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

Estrogen has been shown to attenuate the inflammatory response following injury or lipopolysaccharide treatment in several organ systems. Estrogen's actions are transduced through two estrogen receptor sub-types, estrogen receptor (ER) -alpha and estrogen receptor-beta, whose actions may be overlapping or independent of each other. The present study examined the effects of ERalpha- and ERbeta-specific ligands in regulating the inflammatory response in primary astrocyte cultures. Pre-treatment with 17beta-estradiol (ERalpha/ERbeta agonist), HPTE (ERalpha agonist/ERbeta antagonist) and DPN (ERbeta agonist) led to attenuation of IL-1beta, TNFalpha, and MMP-9 in astrocyte media derived from young adult (3-4 mos.) and reproductive senescent female (9-11 mos., acyclic) astrocyte cultures, while pretreatment with PPT (ERalpha agonist) attenuated IL-1beta (but not MMP-9) in both young and senescent-derived astrocyte cultures. Our previous work determined that 17beta-estradiol was unable to attenuate the LPS-induced increase in IL-1beta in olfactory bulb primary microglial cultures derived from either young adult or reproductive senescent females. In young adult-derived microglial cultures, the LPS-induced increase in IL-1beta was not attenuated by pre-treatment with 17beta-estradiol, PPT or HPTE. Interestingly, the ERbeta agonist, DPN significantly decreased IL-1beta following LPS treatment in young adult-derived microglia. Thus while both microglia and astrocytes synthesize and release inflammatory mediators, the present data shows that compounds which bind ERbeta are more effective in attenuating proinflammatory cytokines in both cell types and may therefore be a more effective agent for future therapeutic use.
 ...
PMID:Effects of estrogen receptor agonists on regulation of the inflammatory response in astrocytes from young adult and middle-aged female rats. 1832 72

We here demonstrate an anti-inflammatory action of raloxifene, a selective estrogen receptor modulator, in lipopolysaccharide (LPS)-induced murine macrophage RAW264.7 cells. Treatment with raloxifene at micromolar concentrations suppressed the production of nitric oxide (NO) by down-regulating expression of the inducible nitric oxide synthase (iNOS) gene in LPS-activated cells. The decreased expression of iNOS and subsequent reduction of NO were due to inhibition of nuclear translocation of transcription factor NF-kappaB. These effects were significantly inhibited by exposure to the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY294002, or by expression of a dominant negative mutant of PI 3-kinase. In addition, pretreatment with raloxifene reduced LPS-induced Akt phosphorylation as well as NF-kappa B DNA binding activity and NF-kappa B-dependent reporter gene activity. Thus our findings indicate that raloxifene exerts its anti-inflammatory action in LPS-stimulated macrophages by blocking the PI 3-kinase-Akt-NF-kappa B signaling cascade, and eventually reduces expression of pro-inflammatory genes such as iNOS.
 ...
PMID:Raloxifene, a selective estrogen receptor modulator, inhibits lipopolysaccharide-induced nitric oxide production by inhibiting the phosphatidylinositol 3-kinase/Akt/nuclear factor-kappa B pathway in RAW264.7 macrophage cells. 1851 85

Although administration of 17beta-estradiol (estrogen) following trauma-hemorrhage attenuates the elevation of cytokine production and mitogen-activated protein kinase (MAPK) activation in epidermal keratinocytes, whether the salutary effects of estrogen are mediated by estrogen receptor (ER)-alpha or ER-beta is not known. To determine which estrogen receptor is the mediator, we subjected C3H/HeN male mice to trauma-hemorrhage (2-cm midline laparotomy and bleeding of the animals to a mean blood pressure of 35 mmHg and maintaining that pressure for 90 min) followed by resuscitation with Ringer's lactate (four times the shed blood volume). At the middle of resuscitation we subcutaneously injected ER-alpha agonist propyl pyrazole triol (PPT; 5 microg/kg), ER-beta agonist diarylpropionitrile (DPN; 5 microg/kg), estrogen (50 microg/kg), or ER antagonist ICI 182,780 (150 microg/kg). Two hours after resuscitation, we isolated keratinocytes, stimulated them with lipopolysaccharide for 24 h (5 microg/mL for maximum cytokine production), and measured the production of interleukin (IL)-6, IL-10, IL-12, and TNF-alpha and the activation of MAPK. Keratinocyte cytokine production markedly increased and MAPK activation occurred following trauma-hemorrhage but were normalized by administration of estrogen, PPT, and DPN. PPT and DPN administration were equally effective in normalizing the inflammatory response of keratinocytes, indicating that both ER-alpha and ER-beta mediate the salutary effects of estrogen on keratinocytes after trauma-hemorrhage.
 ...
PMID:Estradiol's salutary effects on keratinocytes following trauma-hemorrhage are mediated by estrogen receptor (ER)-alpha and ER-beta. 1876 38

Steroidal estrogens can regulate inflammatory immune responses and may be involved in the suppression of multiple sclerosis (MS) during pregnancy. However, the risks and side effects associated with steroidal estrogens may limit their usefulness for long-term MS therapy. Selective estrogen receptor modulators (SERMs) could provide an alternative therapeutic strategy, because they behave as estrogen agonists in some tissues, but are either inert or behave like estrogen antagonists in other tissues. In this study, we investigated the ability of two commercially available SERMs (tamoxifen and raloxifene) to regulate myelin specific immunity and experimental autoimmune encephalomyelitis (EAE) in mice. Both tamoxifen and raloxifene suppressed myelin antigen specific T-cell proliferation. However, tamoxifen was more effective in this regard. Tamoxifen treatment reduced the induction of major histocompatibility complex II by lipopolysaccharide stimulated dendritic cells and decreased their ability to activate myelin specific T-cells. At lower doses, tamoxifen was found to increase the levels of Th2 transcription factors and induce a Th2 bias in cultures of myelin-specific splenocytes. EAE symptoms and the degree of demyelination were less severe in mice treated with tamoxifen than in control mice. These findings support the notion that tamoxifen or related SERMs are potential agents that could be used in the treatment of inflammatory autoimmune disorders that affect the central nervous system.
 ...
PMID:Treatment with selective estrogen receptor modulators regulates myelin specific T-cells and suppresses experimental autoimmune encephalomyelitis. 1903 37

Expression of proinflammatory molecules by glial cells is involved in the pathophysiological changes associated with chronic neurological diseases. Under pathological conditions, astrocytes release a number of proinflammatory molecules, such as interleukin-6 (IL-6) and interferon-gamma-inducible protein-10 (IP-10). The ovarian hormone estradiol exerts protective effects in the central nervous system that, at least in part, may be mediated by a reduction of local inflammation. This study was designed to assess whether estradiol affects the production of IL-6 and IP-10 by primary cultures of newborn mice astrocytes exposed to lipopolysaccharide (LPS), a bacterial endotoxin known to cause neuroinflammation. In addition, the possible anti-inflammatory effect of several selective estrogen receptor modulators (SERMs) was also assessed. LPS induced an increase in the expression of IL-6 and IP-10 mRNA levels in astrocytes and an increase in IL-6 and IP-10 protein levels in the culture medium. These effects of LPS were impaired by estradiol and by the four SERMs tested in our study: tamoxifen, raloxifene, ospemifene, and bazedoxifene. All SERMs tested showed a similar effect on IL-6 and IP-10 mRNA levels, but raloxifene and ospemifene were more effective than tamoxifen and bazedoxifene in reducing protein levels in LPS-treated cultures. Finally, we report that news SERMs, ospemifene and bazedoxifene, exert anti-inflammatory actions by a mechanism involving classical estrogen receptors and by the inhibition of LPS-induced NFkappaB p65 transactivation. The results suggest that estrogenic compounds may be candidates to counteract brain inflammation under neurodegenerative conditions by targeting the production and release of proinflammatory molecules by astrocytes.
 ...
PMID:Selective estrogen receptor modulators decrease the production of interleukin-6 and interferon-gamma-inducible protein-10 by astrocytes exposed to inflammatory challenge in vitro. 1953 3

Flavonoids display several biological activities, but exhibit poor oral absorption and rapid metabolism. To improve their pharmacological profile four C8-prenyl flavonoids, structurally related to the anti-inflammatory lead apigenin, were synthesized, and the two least cytotoxic (IC(50)>30 microM) compounds [8-prenylnaringenin (8-PN) and 8-prenylapigenin (8-PA)] in RAW 264.7 murine macrophages were assayed against a panel of biological targets. The anti-inflammatory properties of these compounds were evaluated in an in vitro model of inflammation [cells exposed to 0.1 microg/ml lipopolysaccharide (LPS) for 24h]. Both 8-PN and 8-PA were equally effective and potent in inhibiting the LPS-induced gene expression [tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2] (RT-PCR) and release (ELISA) of pro-inflammatory mediators [TNF-alpha, NO, prostaglandin (PG)E(2)], through mechanisms involving the inhibition of nuclear factor-kappaB (NF-kappaB) activation (EMSA) and reactive oxygen species accumulation [2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) determination]. One-digit nM concentrations of 8-PN or 8-PA induced a significant increase in the basal production of the atheroprotective prostacyclin (PGI(2)) by human umbilical vein endothelial cells (HUVEC), with maximal effects at 10 nM. Both NS-398, a specific COX-2 inhibitor, and ICI 182 780, a non-selective estrogen receptor antagonist, abolished the activity of these compounds, suggesting a COX- and estrogen receptor-dependent mechanism of activity. 8-PA, a weaker estrogenic compound than 8-PN, resulted only 2-fold less potent than 8-PN in potentiating PGI(2) production by HUVEC, qualifying this C8-prenyl flavonoid as a lead for the rational design of new anti-inflammatory and vascularprotective compounds.
 ...
PMID:Anti-inflammatory and vascularprotective properties of 8-prenylapigenin. 1968 24

The expression of chemokines is critical in leukocyte recruitment and inflammation, but the regulatory mechanisms involved remain incompletely defined. While endocrine disrupter chemicals (EDCs) are known to be ubiquitous in the environment and often associated with altered inflammatory response, their potential impact on chemokine expression in monocytes is at present unknown. To this end, the effects of EDCs on the expression of Th1- and Th2-related chemokines in a human monocytic cell line, THP-1, were investigated. THP-1 cells were pre-treated with varying concentrations of EDCs (nonylphenol and 4-octylphenol) with or without the addition of an estrogen receptor (ER) antagonist, ICI 182,780 and then stimulated by lipopolysaccharide (LPS). The levels of chemokines, CXCL10/ IFN-alpha-inducible protein 10 (IP-10, a Th1 chemokine) and monocyte-derived chemokine (MDC)/CCL22, a Th2 chemokine) were measured by ELISA. EDC-mediated signaling events and histone modifications were examined by the use of Western blotting and chromatin immunoprecipitation (ChIP) assay. Nonylphenol and 4-octylphenol were able to suppress LPS-induced MDC and IP-10 expression. This suppressive effect was not reversed by the addition of ICI 182,780. Nonylphenol and 4-octylphenol reduced LPS-induced activation of MAPK signaling pathway, MKK1/2 and ERK, concomitant with decreased levels of LPS-induced acetylated histone 4 (H4) at the IP-10 and MDC gene loci. Nonylphenol and 4-octylphenol suppressed LPS-induced MDC expression in monocytes via, at least in part, the MKK1/2-ERK MAPK pathway and histone H4 acetylation, but not the estrogen receptor.
 ...
PMID:Suppressive effect on MDC and IP-10 expression in monocytes by endocrine disruptor chemicals. 1975 97

Insulin resistance, the major metabolic abnormality underlying type 2 diabetes, is associated with chronic inflammation and heavy macrophage infiltration in white adipose tissue (WAT). The therapeutic properties of the synthetic adrenal steroid Delta(5)-androstene-17alpha-ethynyl-3beta,7beta,17beta-triol (HE3286) were characterized in metabolic disease models. Treatment of diabetic db/db mice with HE3286 suppressed progression to hyperglycemia and markedly improved glucose clearance. Similar effects were also observed in insulin-resistant, diet-induced obese C57BL/6J mice and genetically obese ob/ob mice. This effect appeared to be a consequence of reduced insulin resistance because HE3286 lowered blood insulin levels in db/db and ob/ob mice. Treatment with HE3286 was accompanied by suppressed expression of the prototype macrophage-attracting chemokine monocyte chemoattractant protein-1 in WAT, along with its cognate receptor C-C motif chemokine receptor-2. Exposure of mouse macrophages to HE3286 in vitro caused partial suppression of endotoxin (lipopolysaccharide)-induced nuclear factor kappa-B (NF-kappaB)-sensitive reporter gene expression, NF-kappaB nuclear translocation, and NF-kappaB/p65 serine phosphorylation. Proinflammatory kinases, including IkappaB kinase, c-Jun NH2-terminal kinase, and p38, were also inhibited by HE3286. In ligand competition experiments HE3286 did not bind to classical sex steroid or corticosteroid receptors, including androgen receptor (AR), progesterone receptor, estrogen receptor (ER) alpha or ERbeta, and glucocorticoid receptor (GR). Likewise, in cells expressing nuclear receptor-sensitive reporter genes HE3286 did not substantially stimulate transactivation of AR, ER, GR, or peroxisome proliferator-activated receptor (PPAR) alpha, PPARdelta, and PPARgamma. These findings indicate that HE3286 improves glucose homeostasis in diabetic and insulin-resistant mice and suggest that the observed therapeutic effects result from attenuation of proinflammatory pathways, independent of classic sex steroid receptors, corticosteroid receptors, or PPARs.
 ...
PMID:Amelioration of glucose intolerance by the synthetic androstene HE3286: link to inflammatory pathways. 2006 30

Endothelial cells express both estrogen receptor (ER) alpha and beta. The objective of this study was to investigate if and how mediators of inflammation regulate endothelial cell ERalpha and ERbeta expression. ERalpha and ERbeta transcript and protein expression were determined by real-time quantitative PCR and Western blotting, respectively, in endothelial cell line bEnd.3 cells stimulated with the inflammation promoter lipopolysaccharide (E. coli LPS). Stimulation with LPS (500 ng/ml and 10 microg/ml) for 4 days reduced both ERalpha and ERbeta mRNA levels. The glucocorticoid dexamethasone (1 microM) had no effect on LPS-induced attenuation of ERalpha and beta transcript expression. Full-length 66-67 kDa ERalpha protein was unaffected by 4 days stimulation with LPS, while the 46-kDa ERalpha isoform was reduced by about 20%. ERbeta protein was reduced by about 40% by LPS at 4 days. Treatment with 17beta-estradiol (E(2), 100 nM) for 4 days increased ERbeta mRNA by about 8 times but had no effect on ERalpha mRNA level. The E(2)-induced increase in ERbeta transcript was not associated with increased ERbeta protein. E(2) increased ERbeta mRNA expression also in the presence of LPS, suggesting that inflammation-induced impairment of ERbeta signalling is rescued by estrogen.
 ...
PMID:Down-regulation of endothelial cell estrogen receptor expression by the inflammation promoter LPS. 2007 2

Dietary flavonoids have various biological functions, and there is increasing evidence that reduced prevalence and severity of allergic reactions are associated with the intake of flavonoids. Among natural flavonoids, apigenin is a potent anti-inflammatory agent. However, the mechanisms of apigenin's effect remain uncertain. Monocyte-derived chemokine (MDC) plays a pivotal role in recruiting T-helper (Th) 2 cells in the allergic inflammation process. In the late phase of allergic inflammation, the Th1 chemokine interferon-inducible protein 10 (IP-10) has also been found in elevated levels in the bronchial alveolar fluid of asthmatic children. We used human THP-1 monocyte cells, pretreated with or without apigenin, prior to lipopolysaccharide stimulation. By means of enzyme-linked immunosorbent assay, we found that apigenin inhibited production of both MDC and IP-10 by THP-1 cells and that the suppressive effect of apigenin was not reversed by the estrogen receptor antagonist ICI182780. The p65 phosphorylation of nuclear factor kappaB remained unaffected, but the phosphorylation of p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase mitogen-activated protein kinase pathways were all blocked. We found that inhibition of c-raf phosphorylation might be the target of apigenin's anti-inflammation property.
 ...
PMID:The natural flavonoid apigenin suppresses Th1- and Th2-related chemokine production by human monocyte THP-1 cells through mitogen-activated protein kinase pathways. 2017 Mar 40


<< Previous 1 2 3 4 5 6 7 Next >>