Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This laboratory has previously shown that interleukin-1 (IL-1), a putative intermediary in the ovulatory process, is capable of up-regulating PG biosynthesis by cultured whole ovarian dispersates from immature rats. In part, this phenomenon was attributable to the stimulation of ovarian phospholipase A2 activity. In this communication we examine the possibility that the PG-promoting property of IL-1 is also due to the up-regulation of PG endoperoxide synthase (PGS), the rate-limiting step in prostanoid biosynthesis. The in vivo expression of ovarian PGS-2 transcripts in the course of a simulated estrous cycle rose abruptly to a peak (35-fold increase over the control value; P < 0.05) 8-12 h after hCG administration (i.e. before or during projected ovulation). PGS-1 transcripts, in turn, were not significantly altered during the periovulatory period. Treatment of cultured whole ovarian dispersates with IL-1beta resulted in dose- and time-dependent up-regulation of PGS-2 transcripts (as well as of immunoreactive PGS-2 protein and PGE2 accumulation), characterized by an ED50 of 2 ng/ml and a maximal (72-fold) increase at 10 ng/ml. Although treatment with IL-1beta also led to an increase in PGS-1 transcripts and immunoreactive PGS-1 protein, the relative magnitude of the effect was markedly reduced compared with that of PGS-2. Cotreatment with an IL-1 receptor antagonist completely reversed the IL-1 effects, thereby suggesting mediation via the IL-1 receptor. The ability of IL-1 to up-regulate PGS-2 transcripts proved relatively specific, in that other cellular regulators (insulin-like growth factor I, activin A, endothelin-1, transforming growth factor-alpha, tumor necrosis factor-alpha, vascular endothelial growth factor, leukemia inhibitor factor, hepatocyte growth factor, or keratinocyte growth factor) were not effective. The optimal IL-1 effect required heterologous contact-dependent coculturing of granulosa and thecal-interstitial cells. Taken together, these observations 1) reaffirm (by molecular probing) the granulosa cell as the primary site of ovarian PGS-1 and PGS-2 expression, 2) document an increase in ovarian PGS-2 transcripts before ovulation, and 3) reveal a marked dependence of ovarian PGS (2 >> 1) transcripts, proteins, and activity on IL-1. The effects of IL-1 proved relatively specific, contingent upon somatic cell-cell cooperation, dose and time dependent, and IL-1 receptor mediated. These results are compatible with the proposition that the PG-promoting property of IL-1 is due, in large measure, to the activation of ovarian PGS transcription and translation. The ability of IL-1 to up-regulate ovarian PGS, an obligatory component of ovulation, is in keeping with the idea that IL-1 may constitute an intermediary in the ovulatory process.
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PMID:Rat ovarian prostaglandin endoperoxide synthase-1 and -2: periovulatory expression of granulosa cell-based interleukin-1-dependent enzymes. 956 64

Tumour necrosis factor alpha (TNF-alpha) inflammatory activity is mediated, at least in part, by prostaglandin E(2)(PGE(2)). In osteoarthritis (OA), other cytokines are believed to play a role by interacting with TNF-alpha. Using OA synovial fibroblasts, we investigated the effects of interleukin 8 (IL-8), leukaemia inhibitory factor (LIF) and IL-11 on the level of TNF-alpha-induced PGE(2), and their impact on the TNF-alpha-induced cellular signalling cascades including the TNF-receptor (TNF-R), soluble TNF-R (TNF-sR), cytoplasmic phospholipase A2 (cPLA2), cyclooxygenase 2 (COX-2), and the transcription factors NF-kappaB, C/EBP, CREB and AP-1.IL-8 increased in a synergistic manner (282% at 5 ng/ml) and LIF in an additive fashion (69% at 50 ng/ml) the TNF-alpha-induced PGE(2)release, while IL-11 reduced it (52% at 5 ng/ml). IL-8 (5 ng/ml) and LIF (50 ng/ml) alone upregulated (30%) the TNF-R binding level, but significantly downregulated the TNF-alpha-induced levels (P<0.007 and P<0.004, respectively) and the TNF-sR55 level. In contrast, IL-11 reduced the basal level by 18% (P<0.005) and the TNF-alpha-induced level of TNF-R by 51% (P<0.01) as well as decreasing both TNF-sR55 and TNF-sR75. The COX-2 synthesis level was increased by IL-8 and LIF under TNF-alpha treatment but downregulated by IL-11. IL-8 and LIF either alone or under TNF-alpha treatment increased the cPLA2 synthesis, while IL-11 decreased the level under both conditions. Interestingly, IL-8 induced in a synergistic manner and LIF in an additive fashion, the level of cPLA2 activity. IL-8 and LIF had no effect on the TNF-alpha-induced NF-kappaB accumulation, while IL-11 significantly decreased it (P<0. 02). All three cytokines inhibited TNF-alpha-induced C/EBP, but no true effect was noted for AP-1 and CREB in the presence of TNF-alpha. These results indicate that IL-8 synergizes and LIF potentiates the TNF-alpha PGE(2)effect which appears to be mediated mostly by increasing cPLA2 activity level. On the other hand, IL-11 alone had no effect on the PGE(2)release, but in conjunction with TNF-alpha, this cytokine showed anti-inflammatory properties. This study provides a rational foundation to develop therapeutic strategies for the treatment of OA by shedding light on the mechanisms of action of three prominent cytokines at work in articular joint tissues.
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PMID:Differential effects of IL-8, LIF (pro-inflammatory) and IL-11 (anti-inflammatory) on TNF-alpha-induced PGE(2)release and on signalling pathways in human OA synovial fibroblasts. 1062 27

Cellular entry of human T-cell leukaemia virus type 1 (HTLV-1) was studied by a quantitative assay system using vesicular stomatitis virus (VSV) pseudotypes in which a recombinant VSV (VSVDeltaG*) containing the gene for green fluorescent protein instead of the VSV G protein gene was complemented with viral envelope glycoproteins in trans. Most of the cell lines tested showed susceptibility to VSVDeltaG* complemented with either HTLV-1 envelope glycoproteins (VSVDeltaG*-Env) or VSV G protein (VSVDeltaG*-G), but not to VSVDeltaG* alone, indicating that cell-free HTLV-1 could infect many cell types from several species. High concentration pronase treatment of cells reduced their susceptibility to VSVDeltaG*-Env, while trypsin treatment, apparently, did not. Treatment of the cells with sodium periodate, heparinase, heparitinase, phospholipase A2 or phospholipase C reduced the susceptibility of cells to VSVDeltaG*-Env, but not to VSVDeltaG* complemented with measles virus (Edmonston strain) H and F proteins (VSVDeltaG*-EdHF), which was used as a control. Purified phosphatidylcholine also inhibited the infectivity of VSVDeltaG*-Env, but not VSVDeltaG*-G. These findings indicated that, in addition to cell surface proteins, glycosaminoglycans and phospholipids play an important role in the process of cell-free HTLV-1 entry.
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PMID:Analysis of the molecules involved in human T-cell leukaemia virus type 1 entry by a vesicular stomatitis virus pseudotype bearing its envelope glycoproteins. 1125 87

Short-term (1 h) exposure of cells to a low steady-state concentration of H(2)O(2) causes no immediate cell death but apoptosis occurs several hours later. This delayed cell death may arise from activation of phospholipases, in particular phospholipase A2 (PLA2), which may destabilize lysosomal and mitochondrial membranes. Indeed, the secretory PLA2 (sPLA2) inhibitor 4-bromophenacyl bromide diminishes both delayed lysosomal rupture and apoptosis. Furthermore, sPLA2 activation by mellitin, or direct micro-injection of sPLA2, causes lysosomal rupture and apoptosis. Finally, B-cell leukemia/lymphoma 2 (Bcl-2) over-expression prevents oxidant-induced activation of PLA2, delayed lysosomal destabilization and apoptosis. This supports a causal association between PLA2 activation and delayed oxidant-induced cell death and suggests that Bcl-2 may suppress apoptosis by preventing PLA2 activation.
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PMID:Delayed oxidant-induced cell death involves activation of phospholipase A2. 1174 63

B-cell leukemia/lymphoma 2 (Bcl-2) blocks oxidant-induced apoptosis at least partly by stabilizing lysosomes. Here we report that phosphorylation of Bcl-2 may be required for these protective effects. J774 cells overexpressing wild-type Bcl-2 resist oxidant-induced lysosomal leak as well as apoptosis, and this protection is amplified by pretreatment with phorbol 12-myristate 13-acetate (which promotes protein kinase C (PKC)-dependent phosphorylation of Bcl-2). In contrast, cells overexpressing the Bcl-2 mutant S70A (which cannot be phosphorylated) are not protected in either circumstance. Transfection with Bcl-2(S70E), a constitutively active Bcl-2 mutant which does not require phosphorylation, is protective independent of PKC activation. In contrast, C(2)-ceramide, a putative protein phosphatase 2A activator, abolishes the protective effects of wild-type Bcl-2 overexpression but does not diminish protection afforded by Bcl-2(S70E). Additional results suggest that, perhaps as a consequence of lysosomal stabilization, Bcl-2 may prevent activation of phospholipase A2, an event potentially important in the ultimate initiation of apoptosis.
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PMID:Bcl-2 phosphorylation is required for inhibition of oxidative stress-induced lysosomal leak and ensuing apoptosis. 1174 64

We investigated the effect of antibiotics for the prevention of infectious complications subsequent to endscopic treatment of the colon and rectum. Thirty-three patients who underwent endoscopic polypectomies and/or hot-biopsies were divided into two groups: (A, n = 17) with and (B, n = 16) without prophylactic administration of antibiotics. The oral lavage solution method with isotonic magnesium citrate was used for bowel preparation. For group A, 250 mg of kanamycin was administered orally four times, at 30-min intervals, after the oral lavage solution of isotonic magnesium citrate was administered, and 3.2 g of clavulanic acid-ticarcillin was administered by drip infusion after the endoscopic treatment. Latent inflammatory reactions were assessed based on blood cell analysis, erythrocyte sedimentation rate, serum C-reactive protein, and serum phospholipase A2 activity before and the day after the endoscopic treatment. Postoperative platelet, white blood cell, and neutrophil counts were significantly increased in group B, while increases in these parameters were all suppressed in group A. These results suggested that bacterial infections developed subsequent to endoscopic surgery on the colon and rectum. Although we do not need to administer antibiotics to all patients, in patients at high risk of infection, such as those with leukemia or diabetes mellitus, endoscopic polypectomy or hot-biopsy of the colon and rectum should be performed with the administration of antibiotics.
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PMID:Prevention of infectious complications subsequent to endoscopic treatment of the colon and rectum. 1181 Apr 96

Here we report the synthesis and characterization of a lipophilic phosphatidylcholine containing the omega-3 fatty acid docosahexaenoic acid (DHA) and the cytotoxic drug methotrexate (MTX). This novel phospholipid combines the fatty acid's and the drug's anticancer activities in a molecule amenable to a liposome bilayer for safe, simultaneous delivery of the two agents. Two phosphatidylcholines were synthesized, from 1-stearoyl or 1-docosahexaenoyl, 2-hydroxy-sn-glycero-3-phosphocholine, to contain MTX in the sn-2 position and either stearic acid or DHA in the sn-1 position. The products contain fatty acid, MTX and phosphorus (1:1:1), and the MTX was released by phospholipase A(2), consistent with the proposed phospholipid structure. The predominant product linked MTX to the glycerol moiety through MTX's gamma-carboxyl group. Liposomes composed of 1-stearoyl, 2-oleoyl phosphatidylcholine plus 1-stearoyl, 2-oleoyl phosphatidylethanolamine and various concentrations of the novel phospholipids caused dose-dependent inhibition of murine leukemia cell proliferation in culture. The DHA- and MTX-containing phosphatidylcholine was more effective than that containing stearic acid, and DHA appeared to synergize with MTX when they were added as free agents or covalently linked in the phospholipid. These data show the feasibility of synthesizing, and the inhibitory activity of phosphatidylcholine with DHA in the sn-1 position and MTX in the sn-2 position, and suggest the compound's potential use in cancer chemotherapy.
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PMID:Synthesis of a novel phosphatidylcholine conjugated to docosahexaenoic acid and methotrexate that inhibits cell proliferation. 1198 74

Synthetic analogs of vitamin D for potential use in differentiation therapy should selectively regulate genes necessary for differentiation without inducing any perturbations in calcium homeostasis. PRI-1906, an analog of vitamin D2, and PRI-2191, an analog of vitamin D3 bind nuclear vitamin D receptor (nVDR) with substantially lower affinity than 1,25-dihydroxyvitamin D3 (1,25-D3), but have higher differentiation-inducing activity as estimated in HL-60 leukemia cellmodel. To examine how their increased differentiation-inducing activity is regulated we tested the hypothesis that membrane-mediated events, unrelated to nVDR, take part in the differentiation in response to PRI-1906 and PRI-2191. The induction of leukemia cell differentiation in response to the analogs of vitamin D was inhibited by LY294002 (phosphatidylinositol 3-kinase inhibitor), PD98059 (inhibitor of MEK1,2, an upstream regulator of extracellular-signal regulated kinase) and rapamycin (p70S6K inhibitor) pointing out that activation of signal transduction pathways unrelated to nVDR is necessary for differentiation. On the other hand, inhibition of cytosolic phospholipase A2 accelerated the differentiation of HL-60 cells induced by either 1,25-D3 or by the vitamin D analogs suggesting possible existence of a feedback loop between extracellular-signal regulated kinases and phospholipase A2.
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PMID:Side-chain modified vitamin D analogs require activation of both PI 3-K and erk1,2 signal transduction pathways to induce differentiation of human promyelocytic leukemia cells. 1236 81

Store-operated cation (SOC) channels and capacitative Ca(2+) entry (CCE) play very important role in cellular function, but the mechanism of their activation remains one of the most intriguing and long lasting mysteries in the field of Ca(2+) signaling. Here, we present the first evidence that Ca(2+)-independent phospholipase A(2) (iPLA(2)) is a crucial molecular determinant in activation of SOC channels and store-operated Ca(2+) entry pathway. Using molecular, imaging, and electrophysiological techniques, we show that directed molecular or pharmacological impairment of the functional activity of iPLA(2) leads to irreversible inhibition of CCE mediated by nonselective SOC channels and by Ca(2+)-release-activated Ca(2+) (CRAC) channels. Transfection of vascular smooth muscle cells (SMC) with antisense, but not sense, oligonucleotides for iPLA(2) impaired thapsigargin (TG)-induced activation of iPLA(2) and TG-induced Ca(2+) and Mn(2+) influx. Identical inhibition of TG-induced Ca(2+) and Mn(2+) influx (but not Ca(2+) release) was observed in SMC, human platelets, and Jurkat T-lymphocytes when functional activity of iPLA(2) was inhibited by its mechanism-based suicidal substrate, bromoenol lactone (BEL). Moreover, irreversible inhibition of iPLA(2) impaired TG-induced activation of single nonselective SOC channels in SMC and BAPTA (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid)-induced activation of whole-cell CRAC current in rat basophilic leukemia cells. Thus, functional iPLA(2) is required for activation of store-operated channels and capacitative Ca(2+) influx in wide variety of cell types.
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PMID:Ca2+-independent phospholipase A2 is a novel determinant of store-operated Ca2+ entry. 1254 29

Tinospora smilacina Benth. has been used in Australian indigenous medicine for the treatment of headache, rheumatoid arthritis and other inflammatory disorders. As part of an investigation into the anti-inflammatory potential of plants using an ethnopharmacological approach, the present study sought to evaluate the efficacy and safety of Tinospora smilacina. An ethanol extract of this plant was evaluated in vitro for anti-inflammatory activities on cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LO) and phospholipase A(2) (PA(2)). The ethanol extract of Tinospora smilacina showed inhibitory activities on COX-1, COX-2, 5-LO and PA(2) with the IC(50) values of 63.5, 81.2, 92.1 and 30.5 micro g/mL respectively. Cytotoxic effect of the extracts of Tinospora smilacina was investigated in vitro using ATP-based luminescence assay and the results showed no cytotoxic effect on cell lines of skin fibroblasts (1BR3), human Caucasian hepatocyte carcinoma (Hep G2) and human Caucasian promyelocytic leukaemia (HL-60). This paper also describes the results of fractionations and bioassay guided chemical studies, suggesting that the anti-inflammatory activity is due to triterpene-fatty acid esters and free fatty acids.
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PMID:Anti-inflammatory activity, cytotoxicity and active compounds of Tinospora smilacina Benth. 1475 Feb 6


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