Search PubMed⌕ Search

Biomedical subjects

A Catania

Publications and source records attributed to A Catania.

At least 37 records · Page 2Linked to original sources
PubMed2000

Plasma concentrations of alpha-melanocyte-stimulating hormone are elevated in patients on chronic haemodialysis.

BACKGROUND: Clinical and/or laboratory signs of systemic inflammation occur frequently in patients undergoing long-term haemodialysis. It is likely, therefore, that a compensatory release of endogenous anti-inflammatory molecules occurs to limit host reactions. The aim of the present research was to determine if the potent anti-inflammatory peptide alpha-melanocyte-stimulating hormone (alpha-MSH), a pro-opiomelanocortin derivative, is increased in plasma of haemodialysis patients. Because endotoxin and cytokines induce alpha-MSH in vivo and in vitro, we also measured plasma concentrations of endotoxin, interleukin-6 (IL-6), and tumour necrosis factor alpha (TNF-alpha), and the two circulating products of activated monocytes, nitric oxide (NO) and neopterin. METHODS: Thirty-five chronic haemodialysis patients, 20 patients with chronic renal failure not yet on dialysis, and 35 normal controls were included in the study. In the haemodialysis group, blood samples were obtained before and at the end of a dialysis session. Plasma alpha-MSH was measured using a double antibody radioimmunoassay, and IL-6, TNF-alpha, and neopterin using specific enzyme-linked immunosorbent assays. Plasma nitrites were determined by a colorimetric method, and endotoxin with the quantitative chromogenic LAL (limulus amoebocyte lysate) method. RESULTS: Mean plasma alpha-MSH was higher in haemodialysis patients than in control subjects, with the peptide concentrations being particularly elevated in dialysed patients with detectable endotoxin. High alpha-MSH concentrations were observed in the pre-dialysis samples, with no substantial change at the end of the dialysis session. Plasma concentrations of IL-6, TNF-alpha, neopterin, and NO were generally elevated in chronic haemodialysis patients and there was a negative correlation between circulating alpha-MSH and IL-6. In patients with renal failure not yet on dialysis, mean plasma alpha-MSH was similar to that of normal subjects. CONCLUSIONS: alpha-MSH is increased in the circulation of chronic haemodialysis patients and particularly so in case of detectable endotoxaemia. Reduction of renal clearance is unlikely to contribute to the observed rise of the peptide because alpha-MSH concentration is not increased in patients with chronic renal failure who are not yet on dialysis. It is likely that dialysis-associated endotoxaemia, directly and/or through cytokine release, enhances the production of the anti-inflammatory mediator alpha-MSH that limits host reactions.

Adult↗
PubMed2000

Plasma concentrations and anti-L-cytokine effects of alpha-melanocyte stimulating hormone in septic patients.

OBJECTIVES: The aim of this research was to investigate endogenous concentrations and anti-cytokine effects of the antiinflammatory peptide alpha-melanocyte stimulating hormone (alpha-MSH) in patients with systemic inflammation. The objectives were to determine the following: changes over time of plasma alpha-MSH and relationship with patient outcome, correlation between plasma alpha-MSH and tumor necrosis factor (TNF)-alpha plasma concentration and production in whole blood samples, and influences of alpha-MSH on production of TNF-alpha and interleukin (IL)-1beta in whole blood samples stimulated with lipopolysaccharide (LPS). DESIGN: Prospective, nonrandomized, clinical study. SETTING: Intensive care unit of a university hospital. PATIENTS: A total of 21 patients with sepsis syndrome/septic shock and an equal number of healthy volunteers. INTERVENTIONS: Circulating alpha-MSH and TNF-alpha concentrations and TNF-alpha production in supernatants of LPS (1 ng/mL)-stimulated whole blood were measured repeatedly. To determine whether alpha-MSH can modulate production of TNF-alpha and IL-1 beta, these cytokines were measured in whole blood samples stimulated with LPS (1 ng/mL) in the presence or absence of concentrations of the peptide. MEASUREMENTS AND MAIN RESULTS: Plasma alpha-MSH was low in early samples and gradually increased in patients who recovered but not in those who died. There was a negative correlation between plasma concentrations of alpha-MSH and TNF-alpha. In blood samples taken at early phases of sepsis syndrome, production of TNF-alpha was reduced relative to control values; such production increased in patients who recovered but not in those who died. Addition of alpha-MSH to LPS-stimulated whole blood samples inhibited production of TNF-alpha and IL-1beta in a concentration-dependent manner. CONCLUSIONS: In patients with systemic inflammation, there are substantial changes over time in plasma concentrations of alpha-MSH that are reduced in early phases of the disease. Reduction of this endogenous modulator of inflammation could be detrimental to the host. Addition of alpha-MSH to LPS-stimulated blood samples reduces production of cytokines involved in development of septic syndrome. This inhibition by alpha-MSH, a peptide that is beneficial in treatment of experimental models of sepsis, might therefore be useful to treat sepsis syndrome in humans.

Adult↗
PubMed2000

The neuroimmunomodulatory peptide alpha-MSH.

Alpha-melanocyte-stimulating hormone (alpha-MSH), a neuroimmunomodulatory peptide of ancient origin, is known to be involved in the control of host responses. In inflammatory cells, in the periphery and within the central nervous system, alpha-MSH modulates the production and action of proinflammatory cytokines. This broad influence occurs via endogenous alpha-MSH (melanocortin) receptors. The key to this anti-inflammatory influence is inhibition of NF-kappa B. Indeed alpha-MSH inhibits activation of this nuclear factor through preservation of I kappa B alpha, which binds to NF-kappa B and prevents its migration to the nucleus. Cells transfected with alpha-MSH plasmid vector are resistant to challenge with bacterial lipopolysaccharide. The peptide also act on central melanocortin receptors to modulate inflammation in the periphery. In brief, alpha-MSH and certain of its fragments such as alpha-MSH [11-13] KPV modulate inflammation via three general actions: direct actions on peripheral host cells; actions on inflammatory cells within the brain to modulate local reactions; and descending neural anti-inflammatory pathways that control inflammation in peripheral tissues.

Animals↗
PubMed2000

The neuropeptide alpha-MSH in host defense.

The presence of the ancient peptide alpha-melanocyte-stimulating hormone (alpha-MSH) in barrier organs such as gut and skin suggests that this potent anti-inflammatory molecule may be a component of the innate host defense. In tests of antimicrobial activities, alpha-MSH and its fragment KPV showed inhibitory influences against the gram-positive bacterium Staphylococcus aureus and the yeast Candida albicans. Anti-tumor necrosis factor and antimicrobial effects of alpha-MSH suggest that the peptide might likewise reduce replication of human immunodeficiency virus (HIV). Treatment with alpha-MSH reduced HIV replication in chronically and acutely infected human monocytes. At the molecular level, alpha-MSH inhibited activation of the transcription factor NF-kappa B known to enhance HIV expression. alpha-MSH that combines antipyretic, anti-inflammatory, and antimicrobial effects could be useful in the treatment of disorders in which infection and inflammation coexist.

Animals↗
PubMed2000

Polymorphonuclear integrins, membrane fluidity, and cytosolic Ca(2+) content after activation in essential hypertension.

The purpose of this research was to obtain further information about the role of polymorphonuclear leukocytes in essential hypertension. These cells could be involved in the pathogenesis of organ injury. Thirty subjects (14 men and 16 women) with essential hypertension were enrolled. In these subjects we determined, at baseline and after in vitro activation with 4-phorbol 12-myristate 13-acetate and N:-formyl-methionyl-leucyl-phenylalanine, the polymorphonuclear leukocyte membrane fluidity, obtained by labeling the cells with 1-[4-(trimethylamino)phenyl]-6-phenyl-1,3, 5-hexatriene, cytosolic Ca(2+) concentration, obtained by marking the cells with Fura 2-AM, and integrin pattern (CD11a, CD11b, CD11c, and CD18), by using the indirect immunofluorescence with a flow cytometer. At baseline there was no difference in membrane fluidity between normal subjects and hypertensives, whereas hypertensives showed an increase in cytosolic Ca(2+) content and an increase of the phenotypical expression of CD11a, CD11b, and CD18. In normal subjects and in hypertensives, after activation, no variation was found in membrane fluidity and cytosolic Ca(2+) content. In normal subjects, after activation, we observed a significant increase of the expression of all adhesion molecules, whereas in hypertensives we found an increase of the expression of CD11b, CD11c, and CD18 but also a decrease of CD11a. The behavior of the polymorphonuclear leukocyte integrin profile may have several explanations, and in particular, the trend of CD11a after chemotactic activation may be related to its cleavage or to an altered integrin phosphorylation/dephosphorylation balance hypothetically present in this clinical condition.

Adult↗
PubMed2000

Alpha-melanocyte-stimulating hormone peptides inhibit HIV-1 expression in chronically infected promonocytic U1 cells and in acutely infected monocytes.

The purpose of the present research was to determine if alpha-melanocyte-stimulating hormone (alpha-MSH) and its C-terminal tripeptide [alpha-MSH (11-13), KPV] alter HIV expression in infected cells. The results indicate that chronically HIV-1-infected promonocytic U1 cells produce alpha-MSH and that immunoneutralization of the endogenous peptide enhances HIV expression. Because U1 cells express the alpha-MSH receptor 1 (MC1R), an autocrine-inhibitory circuit based on the peptide and its receptor likely occurs in these cells. To determine effects of pharmacological concentrations of alpha-MSH peptides on HIV expression, we measured p24 antigen release by TNF-alpha-stimulated U1 cells exposed to a wide range of concentrations of synthetic alpha-MSH and KPV. Viral expression was reduced by both peptides. KPV also effectively reduced HIV replication in acutely infected monocyte-derived macrophages (MDM). The basis of the peptide influence on viral replication is at the transcriptional level; KPV inhibited activation of NF-kappaB that is known to enhance viral expression. Endogenous alpha-MSH likely contributes to natural defense against HIV. However, greater concentrations of synthetic peptide are much more effective in reducing HIV expression in infected cells.

DNA, Viral↗
PubMed1999

Autocrine alpha-melanocyte-stimulating hormone inhibits NF-kappaB activation in human glioma.

The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) modulates inflammation by inhibiting production of proinflammatory cytokines. Using a plasmid vector encoding alpha-MSH, we examined whether autocrine alpha-MSH inhibits activation of the nuclear transcription factor NF-kappaB, a factor that is essential to expression of proinflammatory cytokines, in human glioma cells (A-172). Electrophoretic mobility shift assays of nuclear extracts demonstrated that NF-kappaB activation induced by lipopolysaccharide was inhibited in glioma cells transfected with alpha-MSH vector. Western blot analysis revealed that this inhibition was linked to preservation of expression of IkappaBalpha protein. Chloramphenicol acetyltransferase assay indicated that NF-kappaB-dependent reporter gene expression was suppressed in A-172 cells transfected with alpha-MSH vector. Finally, fluorescence staining confirmed that A-172 cells bear alpha-MSH receptors. The findings are consistent with the idea that, in central nervous system (CNS) inflammation, autocrine alpha-MSH exerts anti-inflammatory actions via modulation of NF-kappaB activation by preservation of IkappaBalpha protein. Based on this action of the peptide, it should be possible to treat neurodegenerative disease, stroke, encephalitis, trauma, and other CNS disorders that have an inflammatory component through gene therapy with alpha-MSH vector.

Autocrine Communication↗
PubMed1999

Inhibition of peripheral NF-kappaB activation by central action of alpha-melanocyte-stimulating hormone.

With the rise in the field of neuroimmunomodulation research, there is increased recognition of the influence of the nervous system and neuropeptides in peripheral disease. The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) is a neuroimmunomodulatory agent that modulates production of proinflammatory cytokines and inhibits peripheral inflammation via actions on CNS receptors. We examined whether central alpha-MSH operates by inhibiting activation of the nuclear factor kappa B (NF-kappaB) that is essential to the expression of proinflammatory cytokines and development of inflammation in the periphery. Electrophoretic mobility shift assays of nuclear extracts from the murine foot pad injected with TNF-alpha demonstrated that centrally administered alpha-MSH does inhibit NF-kappaB activation. Western blot analysis revealed that this inhibition was linked to central alpha-MSH-induced preservation of expression of IkappaBalpha protein in the peripheral tissue. The NF-kappaB and IkappaBalpha effects were inhibited in mice with spinal cord transection. Intraperitoneal (i.p.) injection of the nonspecific beta-adrenergic receptor blocker propranolol, and of a specific beta2-adrenergic receptor antagonist, likewise prevented these effects of central alpha-MSH; blockade of cholinergic, alpha-adrenergic, or beta1-adrenergic receptors did not. Centrally administered alpha-MSH inhibited peripheral NF-kappaB activation and IkappaBalpha degradation even in mice with nonfunctional melanocortin 1 receptors (MC1R). These findings indicate that alpha-MSH can act centrally to inhibit NF-kappaB activation in peripheral acute inflammation via a descending neural pathway. The pathway involves beta2-adrenergic receptors, but does not require activation of MC1R within the brain.

Acute Disease↗
PubMed1999

Mechanisms of antiinflammatory action of alpha-MSH peptides. In vivo and in vitro evidence.

alpha-Melanocyte stimulating hormone (alpha-MSH) modulates all forms of inflammation by acting on peripheral inflammatory cells, glial inflammatory cells, and on CNS receptors that activate descending antiinflammatory neural pathways. The multiple actions of this ancient peptide suggest that there is no singular biochemical mechanism through which it exerts its antiinflammatory activity. However, research on IL-10 deficient and Agouti protein hypersecreting mice provide new insights into the actions of the peptide in living animals. Studies of cultured human astrocytes, whole murine brain, and human monocyte/macrophages indicate that a primary effect of the peptide is modulation of activation of the nuclear transcription factor kappa B. The latter influence may underlie the established reduction of gene expression and production of proinflammatory peptides and inducible nitric oxide by alpha-MSH peptides.

Agouti Signaling Protein↗
PubMed1999

alpha-MSH in systemic inflammation. Central and peripheral actions.

Until recently, inflammation was believed to arise from events taking place exclusively in the periphery. However, it is now clear that central neurogenic influences can either enhance or modulate peripheral inflammation. Therefore, it should be possible to improve treatment of inflammation by use of antiinflammatory agents that reduce peripheral host responses and inhibit proinflammatory signals in the central nervous system (CNS). One such strategy could be based on alpha-melanocyte stimulating hormone (alpha-MSH). Increases in circulating TNF-alpha and nitric oxide (NO), induced by intraperitoneal administration of endotoxin in mice, were modulated by central injection of a small concentration of alpha-MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central alpha-MSH. Increase in lung myeloperoxidase (MPO) activity was significantly less in lungs of mice treated with central alpha-MSH. Proinflammatory agents induced by endotoxin were significantly greater after blockade of central alpha-MSH. The results suggest that antiinflammatory influences of neural origin that are triggered by alpha-MSH could be used to treat systemic inflammation. In addition to its central influences, alpha-MSH has inhibitory effects on peripheral host cells, in which it reduces release of proinflammatory mediators. alpha-MSH reduces chemotaxis of human neutrophils and production of TNF-alpha, neopterin, and NO by monocytes. In research on septic patients, alpha-MSH inhibited release of TNF-alpha, interleukin-1 beta (IL-1 beta), and interleukin-8 (IL-8) in whole blood samples in vitro. Combined central and peripheral influences can be beneficial in treatment of sepsis.

Animals↗
PubMed1999

Alpha-MSH peptides inhibit production of nitric oxide and tumor necrosis factor-alpha by microglial cells activated with beta-amyloid and interferon gamma.

Alpha-melanocyte stimulating hormone (alpha-MSH) is an ancient tridecapeptide with potent inhibitory activity in all major forms of inflammation. The anti-inflammatory message sequence of alpha-MSH resides in the COOH-terminal tripeptide alpha-MSH[11-13]. We tested the influence of alpha-MSH[1-13] and of alpha-MSH[11-13] in a cultured murine microglia cell line known to produce nitric oxide (NO(-)(2)) and tumor necrosis factor (TNFalpha) when stimulated with beta-amyloid protein (Abeta). Melanocortin peptides significantly inhibited release of both NO(-)(2) and TNFalpha into cell-free supernatants from microglia stimulated with Abeta[1-42] or Abeta[25-35] peptides and interferon gamma (IFNgamma). Northern blot analysis demonstrated that alpha-MSH[1-13] and alpha-MSH[11-13] inhibited accumulation of inducible nitric oxide synthase (iNOS) and TNFalpha mRNA was triggered by Abeta stimulation. Abeta/microglial interaction is believed to promote the progression of inflammatory and neurodegenerative changes in senile plaques in Alzheimer's disease. Our data indicate that alpha-MSH peptides might be used to modulate the local response of the brain to Abeta deposition in this neurodegenerative disease.

Amyloid beta-Peptides↗
PubMed1999

Systemically administered alpha-melanocyte-stimulating peptides inhibit NF-kappaB activation in experimental brain inflammation.

The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) and its C-terminal tripeptide alpha-MSH11-13 modulate production of proinflammatory cytokines and inhibit inflammation. We examined whether systemic alpha-MSH and alpha-MSH11-13 inhibit activation of the nuclear transcription factor, nuclear factor kappa B (NF-kappaB), a factor that is essential to expression of proinflammatory cytokines, in experimental murine brain inflammation induced by lipopolysaccharide. Electrophoretic mobility shift assays of nuclear extracts demonstrated that parenteral alpha-MSH inhibited NF-kappaB activation. Western blot analysis revealed that this inhibition was linked to alpha-MSH-induced preservation of expression of IkappaBalpha protein in the brain. The effects of alpha-MSH on NF-kappaB and IkappaBalpha were paralleled by pretreatment with alpha-MSH11-13. Similar effects of the two peptides were observed in mice with nonfunctional melanocortin 1 receptors (MC1R), ruling out the possibility that this receptor subtype is essential to the influence on NF-kappaB. These findings indicate that alpha-MSH peptides given systemically can inhibit NF-kappaB activation induced in acute brain inflammation even in the absence of MC1R.

Animals↗
PubMed1999

alpha-melanocyte-stimulating hormone inhibits NF-kappaB activation and IkappaBalpha degradation in human glioma cells and in experimental brain inflammation.

The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) modulates production of proinflammatory cytokines in brain tissue and in peripheral inflammatory cells. Transcription of the genes for these proinflammatory cytokines is regulated by the nuclear factor kappaB (NF-kappaB). NF-kappaB is also activated by proinflammatory cytokines. Degradation of the cytoplasmic inhibitor IkappaBalpha protein results in activation of NF-kappaB. Because of increasing evidence that NF-kappaB is involved in brain injury and inflammation and neurodegenerative disease, we examined whether alpha-MSH inhibits activation of NF-kappaB and limits degradation of IkappaBalpha protein induced by lipopolysaccharide (LPS) in human glioma cells (A-172) and in mouse brain. Electrophoretic mobility shift assays of nuclear extracts from A-172 cells and whole mouse brains stimulated with LPS revealed that alpha-MSH does suppress NF-kappaB activation. Western blot analysis demonstrated that alpha-MSH preserved expression of IkappaBalpha protein in vitro (glioma cells) and in vivo (brain tissue). Chloramphenicol acetyltransferase assay indicated that alpha-MSH suppresses NF-kappaB-dependent reporter gene expression induced by LPS in A-172 cells. The findings are consistent with the possibility that the anti-inflammatory action of alpha-MSH in CNS inflammation occurs via modulation of NF-kappaB activation by peptide-induced inhibition of degradation of IkappaBalpha protein.

Animals↗
PubMed1999

Elevated concentrations of plasma alpha-melanocyte stimulating hormone are associated with reduced disease progression in HIV-infected patients.

To determine whether concentrations of the anti-inflammatory peptide alpha-melanocyte stimulating hormone (alpha-MSH) are associated with accelerated or reduced disease progression in patients with HIV infection, plasma concentrations of alpha-MSH and two other anticytokine molecules, interleukin-1 receptor antagonist (IL-1 ra) and soluble tumor necrosis factor receptor (s TNF r), were taken repeatedly from HIV-positive patients over a 1-year period. Samples from 87 patients were collected by using special precautions to ensure accurate measurement of the peptide. Alpha-MSH concentrations were determined by radioimmunoassay; IL-1 ra and s TNF r concentrations were measured by using enzyme-linked immunosorbent assays. Clinical and immunologic variables were recorded to determine whether there is an association between cytokine antagonist concentrations and disease progression. Elevated concentrations of circulating alpha-MSH were associated with reduced progression of the disease. Circulating alpha-MSH was greater in non-progressors than in progressors; the association between elevated alpha-MSH and reduced disease progression was even more pronounced in patients with baseline CD4+ T cell counts less than 200/microL. No such association was observed for the other two anticytokine molecules, and there was no significant correlation between the plasma concentration of either cytokine antagonist and alpha-MSH. The present evidence and previous findings indicate that elevated concentrations of alpha-MSH are associated with reduced disease progression in HIV-infected patients.

Adult↗
PubMed1999

Diabetes mellitus: polymorphonuclear leukocyte (PMN) filtration parameters and PMN membrane fluidity after chemotactic activation.

The goal of this research was to determine leukocyte rheology at baseline and after chemotactic activation in type I and type II diabetics. In 19 normal subjects, 21 type I diabetics, and 16 type II diabetics at baseline and after in vitro chemotactic activation (prolonged for 5 and 15 minutes) with two stimulating agents (4-phorbol 12-myristate 13-acetate [PMA] and N-formyl-methionyl-leucyl-phenylalanine [fMLP]), we evaluated polymorphonuclear (PMN) filtration parameters (using a St. George filtrometer [Carri-Med, Dorking, UK] and considering the initial relative flow rate [IRFR] and the concentration of clogging particles [CP]) and PMN membrane fluidity (obtained by marking PMNs with the fluorescent probe 1-(4-[trimethylamino]phenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH). At baseline, there was a difference between normals and type I and II diabetics for PMN membrane fluidity only. After activation in normals and diabetics of both types, a significant variation was present in PMN filtration parameters (IRFR and CP) at both 5 and 15 minutes. In normals, no variation was present in PMN membrane fluidity after activation with PMA or fMLP. After PMN activation, only in type I diabetics was a significant decrease in PMN membrane fluidity present at both 5 and 15 minutes. After PMN activation with either PMA or fMLP in comparison to basal values, only the mean variation (delta%) of the IRFR was significantly different between normals, type I diabetics, and type II diabetics at both 5 and 15 minutes. From the data obtained, it is evident that after activation, the PMN filtration pattern shows a specific behavior in diabetics of both types, while PMN membrane fluidity changes only in type I diabetics. The latter finding may be the basis of a metabolic pattern present in PMNs of this type, revealed after in vitro activation.

Adolescent↗
PubMed1999

alpha-MSH and its receptors in regulation of tumor necrosis factor-alpha production by human monocyte/macrophages.

The hypothesis that macrophages contain an autocrine circuit based on melanocortin [ACTH and alpha-melanocyte-stimulating hormone (alpha-MSH)] peptides has major implications for neuroimmunomodulation research and inflammation therapy. To test this hypothesis, cells of the THP-1 human monocyte/macrophage line were stimulated with lipopolysaccharide (LPS) in the presence and absence of alpha-MSH. The inflammatory cytokine tumor necrosis factor (TNF)-alpha was inhibited in relation to alpha-MSH concentration. Similar inhibitory effects on TNF-alpha were observed with ACTH peptides that contain the alpha-MSH amino acid sequence and act on melanocortin receptors. Nuclease protection assays indicated that expression of the human melanocortin-1 receptor subtype (hMC-1R) occurs in THP-1 cells; Southern blots of RT-PCR product revealed that additional subtypes, hMC-3R and hMC-5R, also occur. Incubation of resting macrophages with antibody to hMC-1R increased TNF-alpha concentration; the antibody also markedly reduced the inhibitory influence of alpha-MSH on TNF-alpha in macrophages treated with LPS. These results in cells known to produce alpha-MSH at rest and to increase secretion of the peptide when challenged are consistent with an endogenous regulatory circuit based on melanocortin peptides and their receptors. Targeting of this neuroimmunomodulatory circuit in inflammatory diseases in which myelomonocytic cells are prominent should be beneficial.

Adrenocorticotropic Hormone↗