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S Specter

Publications and source records attributed to S Specter.

At least 37 records · Page 2Linked to original sources
PubMed1996

Anti-retroviral activity of methionine enkephalin and AZT in a murine cell culture.

Previously, this laboratory has demonstrated that azidothymidine used in combination with methionine enkephalin, an opioid pentapeptide, was more effective than AZT alone in inhibiting disease progression due to murine retrovirus infections. In order to study the mechanism(s) by which Met-ENK mediates-antiviral effects, when used in combination with AZT in Friend leukemia virus infected mice, an in vitro focus forming assay was used. AZT at 1 ng/ml inhibited FLV replication by 30-50% in the susceptible Mus dunni cell line. By contrast, the immunostimulatory neuropeptide, Met-ENK, displayed no direct inhibition of viral replication. This suggests that Met-ENK does not have any direct anti-retroviral activity. Subsequent testing of Met-ENK in the presence of AZT showed no ability of this peptide to promote inhibition of viral replication due to AZT. By contrast, in the presence of mouse spleen cells, as a source of lymphocytes, in vitro combination treatments using AZT and Met-ENK reduced FLV replication by 67%, compared to 47% using AZT alone. The inhibition due to Met-ENK was abrogated when spleen cells were pretreated with naloxone, an opioid antagonist. Therefore, we conclude that Met-ENK effects are mediated via opioid receptors on spleen cells and that the observed anti-FLV activity is dependent on the use of Met-ENK stimulated spleen cells in combination with AZT.

Animals↗
PubMed1996

Dynamic production of tumour necrosis factor-alpha (TNF-alpha) messenger RNA, intracellular and extracellular TNF-alpha by murine macrophages and possible association with protein tyrosine phosphorylation of STAT1 alpha and ERK2 as an early signal.

Tumour necrosis factor-alpha (TNF-alpha), an important mediator in both immune and inflammation responses, is one of the major cytokines released by activated macrophages. The present study shows that, during macrophage activation, protein tyrosine phosphorylation of STAT1 alpha and ERK2 occurred as an immediate early signal, whereas maximum TNF-alpha mRNA transcription appeared at 3 hr, precursor TNF-alpha formation at 3 to 4 hr, and TNF-alpha release at 5 to 6 hr after stimulation of an RPMI-1640-based induction medium containing lipopolysaccharide (100 ng/ml), interferon-gamma (100 U/ml), and 0.5% bovine serum albumin. Herbimycin A, a tyrosine kinase inhibitor, suppresses protein tyrosine phosphorylation of STAT1 alpha and ERK2 and also blocks TNF-alpha production by resident peritoneal macrophages from BALB/c mice, suggesting a possible association between protein tyrosine phosphorylation of STAT1 alpha and ERK2 and macrophage activation resulting in TNF-alpha production.

Animals↗
PubMed1996

The role of interferon-gamma in antiretroviral activity of methionine enkephalin and AZT in a murine cell culture.

The ability of spleen cells treated with methionine enkephalin (Met-ENK) in the presence of 3'-azido-3'-deoxythymidine (AZT) to produce cytokines and inhibit Friend leukemia virus (FLV) replication in Mus dunni cell cultures was investigated. In the presence of murine spleen cells, combination treatments using AZT plus Met-ENK or concanavalin A reduced FLV replication by 63% and 84%, respectively, as compared with 47% for AZT alone. When interleukin (IL)-2, IL-4 and interferon (IFN gamma) levels were measured in FLV-infected cell cultures, both AZT and Met-ENK treatments induced a higher production of IFN gamma and a slight increase in IL-2 and IL-4, as compared with either treatment alone. Subsequent treatment of FLV-infected cells with concanavalin A-stimulated cell supernatants, containing approximately 10 U/ml each of IFN gamma and IL-2, resulted in inhibition of viral replication. Thus, in the absence of spleen cells, IFN gamma was added to cell cultures to determine whether this cytokine contributed to combination antiviral effects. Results show that addition of IFN gamma alone results in a slight suppression of FLV expression, whereas treatment with both AZT and IFN gamma inhibits FLV replication significantly. Subsequently, addition of anti-IFN gamma antibody to cell cultures treated with Met-ENK blocked antiviral effects due to this neuropeptide. Thus anti-FLV effects of spleen cells treated with Met-ENK in combination with AZT are mediated to a large degree by IFN gamma.

Animals↗
PubMed1995

[In vitro synergic lymphocyte stimulation in HIV-1 infected patients using inosine derivatives and radio-detoxified endotoxin].

Restoration of immune functions through promoting cell cycle might delay acquired immunodeficiency syndrome development. Therefore, stimulation of peripheral lymphocytes of human immunodeficiency virus-1 infected patients in successive clinical stages was studied by phytohaemagglutinin and other stimulants. In vitro blastogenesis was quantitated by 3H-thymidine uptake. Stimulation by phytohaemagglutinin decreased in patients with AIDS related complex to 63.1%, with AIDS to 13.6% of control values. Small amount of recombinant interleukin-2 or indomethacin solely not promoting lymphocytes, increased response to phytohaemagglutinin minimally. Alone ineffective methyl-ester and methyl-phosphonate inosine derivatives augmented phytohaemagglutinin-response of controls and patients with AIDS related complex by approx. 1.5-fold, but the effect in the case of AIDS patients was minimal. Radio-detoxified endotoxin alone or in combination with phytohaemagglutinin stimulated lymphocytes of both controls and patients with AIDS related complex slightly. Lymphocyte stimulation of patients with AIDS related complex was augmented in concentration-dependent manner, and by synergic effect it approached phytohaemagglutinin-stimulated blastogenesis of controls. Anergy due to human immunodeficiency virus-1 infection damages synchronisation of secondary messenger systems induced on cell surface receptors, therefore their selective influence by recombinant interleukin-2 or indomethacin is less efficient. Inosine derivatives promote cell cycle by inhibiting cyclic adenosine 3',5'-monophosphate production. In the early stage of virus infection, radio-detoxified endotoxin might bind to receptors of immature T cells and facilitate cell cycle through cyclic guanosine 3',5'-monophosphate stimulation. The clinical trials of radio-detoxified endotoxin (Tolerin) have already been launched.

AIDS-Related Complex↗
PubMed1995

Enterovirus 71 isolated from China is serologically similar to the prototype E71 BrCr strain but differs in the 5'-noncoding region.

Enterovirus 71 H (E71 H), an isolate from an adult patient with hand-food-mouth disease (HFMD) in China, was serologically similar to the prototype strain E71 BrCr, which was isolated from a patient with aseptic meningitis. The study further analyzed the similarity of E71 H to E71 BrCr at the 5'-noncoding region (NCR), a location in genomic RNA that recently was found to be related to neurovirulence in poliovirus and Venezuelan equine encephalitis virus. Using a reverse transcription-polymerase chain reaction (RT-PCR) technique and a unique primer pair I, a 397 bp product was detected from E71 BrCr, Cox A9 (Griggs), Cox A16 (NIH), Cox B1 (HA antigen 201-468), Cox B5 (wild type), and ECHO 11 (Gregory), but not from E71 H, Cox A24 (Joseph), and ECHO 5 (Noyce). However, all of the viruses generated a 154 bp product using a universal enterovirus primer pair II. Further comparative analysis using primer-directed sequencing of both the E71 H and E71 BrCr 154 bp products revealed that they differed by 12 bases. The variations between the two viruses were clustered in two loci, one in the region of nucleotides 43-61 with eight variations, and the other in the region of nucleotides 120-133 with three variations. The differences within the 5'-NCR between the E71 H (HFMD) and the E71 BrCr (aseptic meningitis) viruses might provide a clue to explain why E71 was associated with two different clinical patterns: polio-like disease in the United States. Australia, and Eastern Europe, HFMD in China, Japan, and Singapore.

Adult↗
PubMed1994

Suppression by delta-9-tetrahydrocannabinol of lipopolysaccharide-induced and intrinsic tyrosine phosphorylation and protein expression in mouse peritoneal macrophages.

Lipopolysaccharide (LPS, 100 ng/mL)-induced tyrosine phosphorylation of four proteins (p41, p42, p77, and p82) in mouse resident peritoneal macrophages was observed using a monoclonal anti-phosphotyrosine antibody PY20 immunoblotting method. Macrophages pretreated for 3 hr with 1 microgram delta-9-tetrahydrocannabinol (THC)/mL had decreased tyrosine phosphorylation of p77 and p82 after incubation with LPS for 30 min. Simultaneous treatment of macrophages with THC (10 micrograms/mL) plus LPS for 30 min had a similar effect on p77 and p82 tyrosine phosphorylation. When the THC pretreatment protocol was combined with the simultaneous treatment protocol, 0.5 and 5 micrograms THC/mL, respectively, completely blocked LPS-induced p77 and p82 tyrosine phosphorylation. However, neither simultaneous treatment with THC nor pre- and simultaneous treatment had any effect on LPS-induced tyrosine phosphorylation of p41 and p42 in macrophages. Pretreatment with 1 microgram THC/mL followed by simultaneous treatment with 10 micrograms THC/mL induced a p43 protein that showed tyrosine phosphorylation in place of p41 and p42. Further analysis of THC effects on macrophages revealed an increase in tyrosine phosphorylation as an immediate early even after THC treatment. Prolonged treatment of macrophages with THC resulted in a broad suppression of tyrosine phosphorylation and some cellular protein expression. Three cellular proteins (p65, p70, and p72) seemed most susceptible to inhibition by THC. The data suggest that suppression of tyrosine phosphorylation by THC in macrophages may be one of the mechanisms associated with inhibition of cell function, including the suppression of tumor necrosis factor-alpha release from macrophages.

Animals↗
PubMed1994

Methionine enkephalin combined with AZT therapy reduce murine retrovirus-induced disease.

AZT (7.5 or 15 mg/kg/dose) and the neuropeptide methionine enkephalin (Met-ENK, 1 or 3 mg/kg/dose) were used in a combined protocol for therapy of established murine retroviral infection. In both models used, Friend virus leukemia (FV) and BM5 complex (lymphadenopathy and immune deficiency), the drug combination was able to reduce mortality and splenomegaly. While increasing mean survival time of those animals that did not survive infection by FV, when compared to infected control mice or mice treated with AZT alone, Met-ENK used alone at 1 and 3 mg/kg/mouse had no effect in reducing morbidity or mortality due to either virus. This suggested that Met-ENK had no direct antiviral effect at the concentrations used. In fact, mice treated with either single drug therapy or the combination still yielded virus in their spleen, even when splenomegaly was absent. The data suggest that Met-ENK, which has been reported to be immunostimulatory, acts in combination to improve the efficacy of AZT in reducing progression of disease in murine retrovirus models for human AIDS.

Animals↗
PubMed1994

Delta-9-tetrahydrocannabinol treatment results in a suppression of interleukin-2-induced cellular activities in human and murine lymphocytes.

Delta-9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana, has been shown to suppress a variety of interleukin-2-(IL-2)-dependent cellular functions in both murine and human lymphocytes. These effects were examined in both human peripheral blood lymphocytes (hPBL) and the IL-2-dependent murine cytotoxic T-cell line CTLL-2. Interleukin-2-induced thymidine uptake and uridine uptake were suppressed in a dose related manner when cells were co-incubated for 48 h with 100 U rhIL-2/ml and 1-10 micrograms THC/ml. Interleukin-2-induced protein synthesis was also suppressed in a dose related manner over this THC concentration range, with the hPBL being more susceptible to the suppressive effect of THC than the CTLL-2 cells. Autoradiographic analysis of the synthesized proteins from hPBL cell lysates reveals a generalized suppression of all nascent proteins in THC-treated cultures. Human natural killer cell activity is only affected at the highest concentration tested (10 micrograms THC/ml) while lymphokine-(IL-2)-activated natural killer cell activity is affected throughout the range of 1-10 micrograms THC/ml. Together these results suggest that THC interferes with the IL-2:IL-2 receptor signaling cascade at one or possibly many points causing a decrease in IL-2-induced metabolic activity and cytolytic function.

Animals↗
PubMed1994

Drugs of abuse and infectious diseases.

The association of increased severity of infectious diseases and recreational drug abuse can be traced to the last century with the finding that alcoholics often suffered more severely from bacterial pneumonia than nonalcoholics. More recently there have been numerous associations with use of opiate and other psychogenic drugs and increased incidence and severity of a variety of infectious diseases including the human immunodeficiency virus and development of AIDS. In fact, the AIDS epidemic has heightened awareness of the importance of abused drugs as cofactors in disease precipitation and severity. Evidence is examined for the role of opiates, marijuana, and alcohol as substances that promote infectious diseases.

Acquired Immunodeficiency Syndrome↗
PubMed1994

The effect of delta-9-tetrahydrocannabinol on arachidonic acid metabolism in human peripheral blood mononuclear cells.

Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, is known to inhibit a variety of immune functions. However, the mechanisms of action of THC-induced immunosuppression are unclear. Because THC is known to affect arachidonic acid metabolism in non-lymphoid cells and because arachidonic acid metabolites are important regulators of the immune response, a detailed examination of the effects of THC on arachidonic acid metabolism in human peripheral blood mononuclear cells (PBMC) was performed. THC increased the amount of label released from PBMC prelabeled with [3H]-arachidonic acid. Further studies were performed using RP-HPLC to determine whether the increase in label release from cell membranes was due to the release of free [3H]-arachidonic acid or metabolites. Our results indicated that THC increases the production of the eicosanoid 12-HETE from PBMC. To determine whether other metabolites, such as the leukotrienes, were also affected by THC, leukotriene B4 (LTB4) was measured by enzyme immunoassay. THC was shown to increase markedly the production of LTB4 from PBMC stimulated with the calcium ionophore A23187. These results indicate that THC alters arachidonic acid metabolism in lymphocytes by increasing the production of lipoxygenase products.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1993

Suppression of lymphocyte adenosine 3':5'-cyclic monophosphate (cAMP) by delta-9-tetrahydrocannabinol.

Delta-9-tetrahydrocannabinol (THC) is the major psychoactive component of marijuana. Suppression of mitogen-stimulated blastogenesis of human lymphocytes in vitro by THC was previously demonstrated. This effect was shown to be concentration dependent with the non-toxic concentrations 5, 7.5, and 10 micrograms THC/ml showing the greatest suppression. However, the mechanism(s) by which THC induces suppression are still unclear. The current study examines the effect of THC on the adenosine 3':5'-cyclic monophosphate (cAMP) pathway second messenger system, which is involved in activation of human peripheral blood lymphocytes. Lymphocyte cAMP levels were stimulated using three hormone receptor stimulators, isoproterenol, histamine, or 5'-N-ethylcarboxamide adenosine (NECA), each of which utilizes a different receptor to enhance cAMP production. THC suppressed cAMP levels independently of the hormone and receptor utilized. Levels of cAMP in non-mitogen-stimulated peripheral blood mononuclear cells and plastic non-adherent lymphocytes, as well as cells stimulated with phytohemmagglutinin, were suppressed by THC. Suppression of cAMP production by THC was further examined to determine whether inhibition involved a GTP-binding protein (Gi), which is known to down-regulate cAMP production. Cells were pre-treated with pertussis toxin to inhibit Gi activity; this blocked the THC-induced suppression of cAMP production. These results suggest that THC can exert its effects on second messenger systems at the lymphocyte membrane level, and that a pertussis toxin-sensitive Gi protein may be involved. Thus, second messenger regulated pathways may be involved in THC-induced immune suppression. However, the relationship between alteration of cAMP production and suppression of lymphocyte function due to the presence of THC in the medium remains to be established.

Adult↗
PubMed1993

Delta-9-tetrahydrocannabinol-(THC)-mediated inhibition of macrophage macromolecular metabolism is antagonized by human serum proteins and by cell surface proteins.

Our previous study demonstrated THC-inhibited DNA synthesis and the phagocytic activity of P388D1 cells [Tang, Lancz, Specter & Bullock (1992) Int. J. Immunopharmac., 14, 253-262]. The ability of proteins in human and bovine sera and of constitutive cellular proteins to modulate the biologic activity of THC was investigated. Both human and fetal bovine sera antagonized a THC-mediated inhibition of P388D1 cell DNA synthesis in a dose-dependent manner. This antagonism was proportional to the protein concentration present in the medium. Both albumin and gamma-globulins influenced THC's inhibitory effects, although they were less potent alpha/beta serum lipoproteins. Exclusion of fatty acid moieties from the albumin did not diminish its ability to antagonize THC. Tritium-labeled THC was acid precipitable only after incubation with bovine or human serum albumin but not DNA, suggesting a physical interaction between the cannabinoid and the protein. Further studies showed that pre-treating cells with trypsin to remove surface proteins significantly enhanced the inhibitory activity of sub-toxic concentrations of THC. Thus, the data indicate that the magnitude of THC's biological effects is determined by the presence and concentration of soluble proteins in the microenvironment and by constitutive proteins present on the cell surface.

Animals↗
PubMed1993

Lipopolysaccharide restores anti-Candida albicans growth inhibition activity of polymorphonuclear neutrophils from retrovirus-immunosuppressed mice.

It has been documented that the immune function of leukocytes may be markedly suppressed after infection of mice with the murine retrovirus Friend leukemia virus (FLV). Antimicrobial activity of polymorphonuclear neutrophils (PMNs) against Candida albicans is impaired after retrovirus infection of mice, and this occurs as early as 3 days after infection of genetically susceptible BALB/c mice. By 2 weeks after infection, there was essentially very little growth inhibition of C. albicans by PMNs from the FLV-infected mice. However, when bacterial lipopolysaccharide (LPS), a known activator of macrophages and PMNs, was added to PMNs from the FLV-infected mice, anti-C. albicans activity was restored to normal levels. This restoration of anti-C. albicans activity of FLV-infected mouse PMNs was observed after stimulation with as little as 0.01 micrograms of LPS per ml. The data obtained show that the impaired antimicrobial function of PMNs from retrovirus-infected mice can be readily restored by a biological response modifier such as bacterial LPS.

Animals↗