Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has previously been shown that the immunosuppressive drug deoxyspergualin can inhibit renal injury in experimental glomerulonephritis. This study examined whether deoxyspergualin can modulate the mesangial cell response to glomerular injury. Antiglomerular basement membrane glomerulonephritis was induced in primed rats. Groups of five animals were treated with deoxyspergualin (5 mg/kg per day) or saline from Day 0 until being euthanized on Day 1, 7, 14, or 21. Deoxyspergualin treatment significantly inhibited mesangial cell proliferation (proliferating cell nuclear antigen expression) over the disease course as assessed by double immunohistochemistry staining (P < 0.001 versus saline treated) and reduced glomerular major histocompatibility complex (MHC) class II expression. To demonstrate if this was a direct action of deoxyspergualin, an in vitro system was studied. The addition of deoxyspergualin caused a time- and dose-dependent inhibition of [3H]thymidine uptake by cultured rat mesangial cells. Of particular interest was the finding that deoxyspergualin inhibited the de novo cell surface expression of MHC class II antigens after interferon-gamma stimulation. However, deoxyspergualin did not prevent the cytoplasmic accumulation of MHC class II molecules, indicating that the drug interfered with a posttranslational event in MHC class II processing and/or assembly. Deoxyspergualin was not a general inhibitor of mesangial cells, and it had no effect on constitutive or lipopolysaccharide-induced transforming growth factor beta 1 expression. In conclusion, deoxyspergualin has been shown to inhibit the mesangial cell response to glomerular injury. This novel mode of action may provide an additional therapeutic benefit in the treatment of proliferative forms of glomerulonephritis.
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PMID:Deoxyspergualin inhibits mesangial cell proliferation and major histocompatibility complex class II expression. 762 87

This study was performed to clarify the mechanisms underlying post-resection changes in liver cell proliferation and metabolism. To assess the role of gut-derived endotoxaemia and endogenous cytokines in these changes, the effects of peri-operative treatment with either the lipopolysaccharide-neutralizing bactericidal/permeability-increasing protein or interleukin-1 receptor antagonist were investigated at 24 h after two-thirds hepatectomy in rats. Peri-operative treatment with either agent caused enhanced expression of proliferating cell nuclear antigen (PCNA) and reduced lipid accumulation. Activity of the hexose monophosphate shunt was significantly decreased after partial hepatectomy and restored by interleukin-1 receptor antagonist only. After partial hepatectomy, bile canalicular alkaline phosphatase activity was significantly increased in pericentral zones and redistributed to both bile canalicular and sinusoidal membranes of hepatocytes. These effects were not significantly influenced by either treatment. It is concluded that endotoxin restricts liver cell proliferation and leads to lipid accumulation following partial hepatectomy, and that interleukin-1 is a principal mediator in these processes. Furthermore, interleukin-1 mediates a repression of the pentose phosphate pathway. These changes may be of significance with respect to liver function, at least in the early phase after partial hepatectomy.
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PMID:Endotoxin- and cytokine-mediated effects on liver cell proliferation and lipid metabolism after partial hepatectomy: a study with recombinant N-terminal bactericidal/permeability-increasing protein and interleukin-1 receptor antagonist. 869 33

The myeloid cell line, NFS-60, is dependent on granulocyte colony-stimulating factor (G-CSF) or interleukin-3 (IL-3) for survival and growth. Long-term G-CSF-dependent proliferation was found to be completely inhibited by interferon-gamma (IFN-gamma), cyclic AMP, and dimethylamiloride and partially inhibited by IFN-alpha and lipopolysaccharide. With the exception of IFN-gamma, these agents exhibited a corresponding pattern of inhibition of DNA synthesis in quiescent NFS-60 cells stimulated with G-CSF. IFN-gamma was only a weak inhibitor of DNA synthesis, suggesting that it may act at a later stage to block proliferation. The addition of G-CSF to NFS-60 cells resulted in phosphorylation of the retinoblastoma protein (pRB) and activation of E2F DNA binding activity. The inhibitors were found to suppress the phosphorylation of pRB, lead to the production of higher order E2F complexes, and suppress the expression of c-myc and proliferating cell nuclear antigen (PCNA) to an extent that correlated with their ability to block DNA synthesis. These findings are consistent with the notion that the ratio of free/bound E2F binding activity is critical in controlling cell cycle progression through G1 to S-phase in these cells.
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PMID:Granulocyte colony-stimulating factor-stimulated proliferation of myeloid cells: mode of cell cycle control by a range of inhibitors. 891 Jul 73

Control of cell proliferation involves a finely interwoven network of positive and negative cell cycle regulators. Signal transduction pathways linking c-fms (CSF-1R) to cellular proliferation and differentiation are being explored. Part of the strategy is to use a series of G1 inhibitors to help pinpoint relevant targets. Several inhibitors-8Br-cAMP, interferon gamma (IFN gamma), INF alpha/beta, lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF alpha), and dimethylamiloride-suppress CSF-1-stimulated proliferation in murine bone marrow-derived macrophages (BMM) even when added in the mid- to late-G1 phase of the cell cycle. The down-modulating effects of the inhibitors on the expression of the following cell cycle regulators have been examined: c-myc, cyclin D1 and D2, cdk4, Rb phosphorylation, E2F binding activity, ribonucleotide reductase subunits, and PCNA. Some differences in the negative control of such regulators were found, for example, in the manner in which IFN gamma and cAMP down-regulate c-myc expression. Using blocking antibodies and BMM from type I IFN receptor knockout mice, it appears that one of these inhibitors, IFN alpha/beta, acts as an endogenous inhibitor in CSF-1-treated BMM and is also responsible, at least in part, for the inhibition of cell cycle progression by LPS and TNF alpha. Another strategy has been to attempt to relate early biochemical changes induced by CSF-1 to later changes in the G1 phase, partly by studying cycling versus noncycling macrophages and partly by using cells expressing c-fms with tyrosine mutations in the intracytoplasmic region. CSF-1-mediated effects on the following signal transduction molecules in these systems will be described: PI3-kinase, myelin basic protein kinases, Erks, and STAT transcription factors.
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PMID:CSF-1 and cell cycle control in macrophages. 898 59

IT IS WELL ESTABLISHED THAT apical migration of junctional epithelium (JE) along a root surface is an important factor in periodontal pocket formation and deepening. However, the exact mechanism and, more specifically, the role of inflammatory products in influencing the activity of cells within the JE is not known. To address this issue lipopolysaccharide (LPS) was applied topically into rat molar gingival sulcus and then tissues evaluated immunohistochemically for expression of proliferating cell nuclear antigen (PCNA). Tissues were prepared for histological analysis at designated times. Histologically, infiltration of neutrophils with associated edema was noted in JE and gingival connective tissues 6 hours after LPS application and was prominent at 12 hours. These inflammatory changes persisted in the 2- and 3-day specimens, and disappeared at 5 days. In normal gingiva, before the LPS application, the JE showed few PCNA positive cells, while almost all cells in the basal and suprabasal cell layers of the oral gingival epithelium and the oral sulcular epithelium were PCNA positive. No increase in the number of PCNA positive cells in the JE beyond zero time was observed at 6 and 12 hours after LPS application. One day after LPS application, PCNA positive cells appeared in the basal cell layer of the JE, with a continued increase number of PCNA positive cells in the JE continued at 2 and 3 days. By day 5 the number of PCNA positive cells were decreasing with return to a normal range by 7 days. These results showed that 1) under normal physiological conditions, cells within the JE have minimal mitotic activity and 2) the JE cells can enter the proliferating cell cycle when exposed to LPS, and suggest that the enhanced proliferating activity in the JE is an important factor for the deepening of the periodontal pocket, if the connective tissue attachment is broken down.
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PMID:Reactive change in proliferative activity of the junctional epithelium after topical application of lipopolysaccharide. 920 96

The modifying effects of dietary feeding of a polyisoprenylated benzophenone, garcinol, isolated from Garcinia indica fruit rind on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. We also assessed the effects of garcinol on proliferating cell nuclear antigen (PCNA) index in ACF and activities of detoxifying enzymes of glutathione S-transferase (GST) and quinone reductase (QR) in liver. In addition, we examined the effects of garcinol on 12-O-tetradecanoylphorbol-13-acetate-induced O(2)(-) generation in differentiated human promyelocytic HL-60 cells and lipopolysaccharide (LPS)- and interferon (IFN)-gamma-induced nitric oxide (NO) generation in mouse macrophage RAW 264.7 cells. Western blotting analysis of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression was done in LPS- and IFN-gamma-treated mouse macrophage RAW 264.7 cells. Rats were given subcutaneous injections of AOM (15 mg/kg body wt) once a week for 3 weeks to induce ACF. They also received the experimental diet containing 0.01 or 0.05% garcinol for 5 weeks, starting 1 week before the first dosing of AOM. AOM exposure produced 97 +/- 15 ACF/rat at the end of the study (week 5). Dietary administration of garcinol caused significant reduction in the frequency of ACF: 72 +/- 15 (26% reduction, P < 0.01) at a dose of 0.01% and 58 +/- 8 (40% reduction, P < 0.001) at a dose of 0.05%. Garcinol administration significantly lowered PCNA index in ACF. Feeding of garcinol significantly elevated liver GST and QR activities. In addition, garcinol could suppress O(2)(-) and NO generation and expression of iNOS and COX-2 proteins. These findings might suggest possible chemopreventive ability of garcinol, through induction of liver GST and QR, inhibition of O(2)(-) and NO generation and/or suppression of iNOS and COX-2 expression, on colon tumorigenesis.
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PMID:Prevention of colonic aberrant crypt foci by dietary feeding of garcinol in male F344 rats. 1083 8

The intake of citrus fruits has been suggested as a way to prevent the development of some types of human cancer. Nitric oxide (NO) is closely associated with the processes of epithelial carcinogenesis. We attempted a search for NO generation inhibitors in Citrus unshiu. The active constituent was traced by an activity-guiding separation. NO and superoxide (O2-) generation was induced by a combination of lipopolysaccharide and IFN-gamma in mouse macrophage RAW 264.7 cells, and by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocyte HL-60, respectively. Expression of inducible NO synthase and cyclooxygenase 2 proteins were detected by Western blotting. The in vivo anti-inflammatory and antitumor promoting activities were evaluated by topical TPA application to ICR mouse skin with measurement of edema formation, epidermal thickness, leukocyte infiltration, hydrogen peroxide production, and the rate of proliferating cell nuclear antigen-stained cells. As a result, nobiletin, a polymethoxyflavonoid, was identified as an inhibitor of both NO and O2- generation. Nobiletin significantly inhibited two distinct stages of skin inflammation induced by double TPA application [first stage priming (leukocyte infiltration) and second stage activation (oxidative insult by leukocytes)] by decreasing the inflammatory parameters. It also suppressed the expression of cyclooxygenase-2 and inducible NO synthase proteins and prostaglandin E2 release. Nobiletin inhibited dimethylbenz[a]anthracene (0.19 micromol)/TPA (1.6 nmol)-induced skin tumor formation at doses of 160 and 320 nmol by reducing the number of tumors per mouse by 61.2% (P < 0.001) and 75.7% (P < 0.001), respectively. The present study suggests that nobiletin is a functionally novel and possible chemopreventive agent in inflammation-associated tumorigenesis.
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PMID:Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. 1101 29

Auraptene (AUR), a citrus coumarin derivative, is one of the promising chemopreventive agents against skin, tongue, esophagus and colon carcinogenesis in rodents. We reported previously that AUR suppresses superoxide anion (O(2)(-)) generation from inflammatory leukocytes in in vitro experiments. In the present study, we investigated the anti-inflammatory activities of AUR using a 12-O:-tetradecanoylphorbol-13-acetate-treated mouse skin model, and compared them with those of umbelliferone (UMB), a structural analog of AUR that is virtually inactive toward O(2-) generation inhibition. Double pre-treatments of mouse skin with AUR, but not UMB, markedly suppressed edema formation, hydrogen peroxide production, leukocyte infiltration, and the rate of proliferating cell nuclear antigen-stained cells. These inhibitory effects by AUR are attributable to its selective blockade of the activation stage, as revealed by single pre-treatment experiments. In a murine macrophage line, RAW 264.7, AUR significantly attenuated the lipopolysaccharide-induced protein expression of inducible isoforms of both nitric oxide synthase and cyclooxygenase, with decreased production of nitrite anion and prostaglandin E(2), and yet suppressed the release of tumor necrosis factor-alpha. Conversely, UMB did not show any inhibitory effect. This contrasting activity profile between AUR and UMB was rationalized to be a result of their distinct differences in cellular uptake efficiencies, i.e. the geranyloxyl group in AUR was found to play an essential role in incorporation. Thus, our findings indicate that AUR is an effective agent to attenuate the biochemical responsiveness of inflammatory leukocytes, which may be essential for a greater understanding of the action mechanism that underlies its inhibition of inflammation-associated carcinogenesis.
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PMID:Suppression by citrus auraptene of phorbol ester-and endotoxin-induced inflammatory responses: role of attenuation of leukocyte activation. 1102 42

In the present work the role of calmodulin (CaM) in regulating lipopolysaccharide (LPS)-induced microglial activation and in the spontaneous microglial differentiation has been investigated. We used pure rat microglial cell cultures to examine the effects of W13, a specific inhibitor of CaM, on microglial activation produced by LPS and the effect of CaM inhibition on microglial proliferation induced by the macrophage colony-stimulating factor (M-CSF). Microglial morphological transformation, inducible nitric oxide synthase (iNOS) activity and proliferating cell nuclear antigen (PCNA) immunostaining were determinate. Results show that CaM does not participate in the microglial increase of iNOS produced by LPS. In contrast, it is involved in spontaneous microglial ramification and in the activation of proliferation from quiescence. Multiple second-messenger pathways are involved in the transduction of signals initiated by LPS. The study of these mechanisms may allow us to extend our knowledge of the signals controlling the expression of these mediators.
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PMID:Role of calmodulin in the differentiation/activation of microglial cells. 1137 99

We investigated the effects of inhibitors of cAMP-specific phosphodiesterase type IV (PDE IV) on cultured rat microglial cells. Microglial cells expressed mRNA encoding PDE IV. Rolipram and RO-20-1724, specific inhibitors of PDE IV, elevated the intracellular cAMP level much higher than the other types of PDE inhibitors. cAMP in astrocytes but not in cerebrocortical neurons was similarly increased in response to treatment with PDE IV inhibitors examined. The PDE IV inhibitors, a beta-adrenergic agonist isoproterenol and an adenylyl cyclase stimulant forskolin suppressed the proliferation of microglial cells as revealed by PCNA-immunocytochemical staining. The PDE IV inhibitors suppressed release of TNF alpha and nitric oxide (NO) from lipopolysaccharide-activated microglial cells in pure culture, while they did not affect NO release from microglial cells in neuron-microglia coculture. The PDE IV inhibitors also suppressed superoxide anion production by phorbol ester-treated microglial cells. Isoproterenol and forskolin similarly suppressed the macrophage-like functions of activated microglial cells. However, the PDE IV inhibitors displayed novel effects distinct from those of isoproterenol, forskolin and 8Br-cAMP, regarding expression of mRNAs encoding PDE IV, metallothionein-1 and hemeoxigenase-1. The present data showed that the PDE IV inhibitors can be available to control microglial function and that their effects on glial cells should be taken into account when PDE IV inhibitors are used for treatment of brain diseases, such as multiple sclerosis.
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PMID:Suppressive effects of phosphodiesterase type IV inhibitors on rat cultured microglial cells: comparison with other types of cAMP-elevating agents. 1180 23


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