Biomedical subjects

P Portincasa

Publications and source records attributed to P Portincasa.

At least 19 recordsLinked to original sources

PubMed2006

Indomethacin enhances bile salt detergent activity: relevance for NSAIDs-induced gastrointestinal mucosal injury.

Gastroduodenal toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) is partly independent from cyclooxygenase inhibition, possibly related to increased intermixed micellar-vesicular (nonphospholipid-associated) bile salt concentrations thought to be responsible for bile salt cytotoxicity. We evaluated the effects of indomethacin on bile salt cytotoxicity with complementary in vitro and ex vivo systems. In the erythrocyte model, indomethacin alone did not induce hemolysis. In contrast, indomethacin enhanced and phospholipids decreased hemolysis induced by hydrophobic taurodeoxycholate (TDC). Hydrophilic tauroursodeoxycholate (TUDC) enhanced rather than decreased TDC-induced hemolysis in the presence of indomethacin. Indomethacin did not affect intermixed micellar-vesicular bile salt concentrations or compositions. Indomethacin also increased TDC-induced lactate dehydrogenase release in CaCo-2 cells and bile salt-induced rat colonic mucosal injury, and prevented potential protective effects of TUDC in these systems. Our data show that indomethacin enhances bile salt-induced cytotoxicity without affecting intermixed micellar-vesicular bile salt concentrations or compositions. These findings may be relevant for gastroduodenal injury during NSAID therapy.

Animals↗

PubMed2006

Gallstone disease: Symptoms and diagnosis of gallbladder stones.

The clinical aspects and the diagnostic features of gallstone disease are described. The natural history of silent gallstones is overviewed, and the risk of developing symptoms and complications is also discussed. The importance of colicky pain as a specific gallstone symptom is highlighted, and the role of both laboratory tests and diagnostic investigations for differential diagnosis is discussed. Finally, we describe the diagnostic features of gallbladder stone disease, including indications, sensitivity, specificity, and limitations of different test investigations under special circumstances.

Abdomen↗

PubMed2005

Measurement of hepatic functional mass by means of 13C-methacetin and 13C-phenylalanine breath tests in chronic liver disease: comparison with Child-Pugh score and serum bile acid levels.

AIM: To evaluate and compare the clinical usefulness of 13C-phenylalanine and 13C-methacetin breath tests in quantitating functional hepatic mass in patients with chronic liver disease and to further compare these results with those of conventional tests, Child-Pugh score and serum bile acid levels. METHODS: One hundred and forty patients (50 HCV-related chronic hepatitis, 90 liver cirrhosis patients) and 40 matched healthy controls were studied. Both breath test and routine liver test, serum levels of cholic and chenodeoxycholic acid conjugates were evaluated. RESULTS: Methacetin breath test, expressed as 60 min cumulative percent of oxidation, discriminated the hepatic functional capacity not only between controls and liver disease patients, but also between different categories of chronic liver disease patients. Methacetin breath test was correlated with liver function tests and serum bile acids. Furthermore, methacetin breath test, as well as serum bile acids, were highly predictive of Child-Pugh scores. The diagnostic power of phenylalanine breath test was always less than that of methacetin breath test. CONCLUSION: Methacetin breath test represents a safe and accurate diagnostic tool in the evaluation of hepatic functional mass in chronic liver disease patients.

Acetamides↗

PubMed2005

Indomethacin-induced ileitis is associated with tensiometric, vascular and oxidative changes in the experimental rat model.

BACKGROUND: Indomethacin-induced enteritis is a model of inflammatory bowel disease. MATERIALS AND METHODS: To further characterize this model, rats received two injections of indomethacin (7.5 mg kg(-1)) 24 h apart and histological damage of intestinal mucosa, oxidative stress, alterations of intestinal motility and mesenteric vascular bed (MVB) reactivity were investigated after 5 days. RESULTS: The results show that indomethacin caused several histological and functional changes at the ileal level. In particular, response to carbachol as well as the nonadrenergic-noncholinergic inhibitory response to electrical field stimulation (EFS) was lower in the treated than control rats. Moreover, nitric oxide (NO)-component of the inhibitory response was higher in the treated than control rats. Mesenteric vessels preparations from the treated rats showed increased noradrenaline (NA)-induced perfusion pressure, whereas relaxant responses to acetylcholine, although not significantly reduced in the treated rats, had a higher nitrergic component. This finding suggests that vascular dysfunction may contribute to chronic inflammation. Indomethacin injection also determined acute and severe oxidative stress in ileum mucosa. CONCLUSIONS: In conclusion, our study contributes to further characterize the rat model of indomethacin-induced enteritis and suggests that it is suitable for drug screening in rats, as this model can be obtained in a very short period and is simple and reproducible.

Acetylcholine↗

PubMed2005

Ion transport across the gallbladder epithelium.

The function of the gallbladder is not only to store bile, but also to concentrate it during the interdigestive phase by means of salt-dependent water reabsorption. On the contrary, secretions of water and salt take place during the digestive phase. Dysregulation of ion absorption or secretion are common in many gallbladder diseases, such as colelithiasis. Transepithelial absorptions are determined by the Na+/K+ pump on the basolateral membrane, and by several apical membrane Na(+)-coupled transporters. Among these, some isoforms of Na+/H+ and Cl-/HCO3(-) exchangers have been studied. The presence of a Na(+)-Cl(-) simport has been molecularly and functionally characterized in some animal species. The ion transepithelial secretion is mainly dependent on an apical chloride transport attributable to a CFTR-like cAMP-activated channel with high permeability to HCO3(-). The apical membrane electrical potential is one of the factors influencing anion secretion and is maintained by the activity of cAMP-dependent K+ channels. The regulation of the activity of these channels is complex, because of their sensitivity to voltage, and to intracellular calcium and pH. The coordinated interplay underlying the regulation of transporters and channels needs to be clarified yet, as well as the interactions between transporters, channels and aquaporins.

Animals↗

PubMed2004

Relevance of hereditary defects in lipid transport proteins for the pathogenesis of cholesterol gallstone disease.

In the formation of cholesterol gallstones, cholesterol hypersecretion into bile causing cholesterol supersaturation and crystallization appears to be the primary factor, with disturbed gallbladder and intestinal motility as secondary factors. Although intestinal uptake mechanisms have not yet been fully elucidated, the HDL receptor scavenger receptor B1 (SRB1) may be involved. Since HDL-cholesterol, both from the intestine and peripheral sources, is the preferred type of cholesterol for biliary secretion, increased HDL transport to the liver can also cause cholesterol hypersecretion in bile. In the hepatocyte, bile formation is regulated by several transmembrane proteins, all belonging to the ABC family. A change in the activity in one of these proteins can have a profound impact on biliary lipid secretion. The bile salt export pump (BSEP or ABCB11) regulates the excretion of bile salts into bile and mutations cause severe cholestasis. The second ABC transporter, ABCB4 (MDR3) regulates the secretion in bile of phosphatidylcholine (PC), while ABCG5/G8 is active in the excretion of cholesterol and sterols into bile. These transporters also facilitate transport of sterols back into the intestinal lumen. Mutations in either of these genes cause sitosterolaemia with increased absorption of plant sterols and cholesterol. Until now, evidence for a genetic background of human gallstone disease is mostly indirect and based on ethnic differences. Only two single gene defects are associated with gallstones. One is an ABCB4 mutation which causes a deficiency in biliary PC secretion and the other is a CYP7A1 mutation, the rate-limiting enzyme in the synthesis of bile salts from cholesterol in the liver. Recently, several common DNA polymorphisms in the ABCG8 gene were discovered that are associated with variations in plasma sterols, which could also influence biliary cholesterol secretion, but there is still a paucity of human studies.

Bile↗

PubMed2004

Cholesterol saturation rather than phospholipid/bile salt ratio or protein content affects crystallization sequences in human gallbladder bile.

BACKGROUND: In model biles, cholesterol crystallization (an important factor in gallstone formation) mainly depends on phospholipid/bile salt ratios with characteristic sequences of plate-like (monohydrate) vs. non-plate-like (presumed anhydrous: arcs, needles, tubules, spirals) cholesterol crystals. We now investigate whether the same phenomenon occurs in human bile. METHODS: Appearances of plate-like and non-plate-like cholesterol crystals were determined in filtered bile of 80 cholesterol gallstone patients, and related to biliary lipid and pro-nucleating protein composition. RESULTS: Non-plate-like crystals appeared before plate-like crystals in 9 biles, on the same day in 24 biles, and after plate-like crystals in 31 biles. In 16 biles only plate-like crystals were observed. Crystal sequences did not depend on biliary lipid or protein composition. Cholesterol saturation indexes were higher in biles with than without non-plate-like crystals (150 +/- 6 vs. 125 +/- 12, P = 0.02). In contrast, phospholipid/(bile salt + phospholipid) ratios, bile salt species, phospholipid classes, concentrations of mucin, IgG, IgM, IgA, haptoglobin and alpha-1 acid glycoprotein did not differ. CONCLUSIONS: Cholesterol crystallization sequences in human bile depend on cholesterol saturation index rather than on phospholipid/bile salt ratio.

Bile↗

PubMed2003

Pathways of cholesterol crystallization in model bile and native bile.

Hypersecretion of hepatic cholesterol, chronic supersaturation of bile with cholesterol and rapid precipitation of cholesterol crystals in the gallbladder from cholesterol-enriched vesicles represent the primum movens in cholesterol gallstone formation. Physical-chemical factors and pathways leading to cholesterol crystallization can be investigated in artificial model biles and ex vivo in fresh human bile. Depending on modulatory factors (i.e., lipid concentration, bile salt or phospholipid species, humidity, mucins, etc.), cholesterol can precipitate in several forms (i.e., monohydrate, anhydrous) and habits (i.e., plate-like, needle-like, intermediate arcs, filaments, tubules, spirals). Careful analysis of biliary cholesterol crystals includes biochemical analysis of precipitated crystals, polarizing quantitative light microscopy, and turbidimetric methods. In this paper, recent concepts on cholesterol crystallization in artificial model biles as well as in human bile will be reviewed.

Bile↗

PubMed2003

Gallbladder motility and functional gastrointestinal disorders.

Functional gastrointestinal disorders can be defined as 'a variable combination of chronic or recurrent gastrointestinal symptoms not explained by structural or biochemical abnormalities'. Motor disorders are considered to be one of the pathogenetic mechanisms of these symptoms; in fact, it has been hypothesized that the smooth muscle of the whole gastrointestinal tract could be involved. Gallbladder motility has been evaluated in patients with dysmotility-like dyspepsia, irritable bowel syndrome and biliary disorders without gallstones; results of these observations are often inconclusive, conflicting and not always useful from a clinical point of view. The aim of this review is to explore the relationship between gallbladder motility and functional gastrointestinal disorders from pathogenetic and physiopathological points of view, and also to define the possible impact of these observations on clinical practice.

Acalculous Cholecystitis↗

PubMed2003

Measurements of gallbladder motor function by ultrasonography: towards standardization.

As real-time ultrasonography is a cheap, noninvasive, relatively easy, validated and reproducible technique, it can be repeated over time to document time-related changes of gallbladder motor function. Ultimately, functional ultrasonography estimates gallbladder shape and volume in fasting state and in response to a test meal (liquid or mixed solid-liquid, provided there is sufficient fat content) or exogenous stimulus (e.g., i.v. cholecystokinin or ceruletide). Although functional ultrasonography of the gallbladder has been mainly used for research purposes in specific referral centres, its simplicity makes such a technique appealing in the clinical setting to assess gallbladder motor function in both health and disease. Indications include the study of healthy subjects and of patients during pathophysiologically relevant conditions; in particular when subjects are at risk for gallbladder stasis and gallstone disease or during gallstone disease when a decision concerning medical dissolution therapy is required.

Cholecystolithiasis↗

PubMed2003

Sphingomyelin protects against apoptosis and hyperproliferation induced by deoxycholate: potential implications for colon cancer.

High fecal deoxycholate levels may promote colonic cancer. Phospholipids protect against bile salt-induced cytotoxicity. We therefore aimed to examine whether the dietary phospholipid sphingomyelin could decrease hyperproliferation induced by deoxycholate. In CaCo2 cells, hyperproliferation (by bromodeoxyuridine assay), phosphorylation state of cellular proteins, and apoptosis with concomitant caspase-3 activity were evaluated after incubation with 50-500 microM deoxycholate, with or without sphingomyelin. At 2 and 4 hr of incubation, deoxycholate induced dose-dependent apoptosis, with concomitant caspase-3 activation. At 16 hr, apoptosis had decreased markedly, but there was dose-dependent hyperproliferation (with changed phosphorylation status of cellular proteins) at this time point. Sphingomyelin dose-dependently reduced deoxycholate-induced apoptosis and hyperproliferation. In conclusion, sphingomyelin reduces deoxycholate-induced hyperproliferation and apoptosis. These findings may have implications for colonic cancer prevention by dietary modification.

Apoptosis↗

PubMed2003

Adaptation of subcellular glutathione detoxification system to stress conditions in choline-deficient diet induced rat fatty liver.

The response of fatty liver to stress conditions (t-butyl hydroperoxide [t-BH] or 36 h of fasting) was investigated by assessing intracellular glutathione (GSH) compartmentation and redox status, GSH peroxidase (GSH-Px) and reductase (GSSG-Rx) activities, lipid peroxidation (TBARs) and serum ALT levels in rats on a choline-deficient diet. Baseline cytosolic GSH was similar between fatty and normal livers, while the mitochondrial GSH content was significantly lower in fatty livers. With the except of cytosolic GSH-Px activity, steatosis was associated with significantly higher GSH-related enzymes activities. Liver TBARs and serum ALT levels were also higher. Administration of t-BH significantly decreased the concentration of cytosolic GSH, increased GSSG levels in all the compartments, and increased TBARs levels in cytosol and mitochondria and serum ALT; all these alterations were more marked in rats with fatty liver. Fasting decreased the concentration of GSH in all the compartments both in normal and fatty livers, increased GSSG, TBARs and ALT levels, and decreased by 50% the activities of GSH-related enzymes. Administration of diethylmaleimide (DEM) resulted in cytosolic and microsomal GSH pool depletion. Administration of t-BH to DEM-treated rats further affected cytosolic GSH and enhanced ALT levels, whereas the application of fasting to GSH depleted rats mainly altered the mitochondrial GSH system, especially in fatty livers. This study shows that fatty livers have a weak compensation of hepatic GSH regulation, which fails under stress conditions, thus increasing the fatty liver's susceptibility to oxidative damage. Differences emerge among subcellular compartments which point to differential adaptation of these organelles to fatty degeneration.

Alanine Transaminase↗

PubMed2003

Interleukins 1 beta and 6 induce functional alteration of rat colonic motility: an in vitro study.

BACKGROUND: In rodents, interleukins administration induces intestinal changes similar to those found in inflammatory bowel disease. We investigated the effects of in vivo subchronic treatment with IL-1 beta and IL-6 on rat colonic mucosa and circular smooth muscle. MATERIALS AND METHOD: We evaluated transmucosal electrical parameters (Ussing chambers) and early changes of in vitro direct contractility induced by carbachol and tachykinins. Alterations in excitatory and inhibitory neurotransmission were studied with electrical field stimulation (EFS). RESULTS: Treatment with interleukins induces inflammation proved by fever, early signs of colonic histological damage and changes in mucosal ion transport. Concentration response-curve to carbachol was significantly lower in treated rats (P<0.02) with significant difference in Emax between control (1.67+/-0.17 g) and treated preparations (1.20+/-0.13 g) (P<0.05). Concentration response-curve to NK2 agonist was significantly lower in the treated rats (P<0.005) with a significant difference in Emax between the control (0.26+/-0.04 g) and treated preparations (0.12+/-0.02 g) (P<0.02). None of the drugs used induces changes in EC50. The contractile reflex response to electrically induced distension was significantly higher in the treated rats and more reduced after administration of atropine. Adding NK2 receptor antagonist resulted in a further reduction being observed in the treated and control rats (P=NS). Relaxation by EFS on cholinergic tone was not different between treatments, although pretreatment with L-NNA resulted in greater relaxation in the treated (-21.7%) than in the control rats (-14.8%). CONCLUSION: Early inflammation induced by a subchronic treatment with ILs causes changes in mucosal ionic transport parameters, a reduction in the direct contractile response, and an alteration in the neurotransmission (by an enhancing cholinergic component) that may affect the physiological pattern of colonic motility and the sensory reflex.

Animals↗

PubMed2002

Chromomycin A3 inhibits influenza a virus multiplication in chick embryo fibroblast cells.

The multiplication of Ulster 73 virus, an avian strain of type A influenza virus, was blocked in chick embryo fibroblast cells, CEF, by treatment with 0.5 microg/ml of chromomycin A3 whereas in LLC-MK2 cells no inhibition of replication was observed. Virus-induced polypeptide synthesis in chick embryo fibroblast cells was confined to the synthesis of PB2, PB1 and PA subunits of the RNA dependent-RNA polymerase, the nucleoprotein NP, the non-structural protein NS1, the haemagglutinin HA, the non-structural protein NS2; only the membrane M1 polypeptide synthesis was greatly inhibited. Viral unpolyadenylated cRNAs synthesis was studied at a late time of the infection, 8 hours p.i.: chromomycin A3 was able to inhibit the "novo" synthesis of complementary RNA poly(A)- and segment 7 of virion RNA. The mode of action of the drug in chick embryo fibroblast cells is discussed.

Animals↗

PubMed2001

Mitochondrial oxidative damage and myocardial fibrosis in rats chronically intoxicated with moderate doses of ethanol.

Mitochondrial oxidative balance and myocardial fibrosis were investigated in pair-fed rats received ethanol (3%) or saccharose in drinking water for 8 weeks. The concentrations of glutathione, malondialdehyde, protein carbonyls and sulfhydrils were determined. The presence and distribution of fibronectin were detected by immunohistochemistry. The myocardial concentrations of reduced glutathione and protein sulfhydrils were lower in ethanol treated rats. The oxidised/reduced glutathione ratio, the levels of malondialdehyde and protein carbonyls were higher in ethanol-treated rats. The mitochondrial amount of proteins, glutathione and protein sulfhydrils were lower in ethanol treated rats, whereas the content of protein carbonyls and malondialdehyde were higher. Accumulation of fibronectin was detected at subepicardial and subendocardial districts in ethanol-treated rats, with moderate degree of fibrosis in 20% of the cases. In conclusion, moderate ethanol consumption is associated with oxidative damage to heart mitochondria and fibronectin deposition. These oxidative and ultrastuctural changes may be assumed as basic alterations in the development of alcoholic cardiomyopathy.

Administration, Oral↗

PubMed2001

Inhibition by prostaglandin PGA1 on the multiplication of influenza virus is a dose-dependent effect.

Cyclopentenone prostaglandins (PGs), are strong inhibitors of the multiplicative cycle of a wide variety of enveloped RNA and DNA viruses. Their antiviral activity is generally associated with alterations in the synthesis or maturation of specific virus proteins. In this report, we describe the effect of cyclopentenone PGA1 on the replication of influenza A virus Ulster 73 in LLC-MK2 cells. PGA1 was found to inhibit viral replication in a dose-dependent fashion and virus particle yield was reduced at a PGA1 concentration, which did not suppress protein synthesis in mock-infected cells. The kinetic of late viral protein synthesis was delayed in PGA1-treated cells till 10 h post-infection; after that period, viral polypeptide synthesis appeared to be similar in PGA1-treated as well as untreated cells both infected by Ulster 73 virus. This finding suggests that PGA1 might interfere with one or more events in the viral multiplicative cycle such as protein synthesis and assembly, correct insertion of virus polypeptides into the cell membrane and, or maturation of Ulster 73 virion particles. In particular, inhibition of viral replication in LLC-MK2 cells by PGA1 is accompanied by the induction of a cellular polypeptide of 70K molecular weight. We identified this cell protein as a heat shock protein (HSP) related to the inducible isoform of HSP 70, a polypeptide of 72K molecular weight. Induction of this polypeptide by PGA1 was found to be dose-dependent and a substantial accumulation could be seen at a PGA1 concentration that did not inhibit cell protein synthesis in uninfected cells. HSP 70 synthesis started after the beginning of PGA1 treatment and remained at the same level for at least 10 h, leading us to hypothesize that the delay of production of late Ulster 73 proteins could be the consequence of HSP 70 synthesis. These results suggest that HSP 70 could play a role in the antiviral activity of cyclopentenone PGA1 in LLC-MK2 cells.

Cells, Cultured↗

PubMed2001

Hydrophilic bile salts enhance differential distribution of sphingomyelin and phosphatidylcholine between micellar and vesicular phases: potential implications for their effects in vivo.

BACKGROUND/AIMS: The hepatocyte canalicular membrane outer leaflet contains both phosphatidylcholine (PC) and sphingomyelin (SM). Normally, PC is the exclusive phospholipid in bile. We examined effects of bile salt hydrophobicity on cytotoxicity and on differential SM and PC distribution between detergent-resistant aggregated vesicles (model for detergent-resistant canalicular membrane) and mixed micelles or small unilamellar vesicles (representing lipid phases in bile). METHODS: Aggregated vesicles were obtained by ultracentrifugation of cholesterol-supersaturated model systems containing SM, PC and various bile salts, micelles by ultrafiltration and unilamellar vesicles by dialysis of the supernatant. Erythrocyte hemolysis and lactate dehydrogenase release from CaCo-2 cells upon incubation with various micelles were quantified. RESULTS: Preferential SM distribution and lipid solubilization in aggregated vesicles increased in rank order taurodeoxycholate < taurocholate < tauroursodeoxycholate < taurohyodeoxycholate, with reciprocal PC enrichment in micelles and small unilamellar vesicles. Including small amounts of PC within taurohyodeoxycholate micelles increased cytotoxicity with more erythrocyte hemolysis and LDH release from CaCo-2 cells upon incubation, but decreased cytotoxicity in case of tauroursodeoxycholate micelles. CONCLUSIONS: Hydrophilic but not hydrophobic bile salts preserve integrity of pathophysiologically relevant phosphatidylcholine plus sphingomyelin-containing bilayers. Enhanced biliary phospholipid secretion during taurohyodeoxycholate but not during tauroursodeoxycholate therapy (Hepatology 25 (1997) 1306) may relate to different interactions of these bile salts with phospholipids.

Bile Acids and Salts↗

PubMed2001

Absence of apolipoprotein E4 genotype, good gallbladder motility and presence of solitary stones delay rather than prevent gallstone recurrence after extracorporeal shock wave lithotripsy.

BACKGROUND/AIMS: Extracorporeal shock wave lithotripsy (ESWL) with adjuvant bile salt dissolution therapy may be successful in selected gallstone patients, but the considerable risk of recurrence is a major drawback. Apolipoprotein E4 genotype and impaired gallbladder motility have been identified as major risk factors for recurrence during short-term follow up. We have now examined their relevance during long-term follow up. METHODS: Eighty-four cholesterol gallstone patients (55 solitary and 29 multiple (two to ten) stones) were followed prospectively up to 10 years after complete stone disappearance. Various potential risk factors for recurrence were evaluated. RESULTS: Gallstone recurrence was found in up to 80% of patients at 10 years follow-up. Absence of the apolipoprotein epsilon4 allele, initial solitary stones, good gallbladder emptying (i.e. minimal postprandial volume < or = 6 ml) and 2-year postdissolution ursodeoxycholic acid prophylaxis (in ten patients) all delayed but did not prevent recurrence. In contrast, regular use of non-steroidal anti-inflammatory drugs (NSAIDs) was identified as an independent protective factor, with greatly decreased recurrence (at 10 years: 58 vs 93% in non-NSAID users, P = 0.03). CONCLUSIONS: Non-apolipoprotein E4 genotype, presence of solitary stones and good gallbladder emptying delay rather than prevent recurrence after initially successful ESWL. Regular use of NSAIDs may prevent recurrence.

Adult↗