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Biomedical subjects

G Poli

Publications and source records attributed to G Poli.

At least 109 records · Page 6Linked to original sources
PubMed1998

Mechanisms of inactivation of hepatocyte protein kinase C isoforms following acute ethanol treatment.

Acute ethanol exposure of rat isolated hepatocytes leads to a significant decrease (-30%) in cytosolic enzymatic activity of classic protein kinase C (PKC) isoforms, while immunoreactive protein level measured by Western Blot remains unaffected. The inactivation of classic cytosolic isoforms appears dependent on the modification of the enzyme function, probably due to ethanol metabolism. In fact, pretreatment with 4-methylpyrazole (4MP), an inhibitor of alcohol dehydrogenase, fully prevented such damage. After ethanol treatment, a decrease of about 40% in both enzymatic activity and immunoreactive protein level of novel PKC isoforms was evident both in the soluble and particulate fractions. Even if 4MP cell pre-treatment afforded protection in this case too, the inhibitory action of ethanol on novel PKC hepatocyte isoforms involves a proteolytic mechanism as shown by Western Blot analysis. The reproduction of PKC inactivation by ethanol in hepatocyte lysate excluded a role of peroxisomal hydrogen peroxide in the pathogenesis of the damage investigated. This damage was not reduced by addition of catalase to the lysate model system.

Animals↗
PubMed1998

1,25-Dihydroxyvitamin D3 upregulates functional CXCR4 human immunodeficiency virus type 1 coreceptors in U937 minus clones: NF-kappaB-independent enhancement of viral replication.

U937 cell clones which sustain efficient or poor replication of human immunodeficiency virus type 1 (HIV-1) (referred to herein as plus clones and minus clones, respectively) have been previously described. 1,25-Dihydroxyvitamin D3 (vitamin D3) potently induced HIV-1 replication and proviral DNA accumulation in minus clones but not in plus clones. Vitamin D3 did not induce NF-kappaB activation but selectively upregulated CXCR4 expression in minus clones. The CXCR4 ligand stromal-cell derived factor-1 induced Ca2+ fluxes and inhibited both constitutive and vitamin D3-enhanced HIV replication in minus clones.

Base Sequence↗
PubMed1998

Double doors and gatekeepers: HIV co-receptors and chemokines.

The identification of CD4 as the HIV receptor immediately triggered a search for the development of novel therapeutic agents aimed at blocking receptor binding. Initial experimental approaches to this problem failed, but led to the observation that one or more other receptors for HIV, or co-receptors, must be involved in the entry of the virus in cells. In 1996 evidence was reported of a second viral receptor, already known under several names and renamed "fusin." Shortly thereafter the CCR5 molecule was identified as a co-receptor for the second type of HIV strain. This second discovery left no doubts: the second receptor for the virus encompassed at least two members of the chemokine receptor family. The identification of these co-receptors has led to several important new observations about HIV, including the fact that chemokines are potent in vitro inhibitors of viral replication, at least in T lymphocytes; however, there is still little information on their role in vivo. Nevertheless, unlike chemokines, the role of chemokine receptors in vivo has already emerged as being of substantial importance.

Journal Article↗
PubMed1998

Single dose pharmacokinetics of manidipine in hepatic impaired patients and healthy controls.

The pharmacokinetics and safety of a single oral dose of 20 mg manidipine dihydrochloride have been studied in 8 patients with mild to moderate hepatic impairment (grade A or B in Child's classification, or score < or = 7 in Pugh's modification of Child's classification), and in 12 healthy subjects. They received one 20 mg manidipine dihydrochloride tablet with 100 ml of tap water after a standard breakfast. Manidipine was determined using HPLC with electrochemical detection from plasma samples taken up to 24 or 36 h after dosing. The medication was well tolerated. A trend toward higher Cmax, AUC, and MRT was observed in patients with a more severe hepatic impairment, as a consequence of reduction in the liver metabolic function. Patients with grade A hepatic impairment did not exhibit significantly altered pharmacokinetics with respect to healthy subjects, while grade B impairment patients had significantly higher AUC and MRT. Tmax values pointed to reduced absorption rate in patients compared to healthy subjects; the changes were more evident in grade B than grade A patients, although statistical significance was not reached. The reduction in absorption rate in grade B patients is probably related to their higher mean age, since this effect has been reported for manidipine. The pharmacokinetics of manidipine seem only modified in patients with a certain degree of hepatic impairment (at least Pugh grade 6 and Child grade B); therefore, adaptation of the dosing regimen does not seem to be generally recommendable, but should be modulated according to the liver status of the patient.

Administration, Oral↗
PubMed1997

Effectiveness of anthracycline against experimental prion disease in Syrian hamsters.

Prion diseases are transmissible neurodegenerative conditions characterized by the accumulation of protease-resistant forms of the prion protein (PrP), termed PrPres, in the brain. Insoluble PrPres tends to aggregate into amyloid fibrils. The anthracycline 4'-iodo-4'-deoxy-doxorubicin (IDX) binds to amyloid fibrils and induces amyloid resorption in patients with systemic amyloidosis. To test IDX in an experimental model of prion disease, Syrian hamsters were inoculated intracerebrally either with scrapie-infected brain homogenate or with infected homogenate coincubated with IDX. In IDX-treated hamsters, clinical signs of disease were delayed and survival time was prolonged. Neuropathological examination showed a parallel delay in the appearance of brain changes and in the accumulation of PrPres and PrP amyloid.

Amyloid↗
PubMed1997

Hemophilia and nonprogressing human immunodeficiency virus type 1 infection.

Seven of 112 hemophiliacs infected with human immunodeficiency virus type-1 (HIV-1) before 1986 through contaminated plasma products are currently healthy, with CD4 T-cell counts above 500 cells/microL, and have never received antiretroviral therapy (long-term nonprogressors [LTNPs]). Seven age and sex-matched hemophiliacs infected in the same period but who have progressive HIV disease (progressors) and one additional slow-progressing individual were also studied. One hundred-fold, 20-fold, and 10-fold lower levels of full-length HIV RNA in plasma, peripheral blood mononuclear cells (PBMCs), and proviral DNA in PBMCs, respectively, were found in LTNPs compared with progressors. Plasma and cell-associated HIV RNA and proviral DNA were lower in LTNPs who tested negative for viral isolation from PBMCs or who were positive only after removal of CD8+ cells. No substantial differences were observed in the in vitro production of chemokines including RANTES, MIP-1 alpha, MIP-1 beta, MCP-1, and interleukin-8 (IL-8) in supernatants of activated PBMCs or CD8-depleted PBMCs of LTNPs, even when HIV isolation was simultaneously accomplished exclusively after removal of CD8+ cells. Low levels of HIV load and replication in peripheral blood are the strongest correlates of nonprogression in this small number of infected hemophiliacs.

Adolescent↗
PubMed1997

Free radical scavenging and antioxidative properties of 'silibin' complexes on microsomal lipid peroxidation.

The antioxidant properties of silibin complexes, the water-soluble form silibin dihemisuccinate (SDH), and the lipid-soluble form, silibin phosphatidylcholine complex known as IdB 1016, were evaluated by studying their abilities to react with the superoxide radical anion (O2-.), and the hydroxyl radical (OH.). In addition, their effect on pulmonary and hepatic microsomal lipid peroxidation had been investigated. Superoxide radicals were generated by the PMS-NADH system and measured by their ability to reduce NBT. IC50 concentrations for the inhibition of the NBT reduction by SDH and IdB 1016 were found to be 25 microM and 316 microM respectively. Both silibin complexes had an inhibitory effect on xanthine oxidase activity. SDH reacted rapidly with OH radicals at approximately diffusion controlled rate and the rate constant was found to be (K = 8.2 x 10(9) M-1 s-1); it appeared to chelate Fe2+ in solution. In hepatic microsomes, when lipid peroxidation was induced by Fe2+, SDH inhibited by 39.5 per cent and IdB 1016 by 19.5 per cent, whereas when lipid peroxidation was induced by CuOOH, IdB 1016 exerted a better protective effect than SDH (29.4 per cent and 19.4 per cent inhibition, respectively). In both microsomal systems lipid peroxidation proceeded through a thiol depletion mechanism which could be restored in the presence of silibin complexes. Low levels of lipid peroxidation in pulmonary microsomes point out the differences between in-vitro lipid peroxidation occurring in microsomes of different tissues. The results support the free radical scavenger and antioxidative properties of silibin when it is complexed with a suitable molecule to increase its bioavailability.

Animals↗
PubMed1997

Biogenic 4-hydroxy-2-nonenal activates transcription factor AP-1 but not NF-kappa B in cells of the macrophage lineage.

A large spectrum of pro-oxidant agents, including molecules with lipoperoxidative effect, can modulate gene expression through modification of the DNA binding activity of the transcription factors activator protein 1 (AP-1) and nuclear factor kappa B (NF-kappa B). In this study the effect on these redox-sensitive factors by 4-hydroxy-2-nonenal (HNE), a major aldehydic product of lipid peroxidation, was examined in two cell lines of the macrophage type. Incubation in the presence of microM concentrations of the aldehyde led to a rapid increase of AP-1 binding with a transient maximum 30 min from HNE addition to the culture medium in both cell lines. On the contrary, HNE did not stimulate nuclear translocation of NF-kappa B. The diverging effect of HNE on the two transcription factors is likely related to the demonstrated differential activation pathway of AP-1 and NF-kappa B in macrophages. The HNE-induced activation of AP-1 suggests the aldehyde's involvement in the regulatory mechanisms of cell proliferation and differentiation.

Aldehydes↗
PubMed1997

Genetic polymorphism of CCR5 gene and HIV disease: the heterozygous (CCR5/delta ccr5) genotype is neither essential nor sufficient for protection against disease progression. Swiss HIV Cohort.

Homozygous (delta ccr5/delta ccr5) and heterozygous (CCR5/delta ccr5) deletions in the beta-chemokine receptor 5 (CCR5) gene, which encodes for the major co-receptor for macrophage-tropic HIV-1 entry, have been implicated in resistance to HIV infection and in protection against disease progression, respectively. The CCR5/delta ccr5 genotype was found more frequently in long-term nonprogressors (LTNP) (31.0%) than in progressors (10.6%, p < 0.0001), in agreement with previous studies. Kaplan-Meier survival analyses showed that a slower progression of disease, i.e. higher proportion of subjects with CD4+ T cell counts > 500/microl (p = 0.0006) and a trend toward a slower progression to AIDS (p = 0.077), was associated with the CCR5/delta ccr5 genotype. However, when LTNP were analyzed separately, no significant differences in CD4+ T cell counts (p = 0.12) and viremia levels (p = 0.65) were observed between the wild-type (69% of LTNP) and the heterozygous (31.0%) genotypes. Therefore, there are other factors which play a major role in determining the status of nonprogression in the majority of LTNP. Furthermore, there was no evidence that the CCR5/delta ccr5 genotype was associated with different rates of disease progression in the group of progressors. Taken together, these results indicate that the CCR5/delta ccr5 genotype is neither essential nor sufficient for protection against the progression of HIV disease.

HIV Infections↗
PubMed1997

MCP-1 and CCR2 in HIV infection: regulation of agonist and receptor expression.

Monocyte chemotactic protein-1 (MCP-1) interacts with the chemokine receptor CCR2. Two CCR2 cDNAs have been described. Sequence analysis as well as Northern blotting and RNase protection with different probes revealed that the CCR2 gene is expressed in activated natural killer (NK) cells and mononuclear phagocytes as a predominant long transcript (3.4 kb) consisting of CCR2B followed by a novel sequence (X), corresponding to an intron in the genome, and by a CCR2A specific portion. The predominant long transcript is polyadenylated and present in the cytoplasm. We found that bacterial products and cytokines affect CCR2 expression. Interleukin-2 (IL-2) augmented CCR2 mRNA in monocytes and NK cells. The augmented migratory capacity of IL-2-activated versus resting NK cells was associated with increased CCR2 transcript levels. Lipopolysaccharide (LPS) and other microbial agents caused a rapid and drastic reduction of CCR2 mRNA levels. The rate of nuclear transcription of CCR2 was not affected by LPS, whereas the mRNA half life was reduced. These results suggest that regulation of receptor expression, in addition to agonist production, is probably a crucial point in the regulation of the chemokine system. Down-regulation of chemokine receptor expression may play a role in the modulation of HIV infection in macrophages by LPS. Levels of MCP-1 were markedly elevated in the cerebrospinal fluid (CSF) but not in blood of HIV-infected patients with cytomegalovirus (CMV) encephalitis. The CSF levels of MCP-1 in CMV encephalitis were markedly higher than those found in the CSF of HIV-infected patients with or without unrelated neurological diseases. IL-8, the prototype of C-X-C chemokines and RANTES and macrophage inflammatory protein-1 alpha (C-C chemokines) were not substantially increased in the liquor of CMV encephalitis patients. High levels of MCP-1 may underlie monocyte recruitment and tissue damage in CMV encephalitis and may represent a rapid and useful tool in the diagnostic armamentarium for neurological disorders associated with HIV.

AIDS Dementia Complex↗
PubMed1997

Role of pro-inflammatory cytokines and beta-chemokines in controlling HIV replication.

Several members of the cytokine network play an important role in controlling the replication of the human immunodeficiency virus (HIV) in several experimental systems. Their effects can be categorized in the following three functional groups: (1) HIV-inductive cytokines; (2) HIV-suppressive cytokines; (3) cytokines with both activating and inhibiting capacities. Studies on the mechanism of action of these molecules have highlighted the fact that several steps of the retrovirus life cycle, from binding to budding of progeny virions from the infected cell, are affected by cytokines. This general concept has been recently substantiated by the discovery that certain beta-chemokines can act as blockers of viral entry by interfering with HIV co-receptors. Finally, it is important to recognize that cytokines have gone beyond their role as potential pathogenetic or protective endogenous cofactors in HIV replication and disease progression, and are becoming experimental therapeutic agents for HIV disease, best illustrated thus far by the case of interleukin-2.

Chemokines↗
PubMed1997

Expression of monocyte chemotactic protein-3 in human monocytes exposed to the mycobacterial cell wall component lipoarabinomannan.

Monocyte chemotactic protein-3 (MCP-3) is a C-C chemokine which interacts with the CCR1, CCR2 (MCP-1) and CCR3 receptors and has a distinct spectrum of action. The present study was designed to assess whether mycobacterial components were able to induce expression and production of MCP-3 in human monocytes. Mycobacterial lipoarabinomannan (LAM) induced expression of MCP-3 mRNA in human peripheral blood mononuclear cells. The non-mannose-capped version of lipoarabinomannan (AraLAM) was considerably more potent than the mannose-capped version ManLAM or the simpler version phosphatidylinositol mannoside (PLM). Among mononuclear cells, monocytes were responsible for LAM-induced MCP-3 mRNA expression. Whole mycobacteria (Mycobacterium bovis BCG) strongly induced MCP-3 expression. Pretreatment with actinomycin D abolished LAM-induced MCP-3 expression, whereas cycloheximide only partially reduced the expression. LAM-induced MCP-3 expression was associated with the production of immunoreactive PTX3. Interleukin 10 (IL-10) and IL-13 inhibited the induction of MCP-3 by LAM. Thus mycobacterial cell wall components induced expression of MCP-3 in human monocytes. MCP-3, a chemokine active on mononuclear phagocytes, NK cells, T cells and dendritic cells, may be relevant to the induction and expression of immunity against mycobacteria.

C-Reactive Protein↗
PubMed1997

Activation of human immunodeficiency virus long terminal repeat by arachidonic acid.

Arachidonic acid is the precursor of highly reactive mediators, including prostaglandins and leukotrienes, and the most abundant n-6 polyunsaturated fatty acid in mammalian cell membranes. It is released from phospholipids upon many inflammatory stimuli. In this study, a chloramphenicol acyltransferase reporter gene, under control of the human immunodeficiency virus-1 long terminal repeat, was strongly induced upon treating human promonocytes with arachidonic acid. The n-3 fatty acid eicosapentenoic, found in abundance in fish oil, had no effect. HIV-1 long terminal repeat activation by arachidonic acid was suppressed by inhibitors of both lipoxygenase and cyclooxygenase pathways, suggesting that metabolites, rather than arachidonic acid itself, mediated the stimulatory effect. This is the first report linking HIV-1 expression to the metabolism of arachidonic acid.

Analysis of Variance↗