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Biomedical subjects

A Novogrodsky

Publications and source records attributed to A Novogrodsky.

At least 73 records · Page 4Linked to original sources
PubMed1986

1,25-Dihydroxyvitamin D3 enhances prostaglandin E2 production by monocytes. A mechanism which partially accounts for the antiproliferative effect of 1,25(OH)2D3 on lymphocytes.

Partial removal of monocytes from human peripheral blood mononuclear cells, or the addition of indomethacin, reduced the antiproliferative effect of 1,25(OH)2D3 on mitogen-stimulated mononuclear cells. Addition of 1,25(OH)2D3 (1 nM) to mitogen-stimulated mononuclear cells caused a 2-4-fold increase in prostaglandin E2 production during the second day of culture. The inhibitory effect of 1,25(OH)2D3 on lymphocyte proliferation is greatly augmented up to 7-fold in the presence of prostaglandin E2. We conclude that monocytes are involved in the inhibitory effect of 1,25(OH)2D3 on the mitogenic stimulation of human lymphocytes and that their action is probably mediated by prostaglandins.

Calcitriol↗
PubMed1986

Anti-tumor properties of lymphocytes activated by the oxidizing mitogens.

Human peripheral blood mononuclear cells when activated with the oxidizing mitogens, neuraminidase/galactose oxidase or sodium periodate, express cytolytic activity for freshly isolated tumor cells and for a variety of cell lines, including NK-resistant solid tumor lines. Normal lymphoid cells are not targets for cytotoxicity and do not inhibit lysis of susceptible targets mediated by the oxidizing mitogen-activated mononuclear cells. The cytotoxic response is rapidly generated and reaches peak levels at 48 hr. The oxidizing mitogens induce expression of IL 2 receptors on peripheral blood mononuclear cells. Combined treatment of cells with IL 2 and the oxidizing mitogens results in a marked enhancement of cytotoxicity. Enhancement is achieved at levels of IL 2 that alone result in minimal generation of cytotoxic cells. Growth of a human renal cancer cell line in nude mice was inhibited when the renal cancer cells were injected together with oxidizing mitogen-activated human mononuclear cells. These studies indicate that oxidizing mitogen-activated cells provide a potentially valuable source of material for the adoptive immunotherapy of tumors.

Adjuvants, Immunologic↗
PubMed1986

Growth inhibition of murine melanoma by butyric acid and dimethylsulfoxide.

Treatment of B16-F10 melanoma cells with dimethylsulfoxide (DMSO) or butyric acid (BA) inhibits cell growth and delays tumor appearance in syngeneic mice. Both agents induce morphological changes in these cells. Treatment of melanoma cells with DMSO results in a marked increase in tyrosinase activity and melanin content. BA, on the other hand, does not increase melanin content and decreases tyrosinase activity. The data show that there are marked differences in the effect of DMSO and BA on melanin biosynthesis, whereas both agents inhibit cell growth and cause a delay in tumor appearance. These findings indicate that decreased proliferation of melanoma cells and induction of melanin biosynthesis are not necessarily associated phenomena.

Animals↗
PubMed1986

Early effects of TPA on protein kinase activity in murine thymocytes. Reduction of protein kinase C activity in the cytosol and increase of Ca2+ and phospholipid-independent kinase activity in the particulate fractions.

Brief treatment of intact thymocytes with TPA and other tumor promoters causes a reduction in protein kinase C activity from the cytosol and an increase in kinase activity in the particulate fraction. In contrast to the activity in the cytosol, which is absolutely dependent on the addition of Ca2+, phosphatidylserine and diolein, the activity in the particulate fraction is independent of these agents. Analysis of target specificity of the particulate kinase activity using exogenous and endogenous substrates suggests that the increased phosphorylation in the particulate fraction is catalysed by protein kinase C with altered catalytic properties. Although interleukin-1 and TPA are both co-mitogens for murine thymocytes, interleukin-1 does not share with TPA its property to alter protein kinase activity in the cytosolic and particulate fractions.

Animals↗
PubMed1985

Differential effects of tumor promoters on cAMP production: inhibition of receptor-mediated and potentiation of cholera toxin-mediated stimulation.

Tetradecanoylphorbol-acetate and other tumor promoters inhibit prostaglandin E2 and isoproterenol-induced cAMP accumulation in mouse thymocytes but markedly potentiate cAMP production induced by cholera toxin. Cholera toxin is known to stimulate cAMP production by inducing ADP-ribosylation of the alpha-subunit of a guanine nucleotide-binding regulatory (G) protein, resulting in activation of the catalytic unit of adenylate cyclase. G proteins have been implicated as plasma membrane transducers for a variety of additional signals. It is possible that the growth promoting and co-mitogenic properties of tumor promoters are related to their effects on G proteins.

Animals↗
PubMed1985

Selective effects of TPA and IL-1 on protein phosphorylation in murine thymocytes.

Protein kinase C activity was demonstrated in murine thymocytes and the effects of TPA and IL-1 on this enzyme were studied. TPA, but not IL-1, could substitute for diacylglycerol in protein kinase C activation. Although TPA and IL-1 are both potent comitogens for murine thymocytes they markedly differ in their effects on protein phosphorylation and protein kinase C activation. Treatment of intact thymocytes with TPA resulted in a marked increase in the phosphorylation of an endogenous protein with Mr approximately 44,000. Enhanced phosphorylation of this protein was also observed when protein kinase C was activated in thymocyte extracts. In contrast to TPA, IL-1 neither induced phosphorylation of the 44,000-Da protein nor activated protein kinase C. The data suggests that protein kinase C does not mediate the comitogenic effect of IL-1 in murine thymocytes.

Animals↗
PubMed1985

12-O-Tetradecanoylphorbol-13-acetate enhances glycolysis in rat thymocytes.

The potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) induced a rapid increase in glycolysis in rat thymocytes. The increase in the glycolytic flux was also reflected by elevated fructose 1,6-diphosphate levels. TPA treatment did not result in an increase of hexokinase, phosphofructokinase or pyruvate kinase when measured in cell homogenates. It is suggested that the early increase in glycolysis in TPA treated lymphocytes may result from TPA-mediated increase in glucose transport.

Animals↗
PubMed1985

Dimethylthiourea inhibition of melanoma cell growth in vitro and in vivo.

The effect of dimethylthiourea (DMTU), an agent known as a hydroxyl radical scavenger, was determined on growth and differentiation of the B16 murine melanoma cell line. DMTU inhibited melanoma cell growth in vitro and induced changes in the morphology of melanoma cells. Prolonged treatment of cells with DMTU resulted in an increase in melanin content. DMTU-treated melanoma cells had a decreased capacity to form tumors in syngeneic mice. Systemic administration of DMT to C57BL/6J mice inoculated with melanoma cells resulted in a delay in tumor appearance and a prolongation of survival. The doses of DMTU used did not cause any apparent toxic effects. A potential therapeutic role for DMTU in the treatment of melanoma is suggested.

Animals↗
PubMed1985

Defective binding and function of 1,25-dihydroxyvitamin D3 receptors in peripheral mononuclear cells of patients with end-organ resistance to 1,25-dihydroxyvitamin D.

Lectin-induced DNA synthesis by peripheral mononuclear cells from 17 normal donors was inhibited (40-60%) by 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) at physiological concentrations (10(-10)-10(-9) M). The lymphocytes acquire specific receptors for 1,25(OH)2D3 upon activation by the lectins. This process precedes the inhibitory effect of 1,25(OH)2D3. We studied lymphocytes from six patients from four different kindreds with the syndrome of hereditary end-organ resistance to 1,25(OH)2D (the so-called vitamin D-dependent rickets type II). In five patients (three kindreds) peripheral blood mononuclear cells did not acquire receptors for 1,25(OH)2D3 upon phytohemagglutinin-induced activation. Moreover, in contrast to normal lymphocytes, the mitogenic stimulation of these patients' lymphocytes by phytohemagglutinin and concanavalin A was not inhibited by 1,25(OH)2D3. Activated lymphocytes of the sixth patient from a fourth kindred exhibited normal binding of [3H]1,25(OH)2D3 but the hormone failed to inhibit the mitogenic stimulation. A similar pattern of the vitamin D effector system was previously observed in fibroblasts cultured from skin biopsies of the same group of patients. The conclusions from these findings are: (a) the inhibition of mitogenic stimulation by 1,25(OH)2D3 is mediated by specific functional receptors to the hormone; and (b) the receptors for 1,25(OH)2D3 in mononuclear cells are probably controlled genetically by the same mechanisms as the effector system in well-characterized target organs of the hormone, such as intestine and kidney.

Adolescent↗
PubMed1985

Human B lymphoblastoid cell lines provide an interleukin 1-like signal for mitogen-treated T lymphocytes via direct cell contact.

The B lymphoblastoid cell lines (B-LCL) 8392, SB, 1788, and Daudi provide accessory cell activity for mitogen-treated T cells, whereas the T lines MOLT-4, 8402, CEM, and HSB do not provide this function. Direct cell contact is required for the accessory cell activity, and active lymphocyte growth factors could not be detected in the supernatants of the B-LCL. The B-LCL also present alloantigens to responding T cells, and this response is independent of additional accessory cells. The target for the B-LCL is the responding T cell itself, rather than a minor contaminating population of endogenous accessory cells. This conclusion is based on the finding that, under culture conditions in which T cells do not proliferate in response to PHA, accessory cell activity of the B-LCL is maintained. Paraformaldehyde- or glutaraldehyde-treated B-LCL retain their accessory cell activity at levels of these agents that completely eliminate metabolic activity of the B-LCL, as determined by incorporation of leucine, thymidine, and uridine into macromolecules. This treatment eliminates alloantigen presentation by the B-LCL. T cells treated with IO-4 or with monoclonal anti-T3 antibodies fail to respond to highly purified IL 1, and respond minimally to supra-optimal concentrations of IL 2. Nevertheless, these cells respond maximally to the accessory cell activity of the B-LCL. The IO-4 treated cells or cells exposed to anti-T3 also proliferate in response to TPA. Together, our data suggest that the B-LCL provide an IL 1-like signal for mitogen-treated T cells via direct cell contact, in the absence of detectable soluble IL 1.

Antigen-Presenting Cells↗
PubMed1985

Inhibition of pokeweed mitogen-induced B cell differentiation by compounds containing primary amine or hydrazine groups.

The present study examined the effect of two drugs, which contain either an aromatic amine or hydrazine moiety and are known to induce lupus like syndromes in man (procainamide and hydralazine) and an aliphatic amine (dansylcadaverine), on pokeweed mitogen (PWM)-induced B cell production of immunoglobulin G (IgG). These compounds all inhibited IgG production and generation of IgG plaque forming cells, whereas derivatives of them, without free amine groups, had little or no effect. The compounds inhibited differentiation of B cells to plasma cells, rather than production and secretion of IgG. Mitogen free culture supernatants of peripheral blood mononuclear cells (PBM) activated by the oxidizing mitogen, neuraminidase and galactose oxidase (NAGO), prevented the inhibition of B cell maturation. Moreover, incubation of NAGO treated PBM with hydralazine prevented the production of soluble factors capable of promoting B cell maturation in the presence of hydralazine. We conclude from these studies that procainamide, hydralazine and dansylcadaverine inhibit PWM-induced B cell maturation to plasma cells by an indirect mechanism, via inhibition of production of lymphokines by helper cells. The primary amine or hydrazine group appears to be required for the inhibitory effect, since analogues of the inhibitory compounds, without primary amine groups, are non-inhibitory.

Adult↗
PubMed1984

1,25-Dihydroxyvitamin D3 inhibits selectively the mitogenic stimulation of mouse medullary thymocytes.

Mouse thymocytes were separated into cortical and medullary subpopulations by differential agglutination with peanut agglutinin. A high-affinity receptor for 1,25-dihydroxyvitamin D3 is present in medullary immunocompetent mouse thymocytes and is absent from cortical immature cells. 1,25-dihydroxyvitamin D3, at physiological concentrations, inhibits the mitogenic response of the medullary cells to phytohemagglutinin and interleukin-2, but has no effect on the cortical subpopulation. Other less active metabolites of vitamin D had little or no effect on medullary cell stimulation.

Animals↗
PubMed1984

Mitogenic and comitogenic properties of the indole alkaloid class of tumor promotors.

We determined the mitogenic and comitogenic properties of tumor promoters in the indole alkaloid series; agents that differ structurally from 12-0-tetradecanoylphorbol-13-acetate (TPA), which is known to be a lymphocyte mitogen. Teleocidin and dihydroteleocidin B were mitogenic for human lymphocytes, and lyngbyatoxin A elicited little or no mitogenesis. Catalase enhanced the mitogenicity of teleocidin and dihydroteleocidin B, and lyngbyatoxin A was also mitogenic in the presence of catalase. The potency of the agents was TPA = teleocidin greater than dihydroteleocidin B greater than lyngbyatoxin A. Dimethylsulfoxide and butyric acid markedly inhibited proliferation induced by these agents in human lymphocytes. The indole alkaloid tumor promoters were all comitogenic for murine thymocytes and induced production of interleukin-2. While the comitogenic effect of teleocidin was similar to that of TPA in its susceptibility to inhibition by dimethylsulfoxide and butyric acid, the comitogenic effect of dihydroteleocidin B and lyngbyatoxin A were less susceptible to these agents. These findings may facilitate the identification of cellular sites responsible for the inhibitory effect of differentiating agents on proliferative responses of lymphocytes.

Alkaloids↗
PubMed1984

The Na+-ionophore monensin enhances glucose uptake in mouse thymocytes.

Monensin enhanced 2-deoxyglucose uptake and 3-O-methyl glucose transport in mouse thymocytes, but had no effect on L-glucose transport. Cytochalasin B inhibited monensin induced as well as basal glucose uptake. The enhanced 2-deoxyglucose uptake was time and dose-dependent. The increase in the rate of 2-deoxyglucose uptake induced by monensin was more rapid than that of Na+ uptake. Ouabain did not inhibit monensin-enhanced 2-deoxyglucose uptake. Monensin failed to stimulate 2-deoxyglucose uptake at low concentrations of Na+ (13 mM) or K+ (17 mM), higher concentrations of either cation were required for stimulation. Monensin enhanced glucose uptake also in Ca2+-free medium. The data indicate that the stimulation of 2-deoxyglucose uptake by monensin results from activation of carrier-mediated transport.

Animals↗
PubMed1984

Inhibition of 6-phosphogluconate dehydrogenase by glucose 1,6-diphosphate in human normal and malignant colon extracts.

Increased activity of 6-phosphogluconate dehydrogenase was found in human colon tumors as compared to the adjacent unaffected mucosa. Glucose 1,6-diphosphate (Glc-1,6-P2), an endogenous potent regulator of glucose metabolism, markedly inhibited the activity of 6-phosphogluconate dehydrogenase (6-PGD) in extracts of the normal and malignant human colon. Glc-1,6-P2 also inhibited the activity of hexokinase in these extracts. The endogenous levels of Glc-1,6-P2 in the colon and tumors were measured. Since the pentose cycle can be inhibited by Glc-1,6-P2, means to increase endogenous levels of Glc-1,6-P2 or to introduce it into cells, might result in antitumor effects.

Colonic Neoplasms↗
PubMed1984

Mitogenic properties of neuraminidase and galactose oxidase-treated lymphoblastoid cells and plasma membranes for peripheral blood lymphocytes.

Generation of aldehydes on terminal D-galactose or N-acetyl-D-galactosamine residues of cell surface glycoproteins by treatment with neuraminidase and galactose oxidase (NAGO) renders some types of cells mitogenic for T lymphocytes. The cell surface molecules required for the presentation of mitogenic signals by NAGO-treated cells are unknown. We tested the mitogenic properties of NAGO-treated lymphoblastoid cell lines (LCL) and subcellular fractions as an initial step in the isolation and characterization of cell surface molecules required for stimulation. We report here that the NAGO-LCL of B cell lineage were potent stimulators, whereas the NAGO-LCL of T cell lineage were weaker and more variable stimulators of lymphocyte proliferation. T-LCL that were stimulatory in indirect stimulation did not induce a mixed lymphocyte response, whereas the B-LCL were positive in both assays. Aldehyde-bearing plasma membrane-enriched subcellular fractions, depleted of nuclear, cytosolic, and mitochondrial components, were mitogenic, and the stimulatory activity was dose dependent. The ability to induce mitogenesis was abrogated by reduction of cell surface aldehyde groups. The results indicate that lymphocyte activation, induced by NAGO-treated stimulatory cells, is a plasma membrane-associated event and does not require the metabolic activity of intact cells. Furthermore, the aldehyde moiety is required but not sufficient for presentation of mitogenic signals. The LCL provide a suitable and reproducible source for isolation and characterization of stimulatory cell surface structures.

Aldehydes↗