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Biomedical subjects

A Morelli

Publications and source records attributed to A Morelli.

At least 55 records · Page 3Linked to original sources
PubMed2001

Adenylate kinase activity in rod outer segments of bovine retina.

The rod outer segments of bovine retina contain two different adenylate kinases: a soluble activity, which is not sensitive to calcium ion, and an activity bound to disk membranes, which is dependent on the calcium levels. In fact, the maximal activity associated to the disks is reached at Ca(2+) concentrations between 10(-6) and 10(-7) M, which is the range of calcium level actually present in the rod cell. The Michaelis-Menten kinetics of the enzyme activity on disk membranes was determined and the actual concentrations of ATP, AMP and ADP were measured in the photoreceptor outer segment. Therefore, the physiological relevance of the adenylate kinase activity was discussed considering the above results. The formation of ATP catalyzed by the enzyme seems appropriate to supply at least some of the reactions necessary for phototransduction, indicating that ATP could be regenerated from ADP directly on the disk membranes where the photoreception events take place.

Adenosine Diphosphate↗
PubMed2001

An NO derivative of ursodeoxycholic acid protects against Fas-mediated liver injury by inhibiting caspase activity.

Caspases are key mediators in liver inflammation and apoptosis. In the present study we provide evidence that a nitric oxide (NO) derivative of ursodeoxycholic acid (UDCA), NCX-1000 ([2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester]), protects against liver damage in murine models of autoimmune hepatitis induced by i.v. injection of Con A or a Fas agonistic antibody, Jo2. Con A administration causes CD4(+) T lymphocytes to accumulate in the liver and up-regulates FasL expression, resulting in FasL-mediated cytotoxicity. Cotreating mice with NCX-1000, but not with UDCA, protected against liver damage induced by Con A and Jo2, inhibited IL-1beta, IL-18, and IFN-gamma release and caspase 3, 8, and 9 activation. Studies on HepG2 cells demonstrated that NCX-1000, but not UDCA, directly prevented multiple caspase activation induced by Jo2. Incubating HepG2 cells with NCX-1000 resulted in intracellular NO formation and a DTT-reversible inhibition of proapoptotic caspases, suggesting that cysteine S-nitrosylation was the main mechanism responsible for caspase inhibition. Collectively, these data suggest that NCX-1000 protects against T helper 1-mediated liver injury by inhibiting both the proapoptotic and the proinflammatory branches of the caspase superfamily.

Animals↗
PubMed2001

Nucleotide receptors: an emerging family of regulatory molecules in blood cells.

Nucleotides are emerging as an ubiquitous family of extracellular signaling molecules. It has been known for many years that adenosine diphosphate is a potent platelet aggregating factor, but it is now clear that virtually every circulating cell is responsive to nucleotides. Effects as different as proliferation or differentiation, chemotaxis, release of cytokines or lysosomal constituents, and generation of reactive oxygen or nitrogen species are elicited upon stimulation of blood cells with extracellular adenosine triphosphate (ATP). These effects are mediated through a specific class of plasma membrane receptors called purinergic P2 receptors that, according to the molecular structure, are further subdivided into 2 subfamilies: P2Y and P2X. ATP and possibly other nucleotides are released from damaged cells or secreted via nonlytic mechanisms. Thus, during inflammation or vascular damage, nucleotides may provide an important mechanism involved in the activation of leukocytes and platelets. However, the cell physiology of these receptors is still at its dawn, and the precise function of the multiple P2X and P2Y receptor subtypes remains to be understood.

Animals↗
PubMed2001

Microencapsulation of human parathyroid cells: an "in vitro" study.

BACKGROUND: Patients affected by hypoparathyroidism of variable etiology are currently treated with exogenously administered vitamin D and calcium. Human parathyroid transplantation has long been investigated as a possible mean of treating these patients to prevent long-term hypocalcemia. However, the main obstacle for this treatment is represented by tissue rejection. A reliable method to efficiently protect the transplanted tissue from rejection and to allow long-term survival of the graft is the encapsulation of tissues or cells in alginate-polylysine-alginate membranes, which were successfully used for encapsulation of islets of Langerhans. The microencapsulation of parathyroid tissue fragments or of parathyroid cells becomes, therefore, a potential approach for the successful treatment of permanent symptomatic hypoparathyroidism without pharmacological immunosuppression. MATERIALS AND METHODS: We describe microencapsulation of differentiated human parathyroid cells derived from adenoma or hyperplastic glands. Long-term viability, cell growth, and parathyroid hormone production of microencapsulated cells were evaluated together with responsiveness to extracellular Ca(2+). RESULTS: Microencapsulated parathyroid cells maintained proliferative and differentiative properties for a long term in culture with a good response to extracellular Ca(2+) concentration. CONCLUSIONS: These findings represent a crucial step toward the construction of functional bioartificial parathyroid organoids for the treatment of hypoparathyroidism in humans.

Adenoma↗
PubMed2001

Early and midterm results of model 300 CryoLife O'Brien stentless porcine aortic bioprosthesis.

BACKGROUND: The Cryolife O'Brien (CLOB) is a composite stentless bioprosthesis constructed from noncoronary leaflets of three porcine aortic valves. This study aimed to investigate early and midterm results after aortic valve replacement with CLOB xenograft. METHODS: Between 1993 and 2000, the CLOB was implanted in 125 patients (62 men; mean age 71.3+/-6.4 years). Mean prosthesis size was 23.6+/-2 mm. Mean follow-up time was 37.0+/-12.1 months. Patients underwent echocardiographic studies preoperatively, at discharge, at 6 and 12 months postoperatively, and yearly thereafter. RESULTS: Early (30-day) mortality rate was 2.4% (3 of 125 patients). Of the four late deaths, none was valve related. Actuarial 7-year survival was 93.6%+/-3%. Seven-year freedom from primary valve failure was 98.1%+/-1.8%. All patients showed an improvement of functional status (p < 0.001). ANOVA revealed a significant reduction over time in peak and mean systolic gradients (p < 0.001). Effective orifice area index increased (p < 0.001) and left ventricular mass index significantly reduced in all valve sizes (p < 0.001) during this time interval. CONCLUSIONS: Because the early and midterm results with CLOB xenograft have been satisfactory, we encourage its use as a valve substitute, particularly in patients with small aortic roots.

Aged↗
PubMed2001

Mechanism of non-steroidal anti-inflammatory drug-gastropathy.

Non-steroidal anti-inflammatory drugs are recognized to cause gastrointestinal damage impairing the defense ability of gastric mucosal barrier. A variety of mechanisms due to non-steroidal anti-inflammatory drugs direct irritant (topical) action and to their main pharmacological (systemic) effect, is involved in the pathogenesis of non-steroidal anti-inflammatory drugs induced gastropathy. The systemic activity comprises the inhibition of cyclo-oxygenase, but an increasing body of evidence suggests that cyclo-oxygenase-independent mechanisms are involved in the development of gastric injury. In line with this concept, neither cyclo-oxygenase-1 nor cyclo-oxygenase-2 deficient mice develop spontaneous gastrointestinal ulcers and pharmacological inhibition of cyclo-oxygenase-1 or cyclo-oxygenase-2 with selective inhibitors doesn't elicit gastrointestinal damage; suggesting that both isoforms of cyclo-oxygenase enzymes have to be inhibited to induce ulcers. Moreover non-steroidal anti-inflammatory drugs administration in rats, induces the systemic release of tumor necrosis factor-alpha and drives gastric epithelial cells to apoptosis activating the pro-apoptotic cascade of caspases. In response to non-steroidal anti-inflammatory drugs, neutrophils are recruited into the gastric microcirculation through a process that requires activation of adhesion molecules. Although there is virtually no information regarding the regulation of expression of gastric endothelial cell adhesion molecules in response to non steroidal anti-inflammatory drugs, the nuclear factor-kB may represent a potential modulator. Supporting this view, selective proteasome inhibitors inhibit nuclear translocation of nuclear factor-kB induced by tumor necrosis factor-alpha in human endothelial cells in vitro and reduce indomethacin-induced gastric mucosal injury in vivo.

Animals↗
PubMed2001

Pharmacological and biochemical characterization of A3 adenosine receptors in Jurkat T cells.

1. The present work was devoted to the study of A3 adenosine receptors in Jurkat cells, a human leukemia line. 2. The A3 subtype was found by means of RT-PCR experiments and characterized by using the new A3 adenosine receptor antagonist [3H]-MRE 3008F20, the only A3 selective radioligand currently available. Saturation experiments revealed a single high affinity binding site with K(D) of 1.9+/-0.2 nM and B(max) of 1.3+/-0.1 pmol mg(-1) of protein. 3. The pharmacological profile of [3H]-MRE 3008F20 binding on Jurkat cells was established using typical adenosine ligands which displayed a rank order of potency typical of the A3 subtype. 4. Thermodynamic data indicated that [3H]-MRE 3008F20 binding to A3 subtype in Jurkat cells was entropy- and enthalpy-driven, according with that found in cells expressing the recombinant human A3 subtype. 5. In functional assays the high affinity A3 agonists Cl-IB-MECA and IB-MECA were able to inhibit cyclic AMP accumulation and stimulate Ca(2+) release from intracellular Ca(2+) pools followed by Ca(2+) influx. 6. The presence of the other adenosine subtypes was investigated in Jurkat cells. A1 receptors were characterized using [3H]-DPCPX binding with a K(D) of 0.9+/-0.1 nM and B(max) of 42+/-3 fmol mg(-1) of protein. A2A receptors were studied with [3H]-SCH 58261 binding and revealed a K(D) of 2.5+/-0.3 nM and a B(max) of 1.4+/-0.2 pmol mg(-1) of protein. 7. In conclusion, by means of the first antagonist radioligand [3H]-MRE 3008F20 we could demonstrate the existence of functional A3 receptors on Jurkat cells.

Animals↗
PubMed2001

Time course of left ventricular remodeling after stentless aortic valve replacement.

BACKGROUND: Stentless aortic valves are associated with a significant decrease in left ventricular hypertrophy. This study examined the time course and factors affecting left ventricular mass regression (LVMR) after aortic valve replacement (AVR) with Cryolife O'Brien (CLOB) (Cryolife International, Atlanta, Ga) stentless valves. METHODS: Between 1993 and 2000, 130 consecutive patients underwent AVR with CLOB. Mean age was 71.3 +/- 6.3 years. Sixty-four (49.2%) were male. Mean body surface area (BSA) was 1.7 +/- 0.2 m(2). Mean valve size implanted was 23.6 +/- 2.0 mm. All patients were monitored with serial echocardiograms; the first study was performed preoperatively, and subsequent controls were at 6 months, 1, 2, 3, 4, 5, 6, and 7 years, respectively. Left ventricular mass was calculated by the Devereux formula and indexed by BSA. RESULTS: Analysis of variance showed a significant reduction in the left ventricular mass index (LVMI) over time (P < .001). Most LVMRs occurred within the first 6 months, and after 1 year LVMI had decreased by 37.5% with further, but not statistically significant, reductions at later examinations. We found that baseline BSA > 1.75 m(2), male sex, arterial blood pressure > or = 150 mm Hg, left ventricular ejection fraction < or = 35%, New York Heart Association functional class > or = III, non-sinus rhythm, and prevalent aortic incompetence to be factors influencing LVMR. LVMR was not related to postoperative effective orifice area < or = 0.85 cm/m(2) and prosthetic size. CONCLUSIONS: AVR with a CLOB valve is followed by a significant LVMR that occurs soon after surgery. It is influenced by several patient-related factors: most of them can be predicted preoperatively.

Aged↗
PubMed2001

NO-mesalamine protects colonic epithelial cells against apoptotic damage induced by proinflammatory cytokines.

The activation of a self-amplifying cascade of caspases, of which caspase-8 is the apical protease, mediates Fas-, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-, and TNF-alpha-induced apoptosis in colon cell lines. Nitric oxide (NO) protects from apoptosis induced by Fas and TNF-alpha. We examined whether NCX-456, an NO-releasing derivative of mesalamine, protects colon epithelial cells from cytokine-induced apoptosis. Caco-2 and HT-29 cell lines express death factor receptors and are driven to apoptosis in response to incubation with Fas-agonistic antibody, TNF-alpha/interferon-gamma, and TRAIL. The two novel observations reported here are that 1) cotreatment of cells with NCX-456, but not mesalamine, resulted in concentration-dependent protection against death factor-induced apoptosis and inhibition of caspase activity, and 2) exposure to dithiothreitol, an agent that effectively removes NO from thiol groups, resulted in a 70% recovery of caspase activity, which is consistent with S-nitrosation as a major mechanism for caspase inactivation. These data suggest that caspase S-nitrosation represents a mechanism for protection of colonic mucosal epithelial cells from death factor-induced death.

Aminosalicylic Acids↗
PubMed2001

Nitric oxide-releasing NSAIDs: a review of their current status.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs worldwide owing to their anti-inflammatory, antipyretic and analgesic properties. However, their use is hampered by gastrointestinal (GI) toxicity, the most common drug-related serious adverse event in industrialised nations. Nitric oxide (NO)-releasing NSAIDs, a recently described class of drugs, are generated by adding a nitroxybutyl or a nitrosothiol moiety to the parent NSAID via a short-chain ester linkage. While efficacy of nitrosothiol-NO-NSAIDs still awaits investigation, nitroxybutyl-NO-NSAIDs have been extensively studied in animals, thus the abbreviation NO-NSAIDs used here refers to the latter group of NSAID derivatives. NO-NSAIDs retain the anti-inflammatory and antipyretic activity of original NSAIDs, although they exhibit markedly reduced gastrointestinal toxicity. NO-NSAIDs are nonselective cyclo-oxygenase (COX) inhibitors, and they also exert COX-independent activities that are NO-dependent. Indeed, NO-NSAIDs suppress production of the cytokines interleukin (IL)-1beta, IL-18 and interferon-gamma by causing the S-nitrosilation/inhibition of caspase-1. In acute and chronic animal models of inflammation, it has been demonstrated that NO-NSAIDs abrogated prostaglandin E2 as well as thromboxane B2 generation. In a murine model, NO-naproxen was approximately 10-fold more potent than naproxen in reducing animal writhing after intraperitoneal injection of acetic acid. Similar data have been obtained in chronic models of pain such as rat adjuvant arthritis. In vivo and in vitro studies suggest that NO-aspirin (acetylsalicylic acid) exerts more potent antithrombotic action than aspirin, probably by coupling the ability to inhibit COX-1 with the anti-adhesive effect of NO. Moreover, in a model of renal injury NO-flurbiprofen not only has been demonstrated to be devoid of nephrotoxicity but also to ameliorate renal function. Finally, in an animal model of chronic neurodegenerative disease, NO-flurbiprofen and NO-aspirin attenuated the brain inflammatory response. The GI toxicity of NO-flurbiprofen and NO-naproxen is currently being investigated in healthy individuals.

Animals↗
PubMed2001

Early recovery of left ventricular function after stentless versus stented aortic valve replacement for pure aortic stenosis and severe cardiac dysfunction.

OBJECTIVE: The aim of this study was to evaluate early recovery of systolic function after stentless aortic valve replacement (AVR) versus stented AVR. METHODS: Fifty-four consecutive patients with pure aortic stenosis and impaired left ventricular function (LVEF < or = 35%) were studied retrospectively. Aortic regurgitation, concomitant valvular or coronary artery surgery, atrial fibrillation, and a previous AVR were exclusion criteria. Twenty-two patients (mean age, 70.0 +/- 6.5 years) received a stentless bioprosthesis and 32 (mean age, 58.9 +/- 6.2 years, P =.031 between groups) a mechanical or stented biologic valve. Patients underwent echocardiography preoperatively, at discharge, at 6 months, and at 1 year after surgery. RESULTS: At 6 months, analysis of variance demonstrated significant differences between groups in fractional shortening measured at the endocardium and midwall fractional shortening (<0.001), velocity of circumferential shortening (P <.001) ejection fraction (P =.02), left ventricular mass index (P <.001), systolic meridional wall stress, and circumferential wall stress (P <.001), One-year studies confirmed these findings. CONCLUSION: LV function showed, after a stentless AVR, an early recovery greater than in patients receiving a stented valve.

Aged↗
PubMed2000

IL-1 beta converting enzyme is a target for nitric oxide-releasing aspirin: new insights in the antiinflammatory mechanism of nitric oxide-releasing nonsteroidal antiinflammatory drugs.

Caspase-1, the IL-1beta converting enzyme (ICE), is required for intracellular processing/maturation of IL-1beta and IL-18. NO releasing nonsteroidal antiinflammatory drugs (NSAIDs) are a new class of NSAID derivatives that spare the gastric mucosa. Here, we tested the hypothesis that NCX-4016, a NO-aspirin derivative, inhibits proinflammatory cytokine release from endotoxin (LPS)-challenged monocytes. Our results demonstrated that exposing LPS-stimulated human monocytes to NCX-4016 resulted in a 40-80% inhibition of IL-1beta, IL-8, IL-12, IL-18, IFN-gamma, and TNF-alpha release with an EC(50) of 10-20 microM for IL-1beta and IL-18. Incubating LPS-primed monocytes with NCX-4016 resulted in intracellular NO formation as assessed by measuring nitrite/nitrate, intracellular cGMP concentration, and intracellular NO formation. Exposing LPS-stimulated monocytes to aspirin or celecoxib caused a 90% inhibition of prostaglandin E(2) generation but had no effect on cytokine release. NCX-4016, similar to the NO donor S-nitroso-N-acetyl-D-L-penicillamine, inhibited caspase-1 activity with an EC(50) of approximately 20 microM. The inhibition of caspase-1 by NCX-4016 was reversible by the addition of DTT, which is consistent with S-nitrosylation as the mechanism of caspase-1 inhibition. NCX-4016, but not aspirin, prevented ICE activation as measured by assessing the release of ICE p20 subunit. IL-18 immunoneutralization resulted in a 60-80% reduction of IL-1beta, IL-8, IFN-gamma, and TNF-alpha release from LPS-stimulated monocytes. Taken together, these data indicate that incubating human monocytes with NCX-4016 causes intracellular NO formation and suppresses IL-1beta and IL-18 processing by inhibiting caspase-1 activity. Caspase-1 inhibition is a new, cycloxygenase-independent antiinflammatory mechanism of NO-aspirin.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Evidence of a linkage disequilibrium between polymorphisms in the human estrogen receptor alpha gene and their relationship to bone mass variation in postmenopausal Italian women.

Bone mineral density (BMD), the major determinant of osteoporotic fracture risk, has a strong genetic component. The discovery that inactivation of estrogen receptor alpha (ERalpha) gene is associated with low BMD indicated ERalpha as a candidate gene for osteoporosis. We have investigated the role of three ERalpha gene polymorphisms [intron 1 PVU:II and XBA:I RFLPs and TA dinucleotide repeat polymorphism 5' upstream of exon 1] in 610 postmenopausal women. There was a strong linkage disequilibrium between intron 1 polymorphic sites and also between these sites and the microsatellite (TA)(n) dinucleotide polymorphism, with a high degree of coincidence of the short TA alleles and the presence of PVU:II and XBA:I restriction sites. No significant relationship between intron 1 RFLPs and BMD was observed. A statistically significant correlation between (TA)(n) repeat allelic variants and lumbar BMD was observed (P = 0.04, ANCOVA), with subjects with a low number of repeats (TA < 15) showing the lowest BMD values. We observed a statistically significant difference in the mean +/- SD number of TA repeats between analyzed women with a vertebral fracture (n = 73) and the non-fracture group, equivalent to 2.9 (95% CI 1.56-5.72) increased fracture risk in women with a low number of repeats (TA < 15). We conclude that in this large population sample the (TA)(n) dinucleotide repeat polymorphism at the 5' end of the ERalpha gene accounts for part of the heritable component of BMD and might prove useful in the prediction of vertebral fracture risk in postmenopausal osteoporosis.

Alleles↗
PubMed2000

ATP synthesis in rod outer segments of bovine retina by the reversal of the disk Ca(2+) pump.

Purified disk membranes from rod outer segments of the bovine retina were able to synthesize ATP with a maximal activity (about 52 nmoles ATP/min/mg of protein) at physiological calcium concentrations. This activity was inhibited by vanadate or thapsigargin but not by oligomycin, suggesting the reversal functioning of the disk Ca(2+)-ATPase, which would act as a ATP synthesizer at the expense of the calcium gradient between the disks and the cytoplasm of the rod outer segment. The results are discussed in terms of the need of an immediate source of ATP on the disk membranes where the energy is required to supply the rapid reactions of the photoreception processes.

Adenosine Diphosphate↗
PubMed2000

Galectin-1 exerts immunomodulatory and protective effects on concanavalin A-induced hepatitis in mice.

Galectin-1, an endogenous lectin with immunomodulatory activities, induces selective, Fas-independent apoptosis of activated T cells. The aim of the present study was to evaluate the effect galectin-1 exerts on concanavalin A (Con A)-induced hepatitis, a T-cell-dependent model of liver injury. Con A administration resulted in liver injury, as shown by the increased transaminase plasma levels and liver DNA fragmentation, and caused spleen T-cell activation, which was associated with a strong increment in liver infiltrating T helper cells. Moreover, Con A injection leads to a marked increase in plasma tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) levels. Galectin-1 pretreatment dose-dependently prevented both liver injury and T-helper cell liver infiltration induced by Con A. In vivo and in vitro experiments indicated that the protective effects of galectin-1 depend on the selective elimination of Con A-activated T cells. In addition, galectin-1 almost completely prevented the Con A-induced increase in plasma TNF-alpha and IFN-gamma, an effect that was, at least in part, independent on the elimination of activated T helper cells, because galectin-1 prevented lipopolysaccharide (LPS)-induced release of TNF-alpha and IFN-gamma also from macrophages in vitro, without affecting their viability. The present study suggests that galectin-1 is potentially useful in the treatment of T-cell-mediated human liver disorders.

Adjuvants, Immunologic↗
PubMed2000

High glucose modulates P2X7 receptor-mediated function in human primary fibroblasts.

AIMS/HYPOTHESIS: Purinergic receptors are a family of newly characterized plasma membrane molecules involved in several and as yet only partially known cellular functions such as vascular reactivity, apoptosis and cytokine secretion. Little is known about the effect extracellular microenvironment has on their function. Fibroblasts share several features with smooth muscle cells and are an important constituent of the atherosclerotic plaque. Our aim was to evaluate the effect of high glucose concentration on ATP-mediated responses in human fibroblasts. METHODS: Fibroblasts were obtained by skin biopsies and grown at two different glucose concentrations. We evaluated receptor expression by RT-PCR and immunoblotting and receptor localization by immunofluorescence. Plasma membrane potential and calcium changes were measured by fluorescent indicators. Apoptosis was determined by ethidium bromide staining and caspase-3 activation. RESULTS: We show that cells grown in a medium with high glucose concentration underwent great ATP-mediated morphological changes, enhanced apoptosis, caspase 3 activation and interleukin-6 release. We identified P2X7 as the main purinergic receptor involved in these responses. Furthermore, high glucose concentration triggered the assembly of P2X7 into ring-like structures located at the periphery of the cells. CONCLUSION/INTERPRETATION: Given that ATP is frequently released into the extracellular milieu upon cell and tissue damage, secretory exocytosis or activation of plasma membrane transporters, we hypothesize that ATP receptors participate in the pathogenesis of vascular complications of diabetes.

Adenosine Triphosphate↗
PubMed2000

NO-aspirin protects from T cell-mediated liver injury by inhibiting caspase-dependent processing of Th1-like cytokines.

BACKGROUND & AIMS: Concanavalin A (con A)-induced hepatitis is an immunomediated disease in which assembly of CD4(+) T cells and T helper (Th)1-like cytokines causes Fas-mediated liver cell death. Nitric oxide (NO) modulates Th1 response in vitro. NCX-4016 is an NO-aspirin derivative that spares the gastrointestinal tract and shares molecular targets with NO. The aim of this study was to investigate whether this NO-aspirin modulates Th1-like response induced by con A. METHODS: BALB/c mice were injected with 0.3 mg con A per mouse alone or in combination with NO-aspirin (18-100 mg/kg) or aspirin (10-55 mg/kg). RESULTS: NO-aspirin, but not aspirin, caused a dose-dependent protection against liver damage induced by con A. At a dose of 100 mg/kg, NO-aspirin caused a 40%-80% reduction of interleukin (IL)-1beta, IL-12, IL-18, interferon (IFN)-gamma, and tumor necrosis factor alpha production without affecting cytokine messenger RNA expression. NO-aspirin prevented Fas, Fas ligand, and IL-2 receptor up-regulation on spleen lymphocytes and Fas ligand on hepatocytes and caused the S-nitrosylation/inhibition of IL-1beta-converting enzyme-like cysteine proteases (caspases) involved in the processing and maturation of IL-1beta and IL-18. IL-18 immunoneutralization prevented IFN-gamma release and protected from liver injury induced by con A. In contrast to a selective caspase 1 inhibitor, zVAD.FMK, a pancaspase inhibitor, prevented IFN-gamma release and protected the liver from injury. CONCLUSIONS: Th1-like response induced by con A is mediated by IL-18 and requires activation of multiple caspases. NCX-4016 causes the S-nitrosylation/inhibition of caspases involved in cytokine production. Inhibition of Th1-like response is a new anti-inflammatory mechanism of action of NO-aspirin.

Amino Acid Chloromethyl Ketones↗