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  • The aspirin and heme-binding sites of ovine and murine prostaglandin endoperoxide synthases. 2108169

    Acetylation of Ser-530 of sheep prostaglandin endoperoxide (PGG/H) synthase by aspirin causes irreversible inactivation of the cyclooxygenase activity of the enzyme. To determine the catalytic function of the hydroxyl group of Ser-530, we used site-directed mutagenesis to replace Ser-530 with an alanine. Cos-1 cells transfected with expression vectors containing the native (Ser-530) or mutant (Ala-530) cDNAs for sheep PGG/H synthase expressed comparable cyclooxygenase and hydroperoxidase activities. Km values for arachidonate (8 microM) and ID50 values for reversible inhibition by the cyclooxygenase inhibitors, flurbiprofen (5 microM), flufenamate (20 microM), and aspirin (20 mM), were also the same for both native and mutant PGG/H synthases; however, only the native enzyme was irreversibly inactivated by aspirin. Thus, the "active site" Ser-530 of PGG/H synthase is not essential for catalysis or substrate binding. Apparently, acetylation of native PGG/H synthase by aspirin introduces a bulky sidechain at position 530 which interferes with arachidonate binding. In related studies, a cDNA for mouse PGG/H synthase was cloned and sequenced. A sequence of 35 residues with Ser-530 at the midpoint was identical in the two proteins. Thus, Ser-530 does lie in a highly conserved region, probably involved in cyclooxygenase catalysis. Sequence comparisons of mouse and sheep PGG/H synthase also provided information about the heme-binding site of the enzyme. The sheep HYPR sequence (residues 274-277), which had been proposed to form a portion of the distal heme-binding site, is not conserved in the mouse PGG/H synthase, suggesting that this region is not the distal heme-binding site. One sequence, TIWLREHNRV (residues 303-312 of the sheep enzyme), is very closely related to the sequence TLW(L)LREHNRL common to thyroid peroxidase and myeloperoxidase. The histidine in this latter sequence is the putative axial heme ligand of these peroxidases. We suggest that the histidine (His-309) of sheep PGG/H synthase sequence is the axial heme ligand of this enzyme.
    Document Type:
    Reference
    Product Catalog Number:
    MAB5586

  • Aspirin upregulates expression of urokinase type plasminogen activator receptor (uPAR) gene in human colon cancer cells through AP1. 16893520

    In this study, the effects of acetylsalicylic acid (aspirin) on the expression of uPAR and the mechanism by which it regulates expression of uPAR was examined in two different colon cancer cell lines HCT116 and GEO, respectively. The study shows that under physiological concentration, aspirin upregulates steady-state level expression of uPAR mRNA as well as expression of uPAR protein. Using a transient transfection assay, a region corresponding to -1 to -398 region of uPAR promoter has been identified which shows maximum responsiveness to aspirin treatment and found that this region is sufficient for the aspirin-induced up-regulation of uPAR. A stable integration of a single copy of this region coupled to luciferase reporter gene into the HCT116 genome also behaved similarly. Using gel mobility shift assays, it is found that the distal AP1 region between -171 and -186 is responsible for the aspirin-induced up-regulation of uPAR. Mutation of this region reduced up-regulation. Supershift assays identify that the bound proteins at this region are c-Jun and Fra-1. Real-time PCR analysis showed more than 4-fold increase in the binding of c-Jun and a 1.6-fold increase in the binding of Fra-1 in this region and this up-regulation corresponds to an increased binding of acetylated histone H4 in this region. Since an increase in the expression of uPAR corresponds to an increase in the migration of the cell, a migration assay was performed and result showed a 3-fold increased migration of HCT116 cells through the vitronectin-coated layer. Thus, an AP1 mediated pathway for aspirin induced up-regulation of uPAR has been identified.
    Document Type:
    Reference
    Product Catalog Number:
    07-360
    Product Catalog Name:
    Anti-acetyl-Histone H3 (Lys27) Antibody

  • Aspirin inhibits cell viability and mTOR downstream signaling in gastroenteropancreatic and bronchopulmonary neuroendocrine tumor cells. 25110431

    To investigate the effect of aspirin on neuroendocrine tumor (NET) cell growth and signaling in vitro.Human pancreatic BON1, bronchopulmonary NCI-H727 and midgut GOT1 neuroendocrine tumor cells were treated with different concentrations of aspirin (from 0.001 to 5 mmol/L), and the resulting effects on metabolic activity/cell proliferation were measured using cell proliferation assays and SYBR-DNA-labeling after 72, 144 and 216 h of incubation. The effects of aspirin on the expression and phosphorylation of several critical proteins that are involved in the most common intracellular growth factor signaling pathways (especially Akt protein kinase B) and mammalian target of rapamycin (mTOR) were determined by Western blot analyses. Propidium iodide staining and flow cytometry were used to evaluate changes in cell cycle distribution and apoptosis. Statistical analysis was performed using a 2-tailed Student's t-test to evaluate the proliferation assays and cell cycle analyses. The results are expressed as the mean ± SD of 3 or 4 independently performed experiments. Statistical significance was set at P less than 0.05.Treatment with aspirin suppressed the viability/proliferation of BON1, NCI-H727 and GOT1 cells in a time- and dose-dependent manner. Significant effects were observed at starting doses of 0.5-1 mmol/L and peaked at 5 mmol/L. For instance, after treatment with 1 mmol/L aspirin for 144 h, the viability of pancreatic BON1 cells decreased to 66% ± 13% (P less than 0.05), the viability of bronchopulmonary NCI-H727 cells decreased to 53% ± 8% (P less than 0.01) and the viability of midgut GOT1 cells decreased to 89% ± 6% (P less than 0.01). These effects were associated with a decreased entry into the S phase, the induction of the cyclin-dependent kinase inhibitor p21 and reduced expression of cyclin-dependent kinase 4 and cyclin D3. Aspirin suppressed mTOR downstream signaling, evidenced by the reduced phosphorylation of the mTOR substrates 4E binding protein 1, serine/threonine kinase P70S6K and S6 ribosomal protein and inhibited glycogen synthase kinase 3 activity. We observed the (compensatory) activation of tuberous sclerosis 2, the serine/threonine specific protein kinase AKT and extracellular signal-regulated kinases.Aspirin demonstrates promising anticancer properties for NETs in vitro. Further preclinical and clinical studies are needed.
    Document Type:
    Reference
    Product Catalog Number:
    06-182

  • Cytokines and hs-CRP levels in individuals treated with low-dose aspirin for cardiovascular prevention: a population-based study (CoLaus Study). 24594292

    Pro-inflammatory cytokines and high-sensitive C-reactive protein (hs-CRP) are associated with increased risk for cardiovascular disease. Low-dose aspirin for CV prevention is reported to have anti-inflammatory effects. The aim of this study was to determine the association between pro-inflammatory cytokines and hs-CRP levels and low-dose aspirin use for cardiovascular prevention in a population-based cohort (CoLaus Study). We assessed blood samples in 6085 participants (3201 women) aged 35-75years. Medications' use and indications were recorded. Among aspirin users (n=1'034; 17%), overall low-dose users (351; 5.8%) and low-dose for cardiovascular prevention users (324; 5.3%) were selected for analysis. Pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α were assessed by a multiplex particle-based flow cytometric assay and hs-CRP by an immunometric assay. Cytokines and hs-CRP were presented in quartiles. Multivariate analysis adjusting for sex, age, smoking status, body mass index, diabetes mellitus and immunomodulatory drugs showed no association between cytokines and hs-CRP levels and low-dose aspirin use for cardiovascular prevention, either comparing the topmost vs. the three other quartiles (OR 95% CI, 0.84 (0.59-1.18), 1.03 (0.78-1.32), 1.10 (0.83-1.46), 1.00 (0.67-1.69) for IL-1β, IL-6, TNF-α and hs-CRP, respectively), or comparing the topmost quartile vs. the first one (OR 95% CI, 0.87 (0.60-1.26), 1.19 (0.79-1.79), 1.26 (0.86-1.84), 1.06 (0.67-1.69)). Low-dose aspirin use for cardiovascular prevention does not impact plasma pro-inflammatory cytokine and hs-CRP levels in a population-based cohort.
    Document Type:
    Reference
    Product Catalog Number:
    HCYTOMAG-60K

  • Up-regulation of ciliary neurotrophic factor in astrocytes by aspirin: implications for remyelination in multiple sclerosis. 23653362

    Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor, and the mechanisms by which CNTF expression could be increased in the brain are poorly understood. Acetylsalicylic acid (aspirin) is one of the most widely used analgesics. Interestingly, aspirin increased mRNA and protein expression of CNTF in primary mouse and human astrocytes in a dose- and time-dependent manner. Aspirin induced the activation of protein kinase A (PKA) but not protein kinase C (PKC). H-89, an inhibitor of PKA, abrogated aspirin-induced expression of CNTF. The activation of cAMP-response element-binding protein (CREB), but not NF-κB, by aspirin, the abrogation of aspirin-induced expression of CNTF by siRNA knockdown of CREB, the presence of a consensus cAMP-response element in the promoter of CNTF, and the recruitment of CREB and CREB-binding protein to the CNTF promoter by aspirin suggest that aspirin increases the expression of the Cntf gene via the activation of CREB. Furthermore, we demonstrate that aspirin-induced astroglial CNTF was also functionally active and that supernatants of aspirin-treated astrocytes of wild type, but not Cntf null, mice increased myelin-associated proteins in oligodendrocytes and protected oligodendrocytes from TNF-α insult. These results highlight a new and novel myelinogenic property of aspirin, which may be of benefit for multiple sclerosis and other demyelinating disorders.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Direct regulation of caspase‑3 by the transcription factor AP‑2α is involved in aspirin‑induced apoptosis in MDA‑MB‑453 breast cancer cells. 23292806

    Aspirin has been reported to trigger apoptosis in various cancer cell lines. However, the detailed mechanisms involved remain elusive. The present study aimed to investigate whether aspirin plays a role in apoptosis of MDA-MB-453 cells. The effect of aspirin on the proliferation of human MDA-MB-453 cells breast cancer cells was evaluated using MTT assay, flow cytometry and western blotting. The present study reports that aspirin induces the apoptosis of MDA‑MB‑453 breast cancer cells which was attributed to the increased expression and activation of caspase‑3. Moreover, AP‑2α, a transcription factor highly expressed in MDA‑MB‑453 cells, was identified as a negative regulator of caspase‑3 transcription and AP‑2α was attenuated following aspirin treatment. Therefore, aspirin may increase the expression of caspase‑3 by inducing the degradation of AP‑2α, which increases activated caspase‑3 expression, thereby triggering apoptosis in MDA‑MB‑453 cells. Thus, aspirin may be used in breast cancer therapy.
    Document Type:
    Reference
    Product Catalog Number:
    17-371
    Product Catalog Name:
    EZ-ChIP™

  • Pharmacological inhibition of diabetic retinopathy: aminoguanidine and aspirin. 11423486

    Effects of aminoguanidine and aspirin on the development of retinopathy have been examined in 5-year studies of diabetic dogs. Either agent was administered daily in doses of 20-25 mg. kg(-1). day(-1). Because severity of hyperglycemia greatly influences development of the retinopathy, special effort was devoted to maintaining comparable glycemia in experimental and control groups. The retinal vasculature was isolated by the trypsin digest method, and retinopathy was assessed by light microscopy. Diabetes for 5 years resulted, as expected, in saccular capillary aneurysms, pericyte ghosts, acellular capillaries, retinal hemorrhages, and other lesions. Administration of aminoguanidine essentially prevented the retinopathy, significantly inhibiting the development of retinal microaneurysms, acellular capillaries, and pericyte ghosts compared with diabetic controls. Aspirin significantly inhibited the development of retinal hemorrhages and acellular capillaries over the 5 years of study, but had less effect on other lesions. Although diabetes resulted in significantly increased levels of advanced glycation end products (AGEs) (namely, pentosidine in tail collagen and aorta, and Hb-AGE), aminoguanidine had no significant influence on these parameters of glycation. Nitration of a retinal protein was significantly increased in diabetes and inhibited by aminoguanidine. The biochemical mechanism by which aminoguanidine has inhibited retinopathy thus is not clear. Aminoguanidine (but not aspirin) inhibited a diabetes-induced defect in ulnar nerve conduction velocity, but neither agent was found to influence kidney structure or albumen excretion.
    Document Type:
    Reference
    Product Catalog Number:
    06-284
    Product Catalog Name:
    Anti-Nitrotyrosine Antibody

  • Modulation of insulin signalling by insulin sensitizers. 15787606

    Insulin resistance is a hallmark of Type II diabetes. It is well documented that insulin sensitizers such as peroxisome-proliferator-activated receptor gamma agonists and aspirin improve insulin action in vivo. The detailed mechanisms by which the insulin sensitizers promote insulin signalling, however, are not completely understood and remain somewhat controversial. In the present review, we summarize our studies attempting to explore the molecular mechanisms underlying the effects of insulin sensitizers in cells and in animal models of insulin resistance. In 3T3-L1 adipocytes and/or in HEK-293 cells stably expressing recombinant IRS1 protein (insulin receptor substrate protein 1), the peroxisome-proliferator-activated receptor gamma agonist rosiglitazone and aspirin promote insulin signalling by decreasing inhibitory IRS1 serine phosphorylation. Increased IRS1 Ser-307 phosphorylation and concomitant decreased insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation and Akt threonine phosphorylation were observed in adipose tissues of Zucker obese rats compared with lean control rats. Treatment with rosiglitazone for 24 and 48 h increased insulin signalling and decreased IRS1 Ser-307 phosphorylation concomitantly. Treatment of the Zucker obese rats with rosiglitazone for 24 h also reversed the high circulating levels of free fatty acids, which have been shown to correlate with increased IRS1 serine phosphorylation. Taken together, the results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal may be physiologically relevant to insulin sensitization in vivo.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple