Biomedical subjects

Antonio Morelli

Publications and source records attributed to Antonio Morelli.

At least 55 records · Page 3Linked to original sources

PubMed2003

PAR-2 modulates pepsinogen secretion from gastric-isolated chief cells.

In the present study, we investigated whether activation of protease-activated receptor type 2 (PAR-2) with SLIGRL (SL)NH2, a short mimetic agonistic peptide, directly stimulates pepsinogen secretion from gastric-isolated, pepsinogen-secreting (chief) cells. Immunostaining of gastric-dispersed chief cells with a specific anti-PAR-2 antibody demonstrated expression of PAR-2 receptors on membrane and cytoplasm. SL-NH2 and trypsin potently stimulated pepsinogen secretion (EC50 = 0.3 nM) and caused Ca2+ mobilization (EC50 = 0.6 nM). In contrast to SL-NH2, the scramble peptide LSIGRL-NH2 failed to stimulate pepsinogen release. Exposure to SL-NH2 also resulted in ERK1/2 phosphorylation and activation. Exposure of chief cells to phosphotyrosine kinase inhibitors and 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one, a selective MEK inhibitor, significantly reduced secretion induced by SL-NH2. Pepsinogen secretion induced by SL-NH2 was desensitized by pretreating the cells with the mimetic peptide and trypsin, and exposure to SL-NH2 abrogates pepsinogen secretion induced by carbachol and CCK-8, but not secretion induced by secretin and vasointestinal peptide. Exposure to Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (substance P) but not to calcitonin gene-related peptide increased pepsinogen release. The neurokinin-1 receptor antagonist, N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester, inhibited substance P-stimulated pepsinogen secretion, whereas it did not affect secretion induced by SL-NH2. Collectively, these data indicate that PAR-2 is expressed on gastric chief cells and that its activation causes a Ca2+-ERK-dependent stimulation of pepsinogen secretion.

Animals↗

PubMed2003

Relative contribution of acetylated cyclo-oxygenase (COX)-2 and 5-lipooxygenase (LOX) in regulating gastric mucosal integrity and adaptation to aspirin.

In addition to inhibiting formation of prothrombotic eicosanoids, aspirin causes the acetylation of cyclooxygenase (COX)-2. The acetylated COX-2 remains active, and upon cell activation, initiates the generation of 15R-HETE, a lipid substrate for 5-lipoxygenase (LOX) leading to the formation of 15-epi-LXA4 (also termed "aspirin-triggered lipoxin," or ATL). Because ATL potently inhibits polymorphonuclear cell (PMN) function, we assessed the relative contribution of this lipid mediator in conjunction with another 5-LOX product, the leukotriene (LT)B4, to the pathogenesis of acute damage and gastric adaptation to aspirin. Data presented herein indicate that acute injury and gastric adaptation to aspirin is associated with ATL generation. Administration of COX inhibitors (celecoxib, indomethacin, ketoprofen) to aspirin-treated rats exacerbated acute injury and abolished adaptation to aspirin. Moreover, it inhibited ATL formation and caused a four- to fivefold increase in LTB4 synthesis. In contrast, licofelone, a COX/5-LOX inhibitor, did not exacerbate acute gastric injury nor did it interfere with gastric adaptation to aspirin. Although licofelone blocked ATL and LTB4 formation in aspirin-treated rats, it attenuated aspirin-induced gastric PMN margination. These findings indicate that the balance between the production of LTB4 and ATL modulates PMN recruitment/function and gastric mucosal responses to aspirin.

Acetates↗

PubMed2003

Colonic propulsive impairment in intractable slow-transit constipation.

HYPOTHESIS: Intractable constipation, especially of the slow-transit subtype, may represent several pathophysiologic entities with a common final symptomatic appearance. An overall impairment of colonic propulsive activity may represent a major disease mechanism. DESIGN: Case series. SETTING: Tertiary university hospital. SUBJECTS: Twenty-nine severely constipated patients with clinical and homogeneous features of slow-transit constipation that were unresponsive to conventional medical measures and 16 age-matched healthy volunteers. INTERVENTIONS: Twenty-four-hour manometric recordings obtained in patients and controls to assess high- and low-amplitude colonic propulsive activity. RESULTS: Compared with controls, patients showed heavily reduced high-amplitude propagated activity (average, <1 event per subject per day). No differences were found in low-amplitude propagated activity. CONCLUSIONS: Patients with severe constipation that is refractory to medical treatment may display an important reduction of colonic forceful propulsive activity. This may justify a surgical approach, which may offer the best results in such patients. It is, however, important to obtain thorough physiologic documentation before such a drastic approach is considered. The residual low-amplitude propulsive activity might represent a partially compensatory mechanism in these patients. Studies in more homogeneous groups of such patients are needed.

Adult↗

PubMed2003

Galectin-1 suppresses experimental colitis in mice.

BACKGROUND & AIMS: Uncontrolled T-cell activation plays a critical role in the pathogenesis of inflammatory bowel diseases. Therefore, pharmacologic strategies directed to restore the normal responsiveness of the immune system by deleting inappropriately activated T cells could be efficacious in the treatment of these pathologic conditions. Galectin-1 is an endogenous lectin expressed in lymphoid organs that plays a role in the maintenance of central and peripheral tolerance. The aim of the present study was to evaluate the therapeutic effects of galectin-1 on T-helper cell type 1-mediated experimental colitis induced by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. METHODS: Cells and tissues from mice with TNBS colitis receiving treatment with several doses of human recombinant galectin-1 (hrGAL-1) were analyzed for morphology, cytokine production, and apoptosis. RESULTS: Prophylactic and therapeutic administration of rhGAL-1 resulted in a striking improvement in the clinical and histopathologic aspects of the disease. hrGAL-1 reduced the number of hapten-activated spleen T cells, decreased inflammatory cytokine production, and profoundly reduced the ability of lamina propria T cells to produce IFN gamma in vitro. Moreover, hrGAL-1 led to the appearance of apoptotic mononuclear cells in colon tissue when administered in vivo and induced selective apoptosis of TNBS-activated lamina propria T cells in vitro. CONCLUSION: Collectively, these data show that hrGAL-1 exerts protective and immunomodulatory activity in TNBS-induced colitis and it might be effective in the treatment of inflammatory bowel diseases.

Animals↗

PubMed2003

NCX-1000, a nitric oxide-releasing derivative of ursodeoxycholic acid, ameliorates portal hypertension and lowers norepinephrine-induced intrahepatic resistance in the isolated and perfused rat liver.

BACKGROUND/AIMS: We studied whether acute administration of NCX-1000, a nitric oxide (NO)-releasing derivative of ursodeoxycholic acid (UDCA), to animals with established liver cirrhosis decreases intrahepatic resistance and modulates hepatic vascular hypereactivity to norepinephrine (NE). METHODS: Four-week bile duct ligated (BDL) cirrhotic and control, sham-operated, rats were treated orally with 28 mg/kg per day NCX-1000 or 15 mg/kg per day UDCA for 5 days. Isolated normal and cirrhotic livers were perfused with NE, from 10 nM to 30 microM, in a recirculating system. RESULTS: NCX-1000 administration to BDL cirrhotic rats decreased portal pressure (P<0.01) without affecting mean arterial pressure and heart rate. In the isolated perfused liver system, administration of NE resulted in a dose-dependent increase of intrahepatic resistance. Vasoconstriction caused by 30 microM NE was reduced by 60% in animals treated with NCX-1000 (P<0.001), while UDCA was uneffective. The same portal pressure lowering effect was documented in cirrhotic and sham operated rats. Administration of NCX-1000 to BDL and sham operated rats resulted in a similar increase of nitrite/nitrate and cGMP concentrations in the liver. CONCLUSIONS: By selectively delivering NO to the liver, NCX-1000 increases cGMP concentrations and effectively counteracts the effect of endogenous vasoconstrictors on the hepatic vascular tone.

Animals↗

PubMed2003

Evidence that 5-lipoxygenase and acetylated cyclooxygenase 2-derived eicosanoids regulate leukocyte-endothelial adherence in response to aspirin.

(1) Unlike other nonsteroidal anti-inflammatory drugs that inhibit formation of cyclooxygenase (COX)-dependent eicosanoids, acetylation of COX-2 by aspirin switches eicosanoid biosynthesis from prostaglandin E(2) (PGE(2)) to 15-epi-lipoxin A(4) (15-epi-LXA(4) or aspirin-triggered lipoxin, ATL). ATL formation by activated leukocytes (PMN) requires the intervention of 5-lipoxygenase (5-LOX), an enzyme that is involved in leukotriene B(4) (LTB(4)) formation. (2) In the present study, we have examined the role of acetylated COX-2 and 5-LOX in modulating antiadhesive effects of aspirin on adhesion of PMN to endotoxin (LPS)-primed human umbilical endothelial cells (HUVEC). (3) Treating PMN/HUVEC cocultures with aspirin resulted in a concentration-dependent inhibition of cell-to-cell adhesion induced by LPS. Treating HUVEC with selective COX-2 inhibitors, celecoxib and rofecoxib, caused an approximately 70% reversion of antiadhesive effect of aspirin. In contrast, inhibition of neutrophil's 5-LOX pathway with 1 micro M ZD2138, a selective 5-LOX inhibitor, 1 micro M BAY-X-1005, a FLAP inhibitor, or 100 micro M licofelone, a dual COX/5-LOX inhibitor, did not affect antiadhesive properties of aspirin. (4) Exposure to celecoxib (100 micro M) or rofecoxib (10 micro M) completely suppressed ATL formation caused by aspirin without affecting LTB(4) levels. ZD2138, licofelone and BAY-X-1005 inhibited ATL formation as well as LTB(4) generation. (5) Treatment with LXA(4) reduced PMN adhesion to HUVEC and counteracted the proadhesive effect of celecoxib. In contrast, exposure to Boc-1, an LXA(4) antagonist, counteracts the antiadhesive activities of aspirin. Exposure to U75302, an LTB(4) receptor antagonist, enhances the antiadesive effect of aspirin. (6) Reversal of antiadhesive activities of aspirin by celecoxib was associated with increased expression of LFA-1 on PMN and E-selectin on HUVEC. Addition of LXA(4), ZD2138 and U75302 inhibited these changes. (7) The present results support the notion that inhibition of ATL formation is mechanistically linked to the reversal of the antiadhesive activity of aspirin caused by selective COX-1 inhibitors and suggests that the LTB(4)/ATL balance modulates pro- and antiadhesive activity of nonsteroidal anti-inflammatory drugs at the leukocyte-endothelial cell interface.

Acetates↗

PubMed2003

Gastrointestinal safety of NO-aspirin (NCX-4016) in healthy human volunteers: a proof of concept endoscopic study.

BACKGROUND AND AIMS: NCX-4016 is a nitric oxide-releasing derivative of aspirin with antiplatelet activity. The aim of this study was to investigate the effect of NCX-4016 on gastrointestinal mucosa and platelet functions in healthy human volunteers. METHODS: This was a parallel-group, double-blind, placebo-controlled study. Forty healthy subjects were randomly allocated to receive 7 days of treatment with NCX-4016 (400 and 800 mg twice daily), equimolar doses of aspirin (200 and 420 mg twice daily), or placebo. Upper endoscopies were performed before and at the end of the treatment period, and gastroduodenal lesions were graded using a predefined scoring system. Basal and posttreatment platelet aggregation in response to arachidonic acid (AA) and serum thromboxane (TX) B(2) and AA-stimulated platelet TXB(2) production were investigated. RESULTS: Mucosal endoscopic injury score on day 7 was 0.63 +/- 0.16 in the placebo group and 11.0 +/- 3.0 and 16.1 +/- 1.6 in healthy volunteers treated with 200 and 420 mg aspirin twice daily (P < 0.0001 vs. placebo). NCX-4016 was virtually devoid of gastric and duodenal toxicity, resulting in a total gastric and duodenal endoscopic score of 1.38 +/- 0.3 and 1.25 +/- 0.5 (P < 0.0001 vs. aspirin, not significant vs. placebo). NCX-4016 inhibited AA-induced platelet aggregation as well as serum TXB(2) and platelet TXB(2) generation induced by AA to the same extent as aspirin (not significant vs. aspirin). CONCLUSIONS: In this study, we have proven the concept that addition of an NO-donating moiety to aspirin results in a new chemical entity that maintains cyclooxygenase-1 and platelet inhibitory activity while nearly avoiding gastrointestinal damage.

Adult↗

PubMed2003

Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis.

Hyperfibrinolysis is thought to contribute to bleeding associated with advanced cirrhosis. Thrombin activatable fibrinolysis inhibitor (TAFI) is a plasma precursor of a carboxypeptidase (TAFIa) with antifibrinolytic activity and was recently shown to be reduced in cirrhosis. In this study, we evaluated the influence of TAFI deficiency on in vitro fibrinolysis in cirrhotic patients. Fifty-three patients with cirrhosis and 43 healthy controls were studied. TAFI antigen was measured by enzyme-linked immunosorbent assay and TAFI activity by chromogenic assay. Fibrinolysis was evaluated as tissue plasminogen activator-induced plasma clot lysis time in the absence and in the presence of a specific inhibitor of TAFIa. TAFI antigen and activity levels were markedly reduced in cirrhotic patients (P <.0001). In these patients, the lysis time of plasma clots was shorter than in controls (median, interquartile range: 25 minutes, 21-36 minutes vs. 48 minutes, 40-60 minutes, respectively; P <.0001) and was poorly influenced by the TAFIa inhibitor. Accordingly, TAFIa and thrombin activity, generated in cirrhotic samples during clot lysis, were significantly lower than in control samples. Addition of purified TAFI to cirrhotic plasma prolonged the lysis time and enhanced the response to TAFIa inhibitor in a dose-dependent manner. In conclusion, our results indicate that in vitro plasma hyperfibrinolysis in cirrhosis is largely due to a defective TAFIa generation resulting from low TAFI levels and probably from impaired thrombin generation. Impairment of the antifibrinolytic TAFI pathway might contribute to bleeding associated with this disease.

Adult↗

PubMed2003

Pathophysiological aspects of diverticular disease of colon and role of large bowel motility.

Colonic diverticular disease (diverticulosis) is one of the most common gastrointestinal disorders in Western countries. This disorder is strictly related to aging and fibre intake, and still bears a discrete amount of morbidity. Numerous etiological co-factors have to date been implicated in the pathogenesis of the disease, yet the supporting evidence is still far from absolute. The present review considers the pathophysiology of colonic diverticular disease, with a special emphasis on factors related to abnormal colonic motility.

Colon↗

PubMed2002

NCX-4016 (NO-aspirin) inhibits lipopolysaccharide-induced tissue factor expression in vivo: role of nitric oxide.

BACKGROUND: NCX-4016 is an acetylsalicylic acid (ASA) derivative containing a nitric oxide-releasing moiety. Compared with ASA, NCX-4016 has a broader spectrum of antithrombotic and antiinflammatory activities. We hypothesized that NCX-4016 might inhibit in vivo lipopolysaccharide (LPS)-induced expression of tissue factor (TF). METHODS AND RESULTS: Rats were administered 90 mg/kg NCX-4016 orally for 5 days. Placebo, 50 mg/kg ASA, and 80 mg/kg isosorbide-5-mononitrate (ISMN) were used in control groups. On day 5, rats were injected intraperitoneally with 100 microg/kg LPS and killed 6 hours later. The expression of TF in monocytes was measured by flow cytometry and Western blot analysis. Reverse transcriptase-polymerase chain reaction was performed to assess expression of TF and cyclooxygenase-2 (COX-2) genes. Plasma concentrations of interleukin-1beta and tumor necrosis factor-alpha were measured. Urine samples were collected to evaluate the excretion of the thromboxane metabolite 11-dehydro-thromboxane (TX)B2. Gastric mucosa was inspected. LPS injection was followed by synthesis TF and COX-2 mRNAs in circulating monocytes, which were blunted by NCX-4016 but not by ASA or ISMN. Both NCX-4016 and ISMN reduced TF expression on surface of circulating monocyte. LPS increased the excretion 11-dehydro-TXB2, and this was prevented by NCX-4016 and ASA. Unlike ASA, NCX-4016 reduced plasma interleukin-1beta and tumor necrosis factor-alpha. In addition, NCX-4016 almost completely prevented mucosal damage, whereas ASA increased the extension of gastric lesions in LPS-injected rats. CONCLUSIONS: NCX-4016 prevents monocyte TF expression; this is accompanied by inhibition of TX and cytokine biosynthesis. These additive effects of nitric oxide release and COX inhibition may help explain efficacy and tolerability of NCX-4016.

Administration, Oral↗

PubMed2002

NCX-1015, a nitric-oxide derivative of prednisolone, enhances regulatory T cells in the lamina propria and protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice.

NCX-1015 is a nitric oxide (NO)-releasing derivative of prednisolone. In this study we show NCX-1015 protects mice against the S. A. development and induces healing of T helper cell type 1-mediated experimental colitis induced by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). The beneficial effect of NCX-1015 was reflected in increased survival rates, improvement of macroscopic and histologic scores, a decrease in the mucosal content of T helper cell type 1 cytokines (protein and mRNA), and diminished myeloperoxidase activity in the colon. In contrast to its NO derivative, only very high doses of prednisolone were effective in reproducing these beneficial effects. NCX-1015 was 10- to 20-fold more potent than the parent compound in inhibiting IFN-gamma secretion by lamina propria mononuclear cells. Protection against developing colitis correlated with inhibition of nuclear translocation of p65Rel A in these cells. In vivo treatment with NCX-1015 potently stimulated IL-10 production, suggesting that the NO steroid induces a regulatory subset of T cells that negatively modulates intestinal inflammation.

Active Transport, Cell Nucleus↗

PubMed2002

6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity.

A series of 6alpha-alkyl-substituted analogues of chenodeoxycholic acid (CDCA) were synthesized and evaluated as potential farnesoid X receptor (FXR) ligands. Among them, 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA) was shown to be a very potent and selective FXR agonist (EC(50) = 99 nM) and to be endowed with anticholeretic activity in an in vivo rat model of cholestasis.

Animals↗

PubMed2002

NCX-4016, a nitric oxide-releasing aspirin, protects endothelial cells against apoptosis by modulating mitochondrial function.

We investigated the effect of a nitric oxide (NO)-releasing derivative of aspirin (NCX-4016) on a mitochondria-dependent model of apoptosis in human umbilical endothelial cells (HUVEC). Exposure of HUVEC to staurosporine caused a progressive fall in mitochondrial membrane potential (DeltaPsi(m)) and apoptosis. Exposure to an NO donor, (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO), caused an early (1-3h) hyperpolarization of DeltaPsi(m) and reduction of apoptosis that was followed (at 4-8 h) by an accelerated collapse of DeltaPsi(m) and cell death. In contrast, treatment with NCX-4016, but not with aspirin or a non-NO-releasing analogue of NCX-4016, protected HUVEC against the apoptotic actions of staurosporine for up to 8 h. Confocal microscopy demonstrated that although NCX-4016 released NO in subcellular compartments, DETA-NO caused a generalized increase in cytosolic fluorescence. Exposure to DETA-NO resulted in a rapid and profound inhibition of cell respiration (78.3 +/- 6.4%), whereas NCX-4016 caused a less pronounced reduction in oxygen consumption (43.5 +/- 5.3%). Staurosporine caused a time-dependent activation of proapoptotic caspases. NCX-4016 prevented this activation, whereas DETA-NO failed to inhibit caspase activity. In contrast to DETA-NO, NCX-4016 did not increase mitochondrial oxidative stress. These data demonstrated that NCX-4016 conveys NO directly inside endothelial cells and modulates mitochondrial function.

Apoptosis↗

PubMed2002

Importance of innate immunity and collagen binding integrin alpha1beta1 in TNBS-induced colitis.

Inflammation occurs in the context of integrin-mediated adhesive interactions of cells with their extracellular matrix environment. We investigated the role of the collagen binding integrin alpha1beta1 in a model of colitis. alpha1beta1 was expressed on lamina propria T cells and monocytes during disease. Both alpha1 deficiency and anti-alpha1 mAb treatment (prophylactic and therapeutic) protected against colitis. In vivo alpha1beta1 blockade improved macroscopic and histologic scores, decreased inflammatory cytokine production, and profoundly affected the ability of lamina propria mononuclear cells to proliferate and produce IFN-gamma in vitro. Development and alpha1-mediated inhibition of colitis can be lymphocyte independent, suggesting that activated monocytes also represent a key alpha1beta1-expressing cell type involved in colitis. These results underscore the importance of innate immunity and, specifically, of leukocyte/matrix interactions in regulating local inflammatory responses.

Animals↗

PubMed2002

A NO-releasing derivative of acetaminophen spares the liver by acting at several checkpoints in the Fas pathway.

NCX-701 is a nitric oxide (NO)-releasing acetaminophen (APAP) derivative. In the present study we demonstrated that NCX-701 is as effective as APAP in controlling body temperature in a rat model of endotoxin-induced fever. Liver toxicity is a major complication of APAP overdosing. To investigate whether NCX-701 is hepatotoxic, BALB/C mice were injected with 100 - 500 mg kg(-1) APAP or NCX-701 alone or in combination (i.e. 500 mg kg(-1) of both compounds). Our results demonstrated that although APAP caused a dose-dependent liver injury, NCX-701 was completely devoid of liver toxicity. At the dose of 500 mg kg(-1) APAP caused an approximately 40 fold increase of AST plasma levels and extensive centrilobular necrosis. APAP and NCX-701 share the same metabolic pathway as demonstrated by the time-course of APAP-glucuronide concentrations in plasma and liver. NCX-701 was safe in mice with pre-existing chronic liver disease. Indeed, while C57BL6 transgenic mice expressing the hepatitis B virus (HBV) at the age of 8 months were significantly more susceptible to liver damage induced by APAP (500 mg kg(-1)) than their congenic littermates, treating HBV-transgenic mice with NCX-701, 500 mg kg(-1), caused no damage. Co-administration of NCX-701 at the dose 500 mg kg(-1) to mice treated with APAP, 500 mg kg(-1), completely protected against liver damage induced by APAP. APAP, but not NCX-701, upregulated liver Fas and Fas Ligand mRNA expression in vivo. Incubating mouse hepatocytes with APAP, but not with NCX-701, increased cell surface Fas expression and sensitized hepatocytes to death induced by challenge with a Fas-agonistic antibody. Collectively, these observations suggest that APAP toxicity is Fas mediated and that NCX-701 spares the liver by acting at several checkpoints in the Fas pathway.

Acetaminophen↗

PubMed2002

Cyclooxygenase-2-derived lipoxin A4 increases gastric resistance to aspirin-induced damage.

BACKGROUND & AIMS: Cyclooxygenase-2 (COX-2) has been implicated as contributing to mucosal defense. Acetylation of COX-2 by aspirin can result in production of an antiinflammatory substance, 15(R)-epi-LXA4. We determined whether aspirin-triggered lipoxin (LX) production via COX-2 diminishes aspirin-induced damage in the rat stomach. METHODS: Rats were treated with aspirin plus or minus celecoxib or rofecoxib. Gastric generation of LXA4 was measured. Effect of exogenous LXA4 or an LXA4 receptor antagonist on gastric resistance to aspirin-induced damage was examined. Aspirin-induced leukocyte adherence in mesenteric venules, and the effects of LXA4, were examined by intravital microscopy. RESULTS: Celecoxib and rofecoxib significantly increased the severity of aspirin-induced gastric damage. Aspirin rapidly up-regulated COX-2 expression in the stomach and caused a significant increase in gastric 15(R)-epi-LXA4 production, which was abolished by celecoxib. LXA4 dose dependently (0.25-2.5 microg/kg, intraperitoneally) reduced the severity of aspirin-induced gastric damage and suppressed aspirin-induced leukocyte adherence, whereas an LXA4 antagonist had the opposite effects. CONCLUSIONS: Aspirin administration results in elevated production of 15(R)-epi-LXA4 via COX-2. LXA4 exerts very potent protective actions on the gastric mucosa. Co-administration of aspirin and a selective COX-2 inhibitor results in substantially more severe gastric injury than is produced with either agent alone.

Animals↗

PubMed2002

Inhibition of intestinal bacterial translocation with rifaximin modulates lamina propria monocytic cells reactivity and protects against inflammation in a rodent model of colitis.

BACKGROUND: A modification of the intestinal flora and an increased bacterial translocation is a common finding in patients with inflammatory bowel disease as well as in animal model of colitis. Rifaximin, a non-absorbable derivative of rifamycin, is an effective antibiotic that acts by inhibiting bacterial ribonucleic acid synthesis. AIMS: In the present study, we investigated the effect of the administration of rifaximin (10, 30 and 50 mg/kg/day) or prednisolone (10 mg/kg/day) in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. METHODS: Colitis was induced in mice by intrarectal administration of TNBS (1.5 mg/mouse in 50% ethanol) and disease severity assessed clinically and by histologic scoring of colon damage, determination of interleukin (IL)-2, IL-12, interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha (protein and mRNA and myeloperoxidase (MPO) activity in the colon. Cytokines production by the lamina propria mononuclear cells (LPMC) and luminal bacteria were also measured. RESULTS: Rifaximin administration (30 or 50 mg/kg/day) increased survival rates of colitic mice and reduced colitis severity as demonstrated by improvement of wasting syndrome, histologic scores, decrease in colon IL-2, IL-12, IFN-gamma and TNF-alpha (protein and mRNA) levels, and diminished colon MPO activity. Rifaximin administration caused a significant reduction of colon bacterial translocation towards mesenteric lymph nodes. LPMC obtained from rifaximin-treated mice released significantly lower amount of IFN-gamma in response to ex vivo stimulation with agonistic anti-CD3 and anti-CD28 antibodies. Rifaximin (50 mg/kg/day) significantly accelerates recovery in mice with established colitis. CONCLUSIONS: Luminal bacterial microflora plays a role in the pathogenesis of TNBS-induced colitis in mice. Rifaximin administration reduces the development of colitis and accelerates healing of established disease by preventing bacterial translocation.

Acute Disease↗

PubMedDate not supplied

PCNA positivity in the mesencephalic matrix areas in the adult of a Teleost, Carassius carassius L.

Adult Teleosts still display karyokinetic activity involving also the central nervous system so that physiological neurogenesis does not cease when adult body size is reached but later. In the brain this is due to the persistence in several districts of neural type elements in the ependymal epithelium or in the area surrounding it, which combine to form matrix zones or matrix areas. These elements may undergo proliferative and/or maturational events, including also post-traumatic neurogenic events, either natural or experimentally induced, as a result of which the degree of brain plasticity is inferior only to that observed in the Amphibians. As part of our project of re-examining the matrix areas of normal adult heterothermic Vertebrates based on the use of a recent proliferative marker displaying the expression of the Proliferating Cellular Nuclear Antigen (PCNA). This is a reliable immunocytochemical test owing to its role in the cell cycle and to the ubiquity of PCNA due to the theoretical basis of the method, has now been applied to the mesencephalon of the Teleosts, which is the location of matrix areas that are absent in the Amphibians and Reptiles. The immunocytochemical patterns we observed in Carassius carassius displayed a much strong DNA synthesis activity than that we found in the telencephalon of the same specimens. These spontaneous neurogenic manifestations are not limited to the optic tectum, and are not restricted to the already well-known caudal, ventral and dorsal matrix zones. This evidence is discussed and compared with literature data describing the results of classical histologic, autoradiographic or immunocytochemical techniques under light and electron microscopy in various species of normal adult Teleosts or in specimens that had undergone reparative or regenerative processes after experimental intervention.

Animals↗