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Biomedical subjects

R B Zurier

Publications and source records attributed to R B Zurier.

At least 19 recordsLinked to original sources
PubMed1998

Dimethylheptyl-THC-11 oic acid: a nonpsychoactive antiinflammatory agent with a cannabinoid template structure.

OBJECTIVE: To assess the antiinflammatory activity of dimethylheptyl-THC-11 oic acid (DMH-11C), a nonpsychoactive synthetic derivative of tetrahydrocannabinol. METHODS: Acute inflammation was induced by injection of interleukin-1beta and tumor necrosis factor alpha into subcutaneous air pouches formed on the backs of mice. Inflammation was quantified 6 hours later by pouch fluid leukocyte counts. Adjuvant-induced polyarthritis in rats was used as a model of chronic inflammation and joint tissue injury. Animals were either untreated, treated with safflower oil, or treated with DMH-11C in safflower oil. Arthritis was assessed by clinical observation and by histomorphologic evaluation of tibiotarsal joints. RESULTS: Oral administration of DMH-11C reduced the accumulation of pouch fluid leukocytes and significantly reduced the severity of adjuvant-induced polyarthritis. Histopathologic studies of tibiotarsal joints showed that DMH-11C treatment attenuated pannus formation and joint tissue injury. CONCLUSION: DMH-11C suppresses acute inflammation in the subcutaneous air pouch in mice and chronic joint inflammation characteristic of adjuvant disease in rats. These results demonstrate the potential use of this nonpsychoactive cannabinoid as an antiinflammatory agent.

3T3 Cells↗
PubMed1997

Oral administration of unsaturated fatty acids: effects on human peripheral blood T lymphocyte proliferation.

Oils enriched in certain polyunsaturated fatty acids suppress joint pain and swelling in rheumatoid arthritis (RA) patients. Because T lymphocyte activation is important to propagation of joint tissue injury in patients with RA, we examined the effects of fatty acids administered by mouth in vivo on proliferation of human lymphocytes activated through the T cell receptor complex. T cell proliferation was reduced after oral administration of 2.4 g gammalinolenic acid in capsules of borage seed oil. Oral administration of oils enriched in linoleic acid, the parent n-6 fatty acid, and alpha linolenic acid, the parent n-3 fatty acid, did not influence growth of stimulated cells. Fatty acid analyses indicated that suppression of lymphocyte proliferation after gammalinolenic acid administration was associated with increased plasma and peripheral blood mononuclear cell concentrations of gammalinolenic acid and dihomogammalinolenic acid.

Administration, Oral↗
PubMed1997

Gammalinolenic acid and dihomogammalinolenic acid suppress the CD3-mediated signal transduction pathway in human T cells.

Gammalinolenic acid (GLA; 18:3n6) and dihomogammalinolenic acid (DGLA; 20:3n6) suppress lymphocyte activation, and GLA administration reduces joint swelling and tenderness in rheumatoid arthritis patients with active synovitis. In an effort to dissect the mechanisms whereby GLA, DGLA, and other fatty acids influence lymphocyte function, we examined their effects on anti-CD3 monoclonal antibody (mAb)-mediated early signaling events in human T cells. Peripheral blood mononuclear cells from healthy individuals were incubated overnight at 37 degrees C with or without 10 microg/ml fatty acid and then loaded with the calcium binding fluorescent dye indo-1. Fatty acids did not affect the efficiency of indo-1 loading, and they did not alter cell surface membrane expression of the CD3 molecule. Anti-CD3 mAb (G19-4)-induced intracellular calcium [(Ca2+)i] changes were monitored by flow cytometry in negatively selected human T cells. The ratio of violet to blue fluorescence, which is proportional to (Ca2+)i, was measured over time. Cells enriched with GLA and DGLA but not cells enriched with eicosapentaenoic acid (20:5n3) displayed a significant reduction in anti-CD3 mAb-induced early and late (Ca2+)i responses. T cells loaded with GLA, DGLA, or medium alone displayed similar increases in (Ca2+)i in response to the endoplasmic reticulum Ca2(+)-ATPase inhibitor thapsigargin. Anti-CD3 mAb-mediated inositol phosphate production was also diminished in GLA- and DGLA-treated cells. These experiments suggest that GLA and DGLA suppress T cell activation by interfering with early events in the signal transduction pathway.

8,11,14-Eicosatrienoic Acid↗
PubMed1997

Effects of unsaturated fatty acids on interleukin-1beta production by human monocytes.

Dihomogammalinolenic acid is derived from gammalinolenic acid, administration of which suppresses joint inflammation. It is reported here that interleukin 1beta (IL-1beta) production by human monocytes is enhanced markedly when cells are incubated 18-24 h with the polyunsaturated fatty acids dihomogammalinolenic acid (DGLA) and arachidonic acid (AA), then stimulated with lipopolysaccharide. Effects of eicosapentaenoic acid (EPA) on IL-1beta production are minimal, and palmitic acid (PA) does not influence IL-1beta production.

8,11,14-Eicosatrienoic Acid↗
PubMed1996

gamma-Linolenic acid treatment of rheumatoid arthritis. A randomized, placebo-controlled trial.

OBJECTIVE: To assess the clinical efficacy and adverse effects of gamma-linolenic acid (GLA), a plant seed oil-derived unsaturated fatty acid that suppresses inflammation and joint tissue injury in animal models, in the treatment of active rheumatoid arthritis (RA). METHODS: Fifty-six patients with active RA were randomized to treatment groups in a 6-month, double-blind trial of GLA versus placebo. This was followed by a 6-month, single-blind trial during which all patients received GLA. Patients were treated with 2.8 gm/day of GLA as the free fatty acid or with sunflower seed oil (placebo) administered in identical capsules. RESULTS: Treatment with GLA for 6 months resulted in statistically significant and clinically relevant reductions in the signs and symptoms of disease activity in patients with RA. Overall meaningful responses (at least 25% improvement in 4 measures) were also better in the GLA treatment group (14 of 22 patients versus 4 of 19 in the placebo group; P = 0.015). During the second 6 months, both groups exhibited improvement in disease activity. Thus, patients taking GLA during the entire study showed progressive improvement during the second 6 months. In this group, 16 of 21 patients showed meaningful improvement at 12 months compared with study entry. CONCLUSION: GLA at doses used in this study is a well-tolerated and effective treatment for active RA. GLA is available as a component of several plant seed oils and is usually taken in far lower doses than were used in this trial. It is not approved in the United States for the treatment of any condition, and should not be viewed as therapy for any disease. Further controlled studies of its in RA are warranted.

Adolescent↗
PubMed1996

Effects of unsaturated fatty acids on expression of early response genes in human T lymphocytes.

Administration of gamma-linolenic acid, which is converted rapidly to dihomo-gamma-linolenic acid (DGLA), reduces joint swelling and tenderness in patients with rheumatoid arthritis. Joint tissue inflammation in patients with rheumatoid arthritis is due in part to activation of T lymphocytes. DGLA suppresses T cell activation and production of interleukin-2 (IL-2). The protooncogenes c-myc and c-fos are early response genes which are critical to regulation of T cell proliferation. We therefore examined the effects of gamma-linolenic acid and other unsaturated fatty acids on c-myc and c-fos expression by means of the polymerase chain reaction and Northern blotting. IL-2 production by the human T cell line Jurkat is dependent on a fall in mRNA for c-myc and a rise in mRNA for c-fos. The data presented here indicate that reduction of steady-state levels of mRNA for c-myc and rises in steady-state levels of mRNA for c-fos are both reduced markedly in cells incubated with DGLA. Cells incubated with arachidonic acid, eicosapentaenoic acid or oleic acid exhibit more modest changes in expression of these early response genes.

8,11,14-Eicosatrienoic Acid↗
PubMed1995

Stimulatory effect of unsaturated fatty acids on the level of plasminogen activator inhibitor-1 mRNA in cultured human endothelial cells.

To determine whether unsaturated fatty acids induce changes in the mRNA level of plasminogen activator inhibitor type-1 (PAI-1), Northern analyses were performed on human umbilical vein endothelial cells (HUVEC) and vascular smooth muscle cells that were treated with two common fatty acids. Supplementation of cultured HUVEC with docosahexanoic acid (DHA) or with dihomogamma linolenic acid (DGLA), resulted in a concentration dependent, specific increase of the PAI-1 transcript levels, which was detectable within 2 h. DHA and DGLA treatment of smooth muscle cells did not result in changes in the PAI-1 mRNA levels. Homology search of the upstream regulatory region of the PAI-1 gene sequences identified a consensus nucleotide sequence for a fatty acid-responsive element. Our results indicate that unsaturated fatty acids selectively increase PAI-1 mRNA levels in endothelial cells, the primary source of circulating PAI-1 in vivo.

Amino Acid Sequence↗
PubMed1995

Differential regulation of human T lymphocyte protein kinase C activity by unsaturated fatty acids.

Administration of gamma-linolenic acid suppresses active synovitis in patients with rheumatoid arthritis. We therefore examined the effects of gamma-linolenic acid and its first metabolite, dihomo-gamma-linolenic acid, on protein kinase C, a key element in transduction of signals from cell surface to nucleus. We report here that gamma-linolenic acid and dihomo-gamma-linolenic acid suppress total protein kinase C activity, but facilitate translocation of protein kinase C activity from cytosol to membrane in human peripheral blood T lymphocytes stimulated with phorbol 12-myristate 13-acetate. Arachidonic acid and eicosapentaenoic acid do not influence total protein kinase C activity and have only modest effects on enzyme translocation. These findings in whole cells are in contrast to results of experiments performed with isolated protein kinase C, in which unsaturated fatty acids uniformly enhance protein kinase C activity. The differential effects of unsaturated fatty acids underscore the complexity of protein kinase C regulation and indicate that gamma-linolenic and dihomo-gamma-linolenic acids influence T lymphocyte protein kinase C metabolism in a manner that is unique among unsaturated fatty acid precursors of eicosanoids.

8,11,14-Eicosatrienoic Acid↗
PubMed1995

Botanical lipids: effects on inflammation, immune responses, and rheumatoid arthritis.

OBJECTIVE: This review discusses the rationale and experimental data that led to clinical trials of certain botanical lipids, mainly gammalinolenic acid (GLA), for the treatment of rheumatoid arthritis (RA). DATA SOURCES: Pertinent articles and reviews, and a bibliographic database in English using the following indexing terms: rheumatoid arthritis, fatty acids, gammalinolenic acid, lymphocytes, and monocytes, were used. STUDY SELECTION: All clinical trials in which GLA was used to treat arthritis are included in this review. Data from appropriately peer reviewed in vitro and animal experiments evaluating the effects of botanical lipids as regulators of cell activation and immune responses are also reviewed. DATA SYNTHESIS: GLA treatment is associated with clinical improvement in patients with RA, as evaluated by duration of morning stiffness, joint pain and swelling, and ability to reduce other medications. However, studies vary in terms of duration, GLA dose, whether or not they were placebo controlled, and, if so, what placebo was used, criteria for evaluation, and use of concomitant medication. Studies done in vitro generally indicated that GLA reduces lymphocyte activation and production of mediators of inflammation. CONCLUSIONS: A small number of studies suggest that GLA is effective treatment for RA patients. Further controlled studies of its use in RA seem warranted.

Animals↗
PubMed1994

Effects of fatty acids on proliferation and activation of human synovial compartment lymphocytes.

The object of this study was to determine the effects of eicosanoid precursor fatty acids on activation and proliferation of T lymphocytes from synovial fluid and synovial tissue of rheumatoid arthritis patients. Proliferation was determined by direct cell counts; phenotypic characterization of surfaces molecules was by cytofluorometric analysis. Dihomogammalinolenic acid, arachidonic acid, and eicosapentaenoic acid suppressed proliferation of interleukin-2-dependent lymphocytes by as much as 80%; cell viability was not altered by fatty acids. Administration of particular fatty acids may prove to be a useful therapeutic intervention in rheumatoid arthritis patients because of their ability to suppress activation and proliferation of synovial compartment T lymphocytes.

Arthritis, Rheumatoid↗
PubMed1994

Suppression of monosodium urate crystal-induced inflammation by black currant seed oil.

The subcutaneous air pouch formed in Sprague-Dawley rats was used to study the effect of diets enriched in black currant seed oil (BCSO) on acute inflammation induced by monosodium urate crystals. The BCSO enriched diet suppressed significantly both the cellular and fluid phases of inflammation (polymorphonuclear leucocyte and exudate accumulation). In contrast, administration of normal chow or of a diet enriched in safflower oil (polyunsaturated fatty acid control) did not influence monosodium urate crystal-induced inflammation in this model. The findings indicate that a diet which provides both n-6 (gammalinolenic acid) and n-3 (alpha-linolenic acid) fatty acids as substrates alternative to arachidonatic acid for oxidative metabolism, modifies monosodium urate crystal-induced acute inflammation.

Administration, Oral↗
PubMed1994

Suppression of acute inflammation with liposome associated prostaglandin E1.

Prostaglandin E1 (PGE1) suppresses leucocyte effector function and reduces inflammation in several animal models of acute and chronic inflammation. A drawback to its use as a therapeutic agent is the relatively high doses needed to suppress inflammation. We present evidence in this report that liposome associated PGE1 (LAP) reduces markedly acute inflammation induced in a subcutaneous air pouch by monosodium urate crystals, and by the polypeptide mediators, interleukin 1-beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha). A single dose of 12 micrograms/kg LAP given intravenously 2 hr after inflammation was induced, reduced accumulation of cells and exudate by 31-49%.

Acute Disease↗
PubMed1994

Treatment of rheumatoid arthritis with blackcurrant seed oil.

The objective of this study was to assess the clinical efficacy and side effects of blackcurrant seed oil (BCSO), in a randomized, double-blind, placebo controlled, 24-week trial in patients with RA and active synovitis. BCSO is rich in gammalinolenic acid (GLA) and alphalinolenic acid (ALA). Both GLA and eicosapentaenoic acid which derives from ALA suppress inflammation and joint tissue injury in animal models. Treatment with BCSO resulted in reduction in signs and symptoms of disease activity in patients with RA (P < 0.05). In contrast, patients given a placebo showed no change in disease. Overall clinical responses (significant change in four measures) were no better in the treatment group than in the placebo group. No patients withdrew from BCSO treatment because of adverse reactions. However, many patients withdrew because BCSO and its placebo had to be administered in 15 large capsules daily. Nonetheless, the study indicates that BCSO is a potentially effective treatment for active RA. However, means must be found to reduce the size and number of capsules taken, so that larger studies of longer duration in RA patients can be done.

Adult↗
PubMed1993

Treatment of rheumatoid arthritis with gammalinolenic acid.

OBJECTIVE: To assess the clinical efficacy and side effects of gammalinolenic acid, a plant-seed-derived essential fatty acid that suppresses inflammation and joint tissue injury in animal models. DESIGN: A randomized, double-blind, placebo-controlled, 24-week trial. SETTING: Rheumatology clinic of a university hospital. PATIENTS: Thirty-seven patients with rheumatoid arthritis and active synovitis. INTERVENTION: Treatment with 1.4 g/d gammalinolenic acid in borage seed oil or cotton seed oil (placebo). MEASUREMENTS: Physicians' and patients' global assessment of disease activity; joint tenderness, joint swelling, morning stiffness, grip strength, and ability to do daily activities. RESULTS: Treatment with gammalinolenic acid resulted in clinically important reduction in the signs and symptoms of disease activity in patients with rheumatoid arthritis (P < 0.05). In contrast, patients given a placebo showed no change or showed worsening of disease. Gammalinolenic acid reduced the number of tender joints by 36%, the tender joint score by 45%, swollen joint count by 28%, and the swollen joint score by 41%, whereas the placebo group did not show significant improvement in any measure. Overall clinical responses (significant change in four measures) were also better in the treatment group (P < 0.05). No patients withdrew from gammalinolenic acid treatment because of adverse reactions. CONCLUSION: Gammalinolenic acid in doses used in this study is a well-tolerated and effective treatment for active rheumatoid arthritis. Gammalinolenic acid is available worldwide as a component of evening primrose and borage seed oils. It is usually taken in far lower doses than used in this trial. It is not approved in the United States for the treatment of any condition and should not be viewed as therapy for any disease. Further controlled studies of its use in rheumatoid arthritis are warranted.

Adult↗
PubMed1993

Fatty acids, inflammation and immune responses.

Evidence obtained from experiments in vitro and in vivo suggests that certain unsaturated fatty acids (FA) may be safe and effective antiinflammatory and immunomodulatory agents. Generation of a unique eicosanoid profile with different biological effects by administration of FA precursors other than arachidonic acid is one approach under investigation. In addition to their role as eicosanoid precursors, FA are of major importance in maintaining cell membrane structure, are key determinants of membrane bound enzyme activity and receptor expression. FA can exert these functions directly and therefore may themselves be important regulators of immune responses. For example, certain FA influence cytokine production and proliferation of human T lymphocytes in a manner that is direct and not due to their conversion to eicosanoids. The observations indicate that FA can modulate immune responses by acting directly on T-cells and suggest that alteration of cellular FA may be a worthwhile approach to control of inflammation.

8,11,14-Eicosatrienoic Acid↗