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)

Since nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) has been found to be involved in various pathophysiological processes, including inflammation and carcinogenesis, the modulators of NO synthesis or expression have been considered as potential anti-inflammatory and cancer chemopreventive agents. In this study, to procure the iNOS inhibitors from natural products, we evaluated 57 methanol extracts of natural products including Korean indigenous plants for the inhibition of NO formation on lipopolysaccharide (LPS)-activated mouse macrophage-like RAW 264.7 cells. As a result, several extracts including those from Actinodaphne lancifolia, Calystegia soldanella, Caryratia japonica, Citrus dachibana, Dystaenia takeshimana, Erysimum aurantiacum, Hovenia undulata, Stewartia koreana and Viburnum awabuki showed potent inhibitory activities of NO production (>70% inhibition at the test concentration of 40 microg/ml). In particular, the extract of Calystegia soldanella showed a potential inhibition of NO production in a dose-dependent manner (IC50=4.3 microg/ml). Subsequent study also exhibited that the extract of Calystegia soldanella significantly suppressed iNOS protein and gene expression in a dose-dependent manner. These results suggest that Calystegia soldanella might be a new potential candidate for developing an iNOS inhibitor from natural products and also could be warranted for further elucidation of active principles for the development of new anti-inflammatory and/or cancer chemopreventive agents.
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PMID:Suppressive effects of nitric oxide production and inducible nitric oxide synthase (iNOS) gene expression by Calystegia soldanella methanol extract on lipopolysaccharide-activated RAW 264.7 cells. 1545 55

We hypothesized that superoxide from Kupffer cells (KC) contributes to hepatocarcinogenesis. p47phox(-/-) mice, deficient in phagocyte NADPH oxidase and superoxide generation, received a single dose of the hepatocarcinogen diethylnitrosamine (DEN). The following hepatic effects were observed at time points between 30 min and 35 days. Liver damage after DEN was manifested by loss of body and liver mass and of liver DNA and by an increase in apoptosis, necrosis and signs of inflammation. These effects were massive in wild-type (wt) male mice, but only very mild in p47phox(-/-) mice. Regenerative DNA synthesis subsequent to liver damage was high in wt male mice, but weak in p47phox(-/-) mice. In females the apparent protection by p47phox(-/-) was less pronounced than in males. Therefore, further experiments were performed with males. In KC isolated from wt mice superoxide production was enhanced by DEN pretreatment in vivo. Also, in vitro addition of DEN to KC cultures induced superoxide release, similarly to lipopolysaccharide, a standard KC activator. Thus, DEN directly activates wt KC to produce superoxide. KC from p47phox(-/-) mice did not release superoxide. TNFalpha production by isolated KC was transiently depressed 0.5 h after DEN treatment in vivo, but recovered rapidly. In blood serum TNFalpha levels of wt mice were elevated for the initial 6 h. TNFalpha in KC cultures and in serum of p47phox(-/-) mice was reduced. DEN in vivo induced DNA damage ('comets') in hepatocytes. This damage was extensive in wt mice but much less in p47phox(-/-) mice. These studies suggest two conclusions: (i) superoxide generation by phagocytes during liver damage and inflammation aggravates genotoxic and cytotoxic effects in hepatocytes and may thus contribute to tumor initiation and promotion; (ii) DEN has a direct stimulatory effect on KC to release superoxide and TNFalpha.
Carcinogenesis 2005 Feb
PMID:Superoxide generation from Kupffer cells contributes to hepatocarcinogenesis: studies on NADPH oxidase knockout mice. 1551 30

Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) has played a crucial role in various pathophysiological processes including inflammation and carcinogenesis. Therefore, the inhibitors of NO synthesis or iNOS gene expression have been considered as potential anti-inflammatory and cancer chemopreventive agents. In our continuous search for iNOS inhibitors from natural products we have evaluated indigenous Korean plant extracts using an assay for inhibition of nitric oxide formation on lipopolysaccharide (LPS)-activated mouse macrophage RAW 264.7 cells. As a result, the methanolic stem extract of Actinodaphne lancifolia showed an inhibitory activity of NO production in a dose-dependent manner (IC50 = 2.5 microg/ml). Additional study demonstrated that the extract of Actinodaphne lancifolia significantly suppressed the iNOS protein and gene expression in a dose-dependent manner. These results suggest that Actinodaphne lancifolia could be a potential candidate for developing an iNOS inhibitor from natural products. Further elucidation of active principles for development of new cancer chemopreventive and/or anti-inflammatory agents could be warranted.
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PMID:Suppressive effect of inducible nitric oxide synthase (iNOS) expression by the methanol extract of Actinodaphne lancifolia. 1555 74

The in vitro generation of dendritic cells (DCs) from either blood or bone marrow has been accomplished for humans and a number of other species. This ability has facilitated the opportunity to test the efficacy of DC vaccines in various tumor models. The cottontail rabbit papillomavirus (CRPV) model is the most clinically relevant animal model for human papillomavirus (HPV)-associated carcinogenesis. The CRPV model has been used to test various preventative and therapeutic vaccination strategies, and the availability of rabbit DCs would further expand its utility. However, to date, rabbit DCs have not been phenotypically and/or functionally characterized. Here we show that DCs can be generated in vitro from rabbit bone marrow mononuclear cells (BMMCs) cultured in the presence of the human cytokines GM-CSF and IL-4 and matured with lipopolysaccharide (LPS). These cells show upregulation of MHC class II and CD86, as well as downregulation of CD14, do not have non-specific esterase activity, are able to perform receptor-mediated endocytosis, and are potent stimulators of allogeneic T cell proliferation in mixed lymphocyte reactions. The ability to generate rabbit DCs makes it possible to test the efficacy of DC vaccination in the prevention and treatment of CRPV-induced lesions, which may provide useful preclinical data regarding the use of DC vaccines for HPV-associated lesions, including cervical cancer.
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PMID:Generation of dendritic cells from rabbit bone marrow mononuclear cell cultures supplemented with hGM-CSF and hIL-4. 1562 3

Evidence indicates that the testis possesses a reduced capacity to mount inflammatory and rejection responses, which undoubtedly contributes to the ongoing survival of the highly immunogenic germ cells. The contribution of local cytokine expression to this condition was investigated in adult male rats treated with lipopolysaccharide to induce inflammation. Cytokine mRNA and protein expression were determined in tissue extracts and fluids by Northern blot analysis, quantitative PCR, or RNAse protection assay and specific ELISAs. Testicular expression of the proinflammatory cytokines, interleukin (IL)-1beta and tumor necrosis factor-alpha was considerably attenuated compared with the liver (control tissue); in contrast, the testicular IL-6 response was enhanced. Expression of IL-10, a type 2 immunoregulatory cytokine, was similar in both testis and liver, whereas the immunoregulatory/anti-inflammatory cytokines transforming growth factor-beta(1) and activin A were constitutively elevated in both normal and inflamed testes. The IL-1beta and transforming growth factor-beta(1) proteins were present principally in their latent (inactive) forms, indicating that enzymic processing is an important control mechanism for these two cytokines within the testis. These data indicate that inflammatory and regulatory cytokine activity is regulated at both transcriptional and posttranslational levels in a testis-specific manner. It is concluded that a novel pattern of suppression of proinflammatory cytokine responses and normal or elevated expression of immunoregulatory cytokines may be responsible for reduced inflammatory responses and enhanced graft survival in the testis. These data have important implications for the understanding and treatment of male autoimmune infertility, testicular inflammation. and carcinogenesis.
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PMID:Cytokine profiles in the testes of rats treated with lipopolysaccharide reveal localized suppression of inflammatory responses. 1566 66

Brazilin (7,11b-dihydrobenz[b]indeno[1,2-d]pyran-3,6a,9,10 (6H)-tetrol) isolated from Caesalpinia sappan has been known as a natural red pigment. Many studies suggest that inducible isoform of nitric oxide synthase (NOS) plays an important role in inflammation and carcinogenesis. On this line, we evaluated the inhibitory effect of brazilin on nitric oxide (NO) production and investigated its mechanism of action. As a result, brazilin exhibited the inhibitory effect on lipopolysaccharide (LPS)-stimulated NO production in a dose-dependent manner (IC50=24.3 microM). In addition, brazilin suppressed LPS-induced iNOS protein and mRNA expression in RAW 264.7 macrophage cells, indicating that the inhibitory activity of brazilin possibly involved in the regulation of iNOS expression. To further investigate the mechanism responsible for the suppression of iNOS gene expression by brazilin, the effect of brazilin on LPS-induced transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) activation was examined. The DNA binding activity of NF-kappaB and AP-1 stimulated LPS was inhibited by treatment of brazilin in a dose-dependent manner, suggesting that brazilin-mediated inhibition of NO production might be associated with the regulation of transcription factors NF-kappaB and AP-1. Taken together, these findings suggest that the suppressive effect of iNOS gene expression by brazilin might provide one possible mechanism for its anti-inflammatory and cancer chemopreventive activity.
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PMID:Suppression of lipopolysaccharide-induced expression of inducible nitric oxide synthase by brazilin in RAW 264.7 macrophage cells. 1586 6

Isovitexin, isolated from rice hull of Oryza sativa, has been characterized as a potent antioxidant. Its antioxidant activity, determined on the basis of inhibition of lipid peroxidation by the Fenton reaction, was comparable with that of alpha-tocopherol, a well-established antioxidant. Isovitexin was able to reduce the amount of hydrogen peroxide production induced by lipopolysaccharide (LPS) in mouse macrophage RAW264.7 cells. In this study, we assessed its effects on the production of tumor necrosis factor alpha (TNF-alpha), prostaglandin E2 (PGE2), and the expression of cyclooxygenase-2 (COX-2) in LPS-activated RAW 264.7 macrophages. Isovitexin inhibited the release of TNF-alpha, a proinflammatory cytokine, upon LPS activation with a 50% inhibitory concentration (IC50) of 78.6 microM. Isovitexin markedly reduced LPS-stimulated PGE2 production in a concentration-dependent manner, with an IC50 of 80.0 microM. The expression of COX-2 was also inhibited by isovitexin treatment. Our results suggest that suppression of ROS-mediated COX-2 expression by isovitexin is beneficial in reducing inflammation and carcinogenesis.
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PMID:Inhibitory effects of a rice hull constituent on tumor necrosis factor alpha, prostaglandin E2, and cyclooxygenase-2 production in lipopolysaccharide-activated mouse macrophages. 1596 85

Hepatocellular carcinoma almost always arises in chronically inflamed livers. We developed a culture model to study the role of non-parenchymal cells (NPCs) for inflammation-driven hepatocarcinogenesis. Rats were treated with the carcinogen N-nitrosomorpholine, which induced initiated hepatocytes expressing the marker placental glutathione-S-transferase (GSTp). After 21 days two preparations of hepatocytes were made: (i) conventional ones (Hep-conv) containing NPCs and (ii) hepatocytes purified of NPCs (Hep-pur). Initiated hepatocytes, being positive for GSTp (GSTp-pos) were present in both preparations and were cultured along with normal hepatocytes, being negative for GSTp (GSTp-neg). Under any culture condition DNA synthesis was approximately 4-fold higher in GSTp-pos than in GSTp-neg hepatocytes demonstrating the inherent growth advantage of the first stages of hepatocarcinogenesis. Hepatocytes showed approximately 3-fold lower rates of DNA synthesis in Hep-pur than in Hep-conv, which was elevated above Hep-conv levels by addition of NPC or NPC-supernatant. Pretreatment of NPCs with proinflammatory lipopolysaccharide (LPS) further increased DNA synthesis. Thus, NPCs release soluble growth stimulators. Next we investigated the effect of specific cytokines produced by NPCs. Tumour necrosis factor alpha and interleukin 6 barely altered DNA synthesis, whereas hepatocyte growth factor (HGF), keratinocyte growth factor (KGF) and the heparin-binding epidermal growth factor-like growth factor (HB-EGF) were potent inducers of DNA replication in both, GSTp-neg and GSTp-pos cells. In conclusion, DNA synthesis of hepatocytes is increased by factors released from NPCs, an effect augmented by LPS-stimulation. NPC-derived cytokines, such as KGF, HGF and HB-EGF, stimulate DNA synthesis preferentially in initiated hepatocytes, presumably resulting in tumour promotion. Similar mechanisms may contribute to carcinogenesis in human inflammatory liver diseases.
Carcinogenesis 2006 Jan
PMID:Non-parenchymal liver cells support the growth advantage in the first stages of hepatocarcinogenesis. 1608 14

Garcinol, a polyisoprenylated benzophenone, from the fruit rind of Garcinia spp., has been shown to have anti-inflammatory and anticarcinogenic activities. To study its mechanism of action, we analyzed the effects of garcinol and its derivatives, including cambogin, garcim-1 and garcim-2, on arachidonic acid metabolism and nitric oxide (NO) synthesis in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages as well as in three intestinal cell lines. We also examined the effect of garcinol on cytosolic phospholipase A2 (cPLA2), cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS), and related upstream signaling. At 1 microM, garcinol and its derivatives, added 1 h after LPS stimulation, significantly inhibited the release of arachidonic acid and its metabolites in macrophages; garcinol was the most effective, showing >50% inhibition. Similar inhibitory activity was also observed in intestinal cells, HT-29, HCT-116 and IEC-6 cells, showing 40-50% inhibition by 1 microM garcinol. In LPS-stimulated macrophages, garcinol inhibited the phosphorylation of cPLA2 without altering its protein level, and the effect was related to the inhibition of ERK1/2 phosphorylation. Garcinol inhibited NFkappaB activation and COX-2 expression only when it was added to the cells before LPS stimulation. Garcinol (1 microM) also significantly decreased iNOS expression and NO release from LPS-stimulated macrophages; this is probably due to the inhibition of the signal transducer and activator of transcription-1 (STAT-1), an upstream event in the activation of iNOS synthesis. The results suggest that garcinol modulates arachidonic acid metabolism by blocking the phosphorylation of cPLA2 and decreases iNOS protein level by inhibiting STAT-1 activation. These activities may contribute to the anti-inflammatory and anticarcinogenic actions of garcinol and its derivatives.
Carcinogenesis 2006 Feb
PMID:Modulation of arachidonic acid metabolism and nitric oxide synthesis by garcinol and its derivatives. 1609 50

A heterocyclic amine, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is one of the potent food-born dietary carcinogens derived mainly from burnt meat products. In the present study, we investigated the inductive effect of Trp-P-1 on nitric oxide (NO) production in murine macrophages since NO and its oxidized derivatives are directly involved in triggering mutagenesis and carcinogenesis. Our results show that Trp-P-1 induced mRNA expression of inducible NO synthase (iNOS) and NO production without co-stimulation in murine peritoneal macrophages and RAW 264.7 cells. Trp-P-1 further enhanced both iNOS mRNA expression and NO production, which were primarily induced by lipopolysaccharide (LPS). Electrophoretic mobility shift assay demonstrated that Trp-P-1, alone or in the presence of LPS, facilitated the DNA binding activity of the transcription factor NF-kappaB, and the trans-acting activity of the NF-kappaB was confirmative as determined by in vitro transfection and a luciferase reporter gene assay. Moreover, Trp-P-1 induced increasing intracellular reactive oxygen species (ROS), which play an important role in NF-kappaB activation. These results suggest that Trp-P-1 induces NO production mediated by an increased intracellular ROS, NF-kappaB activation, and subsequent iNOS gene expression.
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PMID:3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), a food-born carcinogenic heterocyclic amine, promotes nitric oxide production in murine macrophages. 1613 43


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