number of mature, H+-K+-ATPase-positive parietal cells and a partial restoration of acid secretion. The results show that gastrin is critically important for the function of the acid secretory system.
Protein kinetics determined in vivo with a multiple-tracer, single-sample protocol: application to lactase synthesis
Authors: Dudley Mary A. , Burrin Douglas G. , Wykes Linda J. , Toffolo Gianna , Cobelli Claudio , Nichols Buford L. , Rosenberger Judy , Jahoor Farook , Reeds Peter J.
Published: December 2017

Precise analysis of the kinetics of protein/enzyme turnover in vivo has been hampered by the need to obtain multiple tissue samples at different times during the course of a continuous tracer infusion. We hypothesized that the problem could be overcome by using an overlapping (i.e., staggered) infusion of multiple stable amino acid isotopomers, which would take the place of multiple tissue samples. We have measured, in pigs, the in vivo synthesis rates of precursor (rapidly turning over) and mature (slowly turning over) polypeptides of lactase phlorizin hydrolase (LPH), a model for glycoprotein synthesis, by using an overlapping infusion of [2H3]leucine, [13C1]leucine, [13C1]phenylalanine, [2H5]phenylalanine, [13C6]phenylalanine, and [2H8]phenylalanine. Blood samples were collected at timed intervals, and the small intestine was collected at the end of the infusion. The tracer-to-tracee ratios of each isotopomer were measured in the plasma and jejunal free amino acid pools as well as in purified LPH polypeptides. These values were used to estimate kinetic parameters in vivo using a linear steady-state compartmental model. The fractional synthesis rates of the high-mannose, complex glycosylated and mature brush-border LPH polypeptides, so determined, were 3.3 ± 1.1%/min, 17.4 ± 11 %/min, and 0.089 ± 0.02 %/min, respectively. We conclude that this multiple-tracer, single-sample protocol is a practicable approach to the in vivo measurement of protein fractional synthesis rates when only a single tissue sample can be obtained. This method has broad application and should be particularly useful for studies in humans.
In vivo three-dimensional EPR imaging of nitric oxide production from isosorbide dinitrate in mice
Authors: Fujii Satoshi , Suzuki Yasuhiro , Yoshimura Tetsuhiko , Kamada Hitoshi
Published: December 2017

Recently, in vivo electron paramagnetic resonance (EPR) spectroscopy and imaging have been widely used to investigate free radical distribution and metabolism in tissues, organs, and whole body of small animals. Endogenous nitric oxide (NO) is an attractive target of this method. In the present study, NO production from a nitrovasodilator, isosorbide dinitrate (ISDN), in live mice was investigated by in vivo EPR spectroscopy and imaging combined with the spin-trapping technique. A highly water-soluble Fe complex with N-(dithiocarboxy)sarcosine (DTCS) was used as an NO-trapping agent. Mice received [14N]ISDN, and the Fe-DTCS complex subcutaneously exhibited the characteristic triplet EPR signal of the NO adduct [14NO-Fe(DTCS)2]2−. Using [15N]ISDN instead of [14N]ISDN, we were able to observe that the doublet EPR signal stemmed from the15NO adduct, which directly demonstrated that NO was produced from ISDN. The three-dimensional EPR images of the upper abdomen of living mice showed that the NO adducts were distributed in the liver and the kidneys. This EPR image combined with the ex vivo EPR measurements of the blood suggested that NO production from ISDN occurred in the liver in this experimental condition.
MUC5B is the prominent mucin in human gallbladder and is also expressed in a subset of colonic goblet cells
Authors: Van Klinken B. Jan-Willem , Dekker Jan , Van Gool Sandy A. , Van Marle Jan , Büller Hans A. , Einerhand Alexandra W. C.
Published: December 2017

To elucidate the roles of human gallbladder mucin (HGBM), such as in gallstone formation and cytoprotection, it is essential to identify HGBM and study its expression. This was performed by metabolic labeling, Western blotting, immunohistochemistry, and RT-PCR. In a large number of individuals, antibodies against purified HGBM and against MUC5B detected a mucin precursor (∼470 kDa) in the gallbladder and colon, but not in the small intestine. In the gallbladder, Western blotting using specific anti-MUC5B antibodies showed that this mucin precursor represented an identical mucin, MUC5B. RT-PCR experiments demonstrated a similar tissue distribution pattern of MUC5BmRNA. Immunohistochemistry with anti-HGBM and anti-MUC5B showed staining in gallbladder epithelial cells and colonic goblet cells in the crypt base, but not in the small intestine; double labeling showed that HGBM was located in small granules within goblet cells, colocalizing to MUC2-containing goblet cells. Metabolic labeling demonstrated the secretion of mature MUC5B in the colon. Conclusively, MUC5B is identified as the prominent HGBM and is also expressed and secreted in the colon.
Canine small bowel motor patterns and contractions are not neurally regulated during enteric nutrient infusion
Authors: Behrns Kevin E. , Sarr Michael G. , Hanson Russell B. , Zinsmeister Alan R.
Published: December 2017

The aims of this study were to determine the effects of duodenal and jejunoileal nutrient infusions on small intestinal motor patterns and intestinal contractions in neurally intact and neurally isolated small bowel. Fifteen dogs were prepared with duodenal and jejunal infusion and manometry catheters and a diverting jejunal cannula. Ten of the dogs underwent in situ neural isolation of the jejunoileum. A mixed nutrient meal (0.5 kcal/ml) was infused into the duodenum or jejunum at 3 ml/min for 5 h. Control experiments involved infusion of a balanced salt solution. Manometric data collected on-line to a microcomputer were analyzed for direction, distance, and velocity of spread of single pressure waves (SPW) and clustered contractions. Isolated duodenal and jejunoileal nutrient infusions inhibited the fasting motor pattern in neurally intact and neurally isolated small bowel. Motor activity (motility index) increased slightly during nutrient infusion within groups, but there were few differences between groups. Neither neural isolation nor nutrient infusion had a consistent effect on spread of SPW or migration of clustered contractions. Isolated duodenal and jejunoileal nutrient infusions in the dog inhibit fasting motor patterns and increase motor activity slightly but have little effect on characteristics of individual and clustered contractions. Extrinsic innervation to the jejunoileum or intrinsic neural continuity of the jejunum with the duodenum had little effect on single or grouped contractions. Although the changes in motor activity demonstrated in this study appear small, alterations in intestinal transit and absorption may still occur and may be of importance physiologically.
Peptidergic and cholinergic neurons and mediators in peptone-induced gastroprotection: role of cyclooxygenase-2
Authors: Ehrlich Karlheinz , Plate Susanne , Stroff Thomas , Gretzer Britta , Respondek Michael , Peskar Brigitta M.
Published: December 2017

This study investigates the neural pathways, mediators, and cyclooxygenase isoenzymes involved in the gastroprotection conferred by peptone in rats. Intragastric perfusion with 8% peptone protected against gross and histological damage induced by subsequent perfusion with 50% ethanol. The gastroprotective effect of peptone was near maximally inhibited by gastrin immunoneutralization, inactivation of capsaicin-sensitive afferent neurons, calcitonin gene-related peptide (CGRP) immunoneutralization, blockade of gastrin receptors, CGRP, bombesin/gastrin-releasing peptide (GRP), or somatostatin receptors, and by the nitric oxide (NO) synthase inhibitor N G-nitro-l-arginine methyl ester and was partially (46%) counteracted by atropine. Indomethacin and the selective cyclooxygenase-2 inhibitors NS-398 and L-745,337 dose dependently (50% inhibitory dose, 4.2, 0.8, and 1.5 mg/kg, respectively) attenuated the peptone-induced protection. Dexamethasone was ineffective. These results indicate that protective effects of peptone involve endogenous gastrin and possibly somatostatin and are mediated by capsaicin-sensitive afferent, cholinergic, and bombesin/GRP neurons. CGRP, NO, and prostaglandins participate as essential mediators. The study provides evidence that prostaglandins derived from a constitutive cyclooxygenase-2 contribute to mucosal defense in the presence of ulcerogens and thus participate in homeostatic functions of the stomach.
Sequential and rapid activation of select caspases during apoptosis of normal intestinal epithelial cells
Authors: Grossmann Johannes , Mohr Susanne , Lapetina Eduardo G. , Fiocchi Claudio , Levine Alan D.
Published: December 2017

Detachment-induced cell death (DICD) is considered to be one of the means by which intestinal epithelial cells (IEC) die of apoptosis as they reach the lumen and are shed. Caspases, a family of cysteine proteases, play a central role in initiating, amplifying, and executing apoptosis; however, the pattern of caspase activation in response to distinct apoptotic stimuli remains unknown. We investigated the kinetics of caspase activation during DICD in freshly isolated human IEC. DNA fragmentation is observed 90 min after detachment and is preceded by the sequential activation of preformed members of the CPP32 family of caspases. Activation of caspase 6 and cleavage of the endogenous caspase substrate poly(ADP-ribose) polymerase (EC 2.4.2.30 ) are detected within 15 min of detachment, 30–45 min before caspase 3 activation. Caspase 1 and caspase 10 are present as proenzymes, yet they remain inactive in response to this trigger of apoptosis. Human IEC are primed to rapidly undergo detachment-induced apoptosis involving the selective and sequential activation of preformed caspases. This study may enhance our understanding of physiological events occurring as IEC are shed. Their rapid apoptotic response to detachment may facilitate the high turnover of cells and ensure homeostasis in the intestinal epithelium.
I. New insights into neuronal injury: a cautionary tale
Authors: Hall Karen E. , Wiley John W.
Published: December 2017

Understanding of the pathophysiology of neuronal injury has advanced remarkably in the last decade. This largely reflects the burgeoning application of molecular techniques to neuronal cell biology. Although there is certainly no consensus hypothesis that explains all aspects of neuronal injury, a number of interesting observations have been published. In this brief review, we examine mechanisms that appear to contribute to the pathophysiology of neuronal injury, including altered Ca2+ signaling, activation of the protease cascades coupled to apoptosis, and mitochondrial deenergization associated with release of cytochrome c, production of free radicals, and oxidative injury. Finally, evidence for neuroprotective mechanisms that may ameliorate cell injury and/or death are reviewed. Little information has been published regarding the mechanisms that mediate injury in the enteric nervous system, necessitating a focus on models outside the gastrointestinal (GI) tract, which may provide insights into enteric nervous system injury.
Early dietary experience influences ontogeny of intestine in response to dietary lipid changes in later life
Authors: Jarocka-Cyrta E. , Perin N. , Keelan M. , Wierzbicki E. , Wierzbicki T. , Clandinin M. T. , Thomson A. B. R.
Published: December 2017

This study was undertaken to test the hypothesis that a change in the mother’s diet at the time of birth and continued during suckling modifies the intestinal transport of nutrients in the suckling offspring. Pregnant rat dams were fed one of four semisynthetic diets during pregnancy [high or low n-6/n-3 diet or a diet enriched with arachidonic acid (AA) or docosahexaenoic acid (DHA)] and were fed the same diet at the time of birth or switched to another diet. The greatest body weight gain was in the suckling rats (15–16 days of age) fed a low n-6/n-3 diet. Switching from this diet caused weight loss, and the observed weight gain with the low n-6/n-3 diet was prevented by previous exposure of the mother to the high n-6/n-3 diet or the AA- or DHA-containing diet. Although continuous feeding of a high n-6/n-3 diet to the mother during pregnancy and lactation was associated with the lowest in vitro rates of fructose uptake, switching the mother to another diet during lactation did not necessarily correct the low absorption. In contrast, continuous feeding of a high n-6/n-3 diet to the mother during pregnancy and lactation is associated with the highest maximal transport rate of glucose uptake into the jejunum and ileum. Jejunal uptake of fatty acids 12:0, 18:0, 18:3(n-3), and cholesterol was less with the low n-6/n-3 diet compared with the high n-6/n-3 diet, whereas the ileal uptake of 18:0 and 18:3(n-3) was higher with the low n-6/n-3 diet. Thus the ontogeny of the intestine is critically influenced by the mother’s diet during gestation as well as during the nursing period. Some of the diet-associated changes in nutrient uptake resulting from the mother’s diet during pregnancy could be corrected by dietary interventions introduced after birth.
Gastric mechanosensory and lower esophageal sphincter function in rumination syndrome
Authors: Thumshirn Miriam , Camilleri Michael , Hanson Russell B. , Williams Donald E. , Schei Alfred J. , Kammer Patricia P.
Published: December 2017

Our hypothesis was that rumination syndrome is associated with gastric sensory and motor dysfunction. We studied gastric and somatic sensitivity, reflex relaxation of the lower esophageal sphincter (LES), and gastric compliance and accommodation postprandially and postglucagon. A barostatically controlled gastric bag and esophageal manometry were used to compare gastric sensorimotor functions and LES relaxation to gastric distension in 12 patients with rumination syndrome and 12 controls. During bag distensions, patients had greater nausea, bloating, and aggregate score, but not pain, compared with controls ( P < 0.05). At 4 and 8 mmHg gastric distension, LES tone reduction was greater in patients than in controls ( P < 0.05). Gastric compliance, accommodation to a standard meal, and response to glucagon were not different in patients and controls; however, 6 of 12 patients had no gastric accommodation; the latter patients had significantly greater pain perception during distension ( P < 0.05) but normal somatic sensitivity compared with healthy controls. Rumination syndrome is characterized by higher gastric sensitivity and LES relaxation during gastric distension. A subgroup of patients also had absent postprandial accommodation.
A polyamine pathway-mediated mitogenic mechanism in enterochromaffin-like cells ofMastomys
Authors: Kidd M. , Tang L. H. , Schmid S. W. , Miu K. , Modlin I. M.
Published: December 2017

We have previously demonstrated that in Mastomys species proliferation of gastric enterochromaffin-like (ECL) cells is predominantly regulated by gastrin and by transforming growth factor-α (TGF-α) in the naive and neoplastic state, respectively. In this study we examined whether these intracellular mitogenic responses are mediated by polyamines and ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine biosynthesis. An ECL cell preparation of high purity was used to measure the effect of the polyamine derivatives putrescine, spermidine, and spermine on DNA synthesis by bromodeoxyuridine uptake. Both putrescine and spermidine augmented gastrin-stimulated, but not basal, DNA synthesis in naive cells. This proliferative response correlated with an increase in ODC activity that was partially inhibited (20%) by difluoromethylornithine (DFMO), an inhibitor of ODC (IC50, 30 pM). In contrast, all polyamines increased both basal and TGF-α-stimulated DNA synthesis as well as ODC activity in tumor ECL cells. DFMO completely inhibited the proliferative response of TGF-α (IC50, 3 pM). Thus polyamine biosynthesis is involved in proliferation of ECL cells and in particular the mitogenesis of tumor cells, suggesting a role for this pathway in the regulation of ECL cell transformation.
IV. Pathophysiology of GI motility related to interstitial cells of Cajal
Authors: Huizinga Jan D.
Published: December 2017

Our understanding of the physiological roles played by interstitial cells of Cajal (ICC) in relation to gastrointestinal (GI) motility is still rudimentary. Nevertheless, studies into the pathophysiology of ICC are emerging at a rapid pace. Caution should be exercised, however, in assuming correlations between changes in Kit immunoreactivity, findings of ultrastructural abnormalities in ICC, and the pathophysiology and symptoms of the patients. Recent studies have revealed reduced numbers or the absence of ICC in small intestine and colon that do not exhibit normal peristaltic activity. Furthermore, important evidence is emerging that motor abnormalities in newborns may be associated with delayed maturation of the ICC network. These preliminary clinical studies provide plausible hypotheses toward the pathophysiology of certain motor disorders and strongly encourage basic scientific studies directed toward discovering the intrinsic properties of ICC as well as obtaining a deeper understanding of the physiological roles played by these cells.
I. TNF-induced liver injury
Authors: Bradham Cynthia A. , Plümpe Jörg , Manns Michael P. , Brenner David A. , Trautwein Christian
Published: December 2017

Tumor necrosis factor-α (TNF-α) functions as a two-edged sword in the liver. TNF-α is required for normal hepatocyte proliferation during liver regeneration. It functions both as a comitogen and to induce the transcription factor nuclear factor-κB, which has antiapoptotic effects. On the other hand, TNF-α is the mediator of hepatotoxicity in many animal models, including those involving the toxins concanavalin A and lipopolysaccharide. TNF-α has also been implicated as an important pathogenic mediator in patients with alcoholic liver disease and viral hepatitis.