Modulation Of AP-1 Research Articles

COMBINED EFFECTS OF QUERCETIN AND MODULATORS OF REDOX SENSITIVE FACTORS ON THE INDICATORS OF SYSTEMIC INFLAMMATORY RESPONSE, CARBOHYDRATE AND LIPID METABOLISM IN RATS EXPOSED TO INTRAPERITONEAL AND INTRAGINGIVAL ADMINISTRATION OF SALMONELLA TYPHI LIPOPOLY

The experiment on 70 white rats was designed to investigate the effects of a water-soluble form of quercetin and modulators of AP-1 and Nrf2 transcription factors on the blood indicators of the systemic inflammatory response (SIR), and carbohydrate and lipid metabolism under the conditions of intraperitoneal and intra-gingival administration of S. typhi lipopolysaccharide (LPS). The animals were divided into 7 groups: the 1st group consisted of intact rats; the 2nd group included animals exposed to combined systemic and local administration of LPS - pyrogenal; the 3rd, 4th and 5th groups included the animals who were respectively injected with water-soluble complex of quercetin and polyvinylpyrrolidone (corvitin) in a dose of 100 mg/kg (10 mg/kg in terms of quercetin), an inhibitor of activation of AP-1 SR 11302 (in a dose of 1 mg / kg) and Keap1 / Nrf2 / antioxidant-responsive element (ARE) signaling pathway inducer epigallocatechin-3-gallate (EGCG, in a dose of 21.1 mg / kg) 3 times a week, starting on the 30th day since the experiment modeling. The 6th and 7th groups of the rats were subjected to combined effects of quercetin + SR 11302 and quercetin + EGCG, respectively. The study has demonstrated the combination of quercetin and SR 11302, or EGCG, in systemic and local administration of S. typhi lipopolysaccharide more effectively prevents the production of ceruloplasmin, a SIR marker, by-products of lipid peroxidation in rats’ blood, as well as increases its antioxidant potential compared to the separate application of these drugs. The combination of quercetin and SR 11302, or EGCG, under the experimental conditions has been found out to more effectively correct carbohydrate metabolism disorders (hyperinsulinemia, insulin resistance) than this occurs under separate usage of the agents, but does not reveal significant synergism in the correction of dyslipoproteinemia.

Exacerbation of Chikungunya Virus Rheumatic Immunopathology by a High Fiber Diet and Butyrate.

Chikungunya virus (CHIKV) is a mosquito transmitted alphavirus associated with a robust systemic infection and an acute inflammatory rheumatic disease. A high fiber diet has been widely promoted for its ability to ameliorate inflammatory diseases. Fiber is fermented in the gut into short chain fatty acids such as acetate, propionate, and butyrate, which enter the circulation providing systemic anti-inflammatory activities. Herein we show that mice fed a high fiber diet show a clear exacerbation of CHIKV arthropathy, with increased edema and neutrophil infiltrates. RNA-Seq analyses illustrated that a high fiber diet, in this setting, promoted a range of pro-neutrophil responses including Th17/IL-17. Gene Set Enrichment Analyses demonstrated significant similarities with mouse models of inflammatory psoriasis and significant depression of macrophage resolution phase signatures in the CHIKV arthritic lesions from mice fed a high fiber diet. Supplementation of the drinking water with butyrate also increased edema after CHIKV infection. However, the mechanisms involved were different, with modulation of AP-1 and NF-κB responses identified, potentially implicating deoptimization of endothelial barrier repair. Thus, neither fiber nor short chain fatty acids provided benefits in this acute infectious disease setting, which is characterized by widespread viral cytopathic effects and a need for tissue repair.

Anticancer effects of monocarbonyl analogs of curcumin: oxidative stress, nuclear translocation and modulation of AP-1 and NF-κB

Purpose: In order to elucidate anticancer effects of monocarbonyl analogs of curcumin (MACs), we have undertaken the present study to obtain information regarding drug targets by using a microarray approach, and to study the cellular localization of EF24 and the activity of two key transcription factors, AP-1 and NF-κB, involved in complex cellular responses of cell survival and death. Methods: Cytotoxic activity of various drugs was evaluated using a Neutral Red Dye assay. Cellular localization of biotinylated EF24 (active) and reduced EF24 (inactive) was determined using light and confocal microscopy. Measurement of transcription factor binding was carried out using Transfactor ELISA kits (BD Clontech, Palo Alto, CA). Gene microarray processing was performed at Expression Analysis, Inc (Durham, NC) using Affymetrix Human U133A Gene Chips. Results: In this study, we demonstrated that EF24 and UBS109 exhibit much more potent cytotoxic activity against pancreatic cancer than the current standard chemotherapeutic agent gemcitabine. EF24, rapidly localizes to the cell nucleus. The compound modulates the DNA binding activity of NF-κB and AP-1 in MDA-MB-231 human breast cancer cells and DU-145 human prostate cancer cells. Immunohistochemical studies utilizing biotinylated-EF24 and chemically-reduced EF24 show that the unsaturated compound and biotinylated EF24, but not reduced EF24, translocates to the nucleus within 30 minutes after the addition of drug. Through a gene microarray study, EF24 is shown to affect genes directly involved in cytoprotection, tumor growth, angiogenesis, metastasis and apoptosis. Conclusion: EF24 and UBS109 warrant further investigation for development of pancreatic cancer therapy. The dualistic modulations of gene expression may be a manifestation of the cell responses for survival against oxidative stress by EF24. However, the cytotoxic action of EF24 ultimately prevails to kill the cells.

Curcumin attenuates carcinogenesis by down regulating proinflammatory cytokine interleukin-1 (IL-1α and IL-1β) via modulation of AP-1 and NF-IL6 in lymphoma bearing mice

Interleukin-1 (IL-1α and IL-1β) is a prototypic, potent, multifunctional proinflammatory cytokine affecting almost all cell types. Expression of IL-1 is up regulated in different tumor phenotypes and is implicated as an important factor in tumor progression via expression of metastatic, angiogenic genes and growth factors. Therefore, down regulation of expression of IL-1 may be able to inhibit cancer progression. Mechanism of transcriptional regulation of mouse IL-1α is not yet reported. AP-1 binding site at -12 to -6 on human IL-1α promotor is highly conserved in rat IL-1α gene and regulates its expression. Based on in silico analysis, regions -12 to -6bp is found to be conserved in human and mouse IL-1α gene promotor and therefore selected to study activation of IL-1α. Further, the regions -12 to -6bp in mouse IL-1α gene promotor corresponding to AP-1 binding element show 3'→5' orientation, necessary for AP-1 binding. The present work is focused on long term effect of curcumin on expression of IL-1α and IL-1β in liver of lymphoma bearing mice. Transcriptional regulation of IL-1α and IL-1β was analyzed by AP-1 and NF-IL-6 respectively. Elevated expression and protein level of IL-1α and IL-1β were found in lymphoma bearing mice compared to normal, which were significantly down regulated by curcumin treatment. Similarly, curcumin treatment down regulated activation of IL-1α and IL-1β via AP-1 and NF-IL-6 respectively. The findings conclude that curcumin attenuates carcinogenesis by down regulating proinflammatory cytokine interleukin-1 (IL-1α and IL-1β) via modulation of AP-1 and NF-IL6 respectively in lymphoma bearing mice.

663 Modulation of AP-1, NF-κB and STAT Transcription Factors by Methoxylated Thiostilbene Derivatives in Human Squamous Carcinoma A431 Cell Line

663 Modulation of AP-1, NF-κB and STAT Transcription Factors by Methoxylated Thiostilbene Derivatives in Human Squamous Carcinoma A431 Cell Line

Abstract B66: Benzo(a)pyrene increases expression of HPV oncoproteins: A potential co-factor for increased cervical cancer among American Indian women living in the Northern Plains

Abstract Introduction: Cervical cancer remains one of the most common and deadly cancers in women worldwide. There is a significant health disparity in the incidence and mortality of cervical cancer between American Indian and Caucasian women, especially for American Indian women residing in the Northern Plains. The development of cervical cancer is closely associated with persistent infection with a high risk genotype of HPV. Additionally, exposure to cigarette smoke is also a risk factor for cervical cancer. Our previous and current studies indicate that American Indian women living in the Northern Plains have a high rate of both HPV infection and exposure to cigarette smoke. While smoking is known to increase the risk of developing cervical cancer, the molecular interactions between HPV and smoke carcinogens are not well known. The purpose of this study was to determine the molecular effects of benzo-a-pyrene (BaP) (a carcinogen in cigarette smoke) on the expression of HPV oncoproteins. Methods: The effects of BaP on HPV associated molecular events was determined using cervical cancer cell lines. Following BaP exposure in either an acute or extended treatment protocol, the levels of HPV oncoproteins, activation of NFkB and AP-1 cell signaling pathways and intracellular reactive oxygen species (ROS) were determined using a combination of techniques including flow cytometry, immunofluorescence and immunoblotting. Cervical cancer cells were also treated with curcumin, a natural anti-cancer and chemopreventive compound. Results: In cervical cancer cells, exposure to BaP increased the expression of HPV oncoproteins in both acute and extended treatment protocols. BaP exposure also increased activation of NFkB and increased levels of ROS. To address the mechanism of increased HPV E7 protein expression, we assessed the ability of BaP to activate AP1 signaling. The AP1 family of transcription factors (including c-Fos) is known to induce transcription of HPV E6/E7 through binding to the Upstream Regulatory Region (URR). We detected an increase in the amount of AP1 (c-Fos) in the nucleus of cervical cancer cells exposed to BaP, suggesting that BaP may increase HPV oncoprotein expression through modulation of AP1. Interestingly, BaP's increase in HPV oncoprotein expression was inhibited by curcumin treatment, likely through curcumin's inhibition of AP-1 and NFkB pathways. Conclusion: Taken together this data imply that a high prevalence of HPV infection and a high exposure rate to BaP may synergize to increase the incidence and mortality of cervical cancer in American Indian women residing in the Northern Plains. Additionally, we have also identified curcumin as a potential compound that may be effective in preventing and/or treating cervical cancer. Increased cervical cancer screening is warranted for American Indian women living in the Northern Plains and additional steps, such as the use of the HPV vaccine and use of dietary agents, such as curcumin, may also be helpful to effectively decrease the health disparity associated with cervical cancer in American Indian women. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B66.

Gestational zinc deficiency affects the regulation of transcription factors AP-1, NF-κB and NFAT in fetal brain

Transcription factors AP-1, nuclear factor κB (NF-κB) and NFAT are central to brain development by regulating the expression of genes that modulate cell proliferation, differentiation, apoptosis and synaptic plasticity. This work investigated the consequences of feeding zinc-deficient and marginal zinc diets to rat dams during gestation on the modulation of AP-1, NF-κB and NFAT in fetal brain. Sprague–Dawley rats were fed from gestation day (GD) 0 a control diet ad libitum (25 μg zinc/g diet, C), a zinc-deficient diet ad libitum (0.5 μg zinc/g diet, ZD), the control diet in the amounts eaten by the ZD rats (restrict fed, RF) or a diet containing a marginal zinc concentration ad libitum (10 μg zinc/g diet, MZD) until GD 19. AP-1-DNA binding was higher (50–190%) in nuclear fraction isolated from ZD, RF and MZD fetal brains compared to controls. In MZD fetal brain, high levels of activation of the upstream mitogen-activated protein kinases JNK and p38 and low levels of ERK phosphorylation were observed. Total levels of NF-κB and NFAT activation were higher or similar in the ZD and MZD groups than in controls, respectively. However, NF-κB- and NFAT-DNA binding in nuclear fractions was markedly lower in ZD and MZD fetal brain than in controls (50–80%). The latter could be related to zinc deficiency-associated alterations of the cytoskeleton, which is required for NF-κB and NFAT nuclear transport. In summary, suboptimal zinc nutrition during gestation could cause long-term effects on brain function, partially through a deregulation of transcription factors AP-1, NF-κB and NFAT.

Tauroursodeoxycholic acid reduces bile acid-induced apoptosis by modulation of AP-1

Ursodeoxycholic acid (UDCA) is used in the therapy of cholestatic liver diseases. Apoptosis induced by toxic bile acids plays an important role in the pathogenesis of liver injury during cholestasis and appears to be mediated by the human transcription factor AP-1. We aimed to study if TUDCA can decrease taurolitholic acid (TLCA)-induced apoptosis by modulating AP-1. TLCA (20 μM) upregulated AP-1 proteins cFos (26-fold) and JunB (11-fold) as determined by quantitative real-time PCR in HepG2-Ntcp hepatoma cells. AP-1 transcriptional activity increased by 300% after exposure to TLCA. cFos and JunB expression as well as AP-1 transcriptional activity were unaffected by TUDCA (75 μM). However, TUDCA significantly decreased TLCA-induced upregulation of cFos and JunB. Furthermore, TUDCA inhibited TLCA-induced AP-1 transcriptional activity and reduced TLCA-induced apoptosis. These data suggest that reversal of bile acid-induced AP-1 activation may be relevant for the antiapoptotic effect of TUDCA in liver cells.

15-hydroxyeicosatrienoic acid (15-HETrE) suppresses epidermal hyperproliferation via the modulation of nuclear transcription factor (AP-1) and apoptosis.

The purpose of this study was to ascertain whether the antiproliferative effect of 15-hydroxyeicosatrienoic acid (15-HETrE), a monohydroxy fatty acid generated from dihomo-gamma-linolenic acid, in an experimentally induced guinea pig hyperproliferative model involves alterations in nuclear transcription factor (AP-1) and apoptosis. The topical application of docosahexaenoic acid (DHA) to normal guinea pig skin elicited a severe hyperplasia which was accompanied by the suppression of AP-1 expression in a time-dependent manner. Since apoptosis is pivotal in tissue turnover, the expression of two apoptotic proteins (Bcl-2 and caspase-3) after DHA and 15-HETrE treatment was explored. DHA-induced hyperproliferation enhanced the expression of Bcl-2 (an antiapoptotic protein) but inhibited the expression of caspase-3 (an apoptotic protein). 15-HETrE, on the other hand, reversed the DHA-induced epidermal hyperplasia, and upregulated epidermal AP-1 expression. These events paralleled the suppression of Bcl-2 and the elevation of caspase-3. Taken together, these results suggest that the antiproliferative effect of 15-HETrE may, at least in part, be via the modulation of AP-1 and apoptosis.

Alpha-melanocyte-stimulating hormone modulates activation of NF-kappa B and AP-1 and secretion of interleukin-8 in human dermal fibroblasts.

Alpha-melanocyte-stimulating hormone (alpha-MSH) has evolved as a mediator of diverse biological activities in an ever-growing number of non-melanocytic cell types. One mechanism by which alpha-MSH exerts its effects is modulation of AP-1 and NF-kappa B. These two transcription factors also play an important role in fibroblasts, in extracellular matrix composition, and in cytokine expression. By use of electric mobility shift assays, we demonstrate that alpha-MSH (10(-6) to 10(-14) M) activates AP-1 in human dermal fibroblasts, whereas coincubation with interleukin-1 beta (IL-1 beta) results in suppression of its activation. alpha-MSH also induces activation of NF-kappa B but does not modulate DNA binding on costimulation with IL-1 beta. Since AP-1 and NF-kappa B are key elements in controlling interleukin-8 (IL-8) transcription, human fibroblasts were treated with alpha-MSH and IL-1 beta for 24 hours, and cytokine levels in the supernatants were measured by ELISA. alpha-MSH alone had little effect, whereas coincubation with IL-1 beta led to marked downregulation of IL-8 secretion (at most 288 +/- 152 ng/mL) when compared to treatment with IL-1 beta alone (919 +/- 157 ng/mL). Our results indicate that alpha-MSH exerts modulatory effects on the activation of NF-kappa B and AP-1, and that it can regulate chemokine secretion in human dermal fibroblasts. These effects of alpha-MSH may have important regulatory functions in extracellular matrix composition, wound healing, or angiogenesis.