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Adenosine A1 Receptor

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Bertil B. Fredholm – One of the best experts on this subject based on the ideXlab platform.

  • Adenosine A1 Receptors regulate bone resorption in mice: Adenosine A1 Receptor blockade or deletion increases bone density and prevents ovariectomy‐induced bone loss in Adenosine A1 Receptor–knockout mice
    Arthritis and rheumatism, 2010
    Co-Authors: Firas M. Kara, Bertil B. Fredholm, Stephen B. Doty, Adele L. Boskey, Steven R. Goldring, Mone Zaidi, Bruce N. Cronstein
    Abstract:

    Objective Accelerated osteoclastic bone resoresorption plays a central role in the pathogenesis of osteoporosis and other bone diseases. Because identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and developing new treatments, we studied the effect of Adenosine A1 Receptor blockade or deletion on bone density. Methods The bone mineral density (BMD) in Adenosine A1 Receptor–knockout (A1R-knockout) mice was analyzed by dual x-ray absorptiometry (DXA) scanning, and the trabecular and cortical bone volume was determined by microfocal computed tomography (micro-CT). The mice were ovariectomized or sham-operated, and 5 weeks after surgery, when osteopenia had developed, several parameters were analyzed by DXA scanning and micro-CT. A histologic examination of bones obtained from A1R-knockout and wild-type mice was carried out. Visualization of osteoblast function (bone formation) after tetracycline double-labeling was performed by fluorescence microscopy. Results Micro-CT analysis of bones from A1R-knockout mice showed significantly increased bone volume. Electron microscopy of bones from A1R-knockout mice showed the absence of ruffled borders of osteoclasts and osteoclast bone resoresorption. Immunohistologic analysis demonstrated that although osteoclasts were present in the A1R-knockout mice, they were smaller and often not associated with bone. No morphologic changes in osteoblasts were observed, and bone-labeling studies revealed no change in the bone formation rates in A1R-knockout mice. Conclusion These results suggest that the Adenosine A1 Receptor may be a useful target in treating diseases characterized by excessive bone turnover, such as osteoporosis and prosthetic joint loosening.

  • Influence of the Adenosine A1 Receptor on blood pressure regulation and renin release
    American journal of physiology. Regulatory integrative and comparative physiology, 2005
    Co-Authors: Russell D. Brown, Bertil B. Fredholm, Peter Thorén, Andreas Steege, Ralf Mrowka, Johan Sällström, Ole Skøtt, A. Erik G. Persson
    Abstract:

    The present study was performed to investigate the role of Adenosine A1 Receptors in regulating blood pressure in conscious mice. Adenosine A1Receptor knockout (A1R−/−) mice and their wild-type (A…

  • Increased nociceptive response in mice lacking the Adenosine A1 Receptor
    Pain, 2005
    Co-Authors: Jing-xia Hao, Linda Halldner, Cecilia Lövdahl, Gary E. Delander, Zsuzsanna Wiesenfeld-hallin, Bertil B. Fredholm
    Abstract:

    The role of the Adenosine A1 Receptor in nociception was assessed using mice lacking the A1 Receptor (A1R-/-) and in rats. Under normal conditions, the A1R-/- mice exhibited moderate heat hyperalgesia in comparison to the wild-type mice (A1R+/+). The mechanical and cold sensitivity were unchanged. The antinociceptive effect of morphine given intrathecally (i.t.), but not systemically, was reduced in A1R-/- mice and this reduction in the spinal effect of morphine was not associated with a decrease in binding of the mu-opioid ligand DAMGO in the spinal cord. A1R-/- mice also exhibited hypersensitivity to heat, but not mechanical stimuli, after localized inflammation induced by carrageenan. In mice with photochemically induced partial sciatic nerve injury, the neuropathic pain-like behavioral response to heat or cold stimulation were significantly increased in the A1R-/-mice. Peripheral nervnerve injury did not change the level of Adenosine A1 Receptor in the dorsal spinal cord in rats and i.t. administration of R-PIA effectively alleviated pain-like behaviors after partial nerve injury in rats and in C57/BL/6 mice. Taken together, these data suggest that the Adenosine A1 Receptor plays a physiological role in inhibiting nociceptive input at the spinal level in mice. The C-fiber input mediating noxious heat is inhibited more than other inputs. A1 Receptors also contribute to the antinociceptive effect of spinal morphine. Selective A1 Receptor agonists may be tested clinically as analgesics, particularly under conditions of neuropathic pain.

Arthur Christopoulos – One of the best experts on this subject based on the ideXlab platform.

  • structural basis for binding of allosteric drug leads in the Adenosine A1 Receptor
    Scientific Reports, 2018
    Co-Authors: Yinglong Miao, Apurba Bhattarai, Anh T. N. Nguyen, Arthur Christopoulos
    Abstract:

    Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the Adenosine A1 Receptor (A1AR), structural binding modes of the Receptor PAMs remain unknown. Using the first X-ray structure of the A1AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A1AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 A away from the Receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A1AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the Receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the Receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist sampled a significantly larger conformational space and even dissociated from the A1AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A1AR, which will greatly facilitate the Receptor structure-based drug design.

  • structure of the Adenosine A1 Receptor reveals the basis for subtype selectivity
    Cell, 2017
    Co-Authors: Alisa Glukhova, Anh T. N. Nguyen, Peter J Scammells, Patrick M Sexton, David M Thal, Elizabeth A Vecchio, Manuela Jorg, Lauren T May, Arthur Christopoulos
    Abstract:

    The Adenosine A1 Receptor (A1-AR) is a G-protein-coupled Receptor that plays a vital role in cardiac, renal, and neuronal processes but remains poorly targeted by current drugs. We determined a 3.2 A crystal structure of the A1-AR bound to the selective covalent antagonist, DU172, and identified striking differences to the previously solved Adenosine A2A Receptor (A2A-AR) structure. Mutational and computational analysis of A1-AR revealed a distinct conformation of the second extracellular loop and a wider extracellular cavity with a secondary binding pocket that can accommodate orthosteric and allosteric ligands. We propose that conformational differences in these regions, rather than amino-acid divergence, underlie drug selectivity between these Adenosine Receptor subtypes. Our findings provide a molecular basis for AR subtype selectivity with implications for understanding the mechanisms governing allosteric modulation of these Receptors, allowing the design of more selective agents for the treatment of ischemia-reperfusion injury, renal pathologies, and neuropathic pain.

  • determination of Adenosine A1 Receptor agonist and antagonist pharmacology using saccharomyces cerevisiae implications for ligand screening and functional selectivity
    Journal of Pharmacology and Experimental Therapeutics, 2009
    Co-Authors: Gregory D Stewart, Peter J Scammells, Celine Valant, Patrick M Sexton, Simon J Dowell, Dalibor Mijaljica, Rodney J Devenish, Arthur Christopoulos
    Abstract:

    The budding yeast, Saccharomyces cerevisiae, is a convenient system for coupling heterologous G protprotein-coupled Receptors (GPCRs) to the pheromone response pathway to facilitate empirical ligand screening and/or GPCR mutagenesis studies. However, few studies have applied this system to define GPCR-G protprotein-coupling preferences and furnish information on ligand affinities, efficacies, and functional selectivity. We thus used different S. cerevisiae strains, each expressing a specific human Gα/yeast GpA1 protein chimera, and determined the pharmacology of various ligands of the coexpressed human Adenosine A1 Receptor. These assays, in conjunction with the application of quantitative models of agonism and antagonism, revealed that (−)-N6-(2-phenylisopropyl)Adenosine was a high-efficacy agonist that selectively coupled to Gpa/1Gαo, GpA1/Gαi1/2, and GpA1/Gαi3, whereas the novel compound, 5′-deoxy-N6-(endo-norborn-2-yl)-5′-(2-fluorophenylthio)Adenosine (VCP-189), was a lower-efficacy agonist that selectively coupled to GpA1/Gαi proteins; the latter finding suggested that VCP-189 might be functionally selective. The affinity of the antagonist, 8-cyclopentyl-1,3-dipropylxanthine, was also determined at the various strains. Subsequent experiments performed in mammalian Chinese hamster ovary cells monitoring cAMP formation/inhibition, intracellular calccalcium mobimobilization, phosphorylation of extracellular signal-regulated kinase 1 and 2 or 35S-labeled guanosine 5′-(γ-thio)triphosphate binding, were in general agreement with the yeast data regarding agonist efficacy estimation and antagonist affinity estimation, but revealed that the apparent functional selectivity of VCP-189 could be explained by differences in stimulus-response coupling between yeast and mammalian cells. Our results suggest that this yeast system is a useful tool for quantifying ligand affinity and relative efficacy, but it may lack the sensitivity required to detect functional selectivity of low-efficacy agonists.

Adriaan P Ijzerman – One of the best experts on this subject based on the ideXlab platform.

  • long residence time Adenosine A1 Receptor agonists produce sustained wash resistant antilipolytic effect in rat adipocytes
    Biochemical Pharmacology, 2019
    Co-Authors: Yi Yun, Adriaan P Ijzerman, Jianmin Chen, Rongfang Liu, Wenbing Chen, Chunji Liu, Ruoqi Wang, Zhongzhi Hou, Ying Sun, Laura H Heitman
    Abstract:

    Abstract Elevated circulating free fattfatty acid (FFA) level is closely linked to the pathogenesis of insulin resistance and type 2 diabdiabetes mellitus. Activation of the Adenosine A1 Receptor (A1R) inhibits lipolysis in adipocytes and hence reduces the concentration of FFA, which represents a potential target for the development of antilipolytic agents. We aimed to assess the binding affinity as well as target binding kinetics of A1R agonists and further delineate a possible relationship with their antilipolytic effect in adipocytes. Radioligand binding assays were performed to determine the affinity and kinetics of three representative A1R agonists, namely CPA, LUF6944 and LUF6941, on the rat A1R. Functional responses to these agonists were examined in both a recombinant cell system and physiologically relevant rat adipocytes. The three A1R agonists displayed similar affinity while divergent target binding kinetics on the rat A1R. Irrespective of equilibrium binding affinity, temporal analysis of Receptor signaling demonstrated persistent functional responses for the long residence time agonist, despite removal of excess agonist, in both a recombinant cell system and in rat adipocytes. By contrast, such effect was less pronounced or even lost for agonists with medium or short Receptor residence time, respectively. Our results indicate that ligand Receptor binding kinetics rather than their affinity or potency play an essential role in regulating cellular responses. The long residence time A1R agonist produces a sustained wash-resistant antilipolytic effect in rat adipocytes and thus may represent a potential antilipolytic alternative for further investigation.

  • hybrid ortho allosteric ligands for the Adenosine A1 Receptor
    Journal of Medicinal Chemistry, 2010
    Co-Authors: Rajeshwar Narlawar, Robert J Lane, Munikumar Reddy Doddareddy, Judy Lin, Johannes Brussee, Adriaan P Ijzerman
    Abstract:

    Many G protprotein-coupled Receptors (GPCRs), including the Adenosine A1 Receptor (A1AR), have been shown to be allosterically modulated by small molecule ligands. So far, in the absence of structural information, the exact location of the allosteric site on the A1AR is not known. We synthesized a series of bivalent ligands (4) with an increasing linker length between the orthosteric and allosteric pharmacophores and used these as tools to search for the allosteric site on the A1AR. The compounds were tested in both equilibrium radioligand displacement and functional assays in the absence and presence of a reference allosteric enhancer, (2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluoromethyl)phenyl]methanone, PD81,723 (1). Bivalent ligand N6-[2-amino-3-(3,4-dichlorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl-9-nonyloxy-4-phenyl]-Adenosine 4h (LUF6258) with a 9 carbon atom spacer did not show significant changes in affinity or potency in the presence of 1, indicating that this ligand bridged both sites o…

  • temperature dependence of the affinity enhancement of selective Adenosine A1 Receptor agonism a thermodynamic analysis
    European Journal of Pharmacology, 2002
    Co-Authors: Alessandro Dalpiaz, Palmarisa Franchetti, Barbara Pavan, Francoise Ngo Ngos, Adriaan P Ijzerman
    Abstract:

    Abstract The 2-amino-benzoylthiophene derivatives LUF 5468 [(2-amino-4-ethyl-5-methyl-3-thienyl)[3-(trifluoromethyl)phenyl]methanone] and LUF 5484 [(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3,4-dichlorophenyl)methanone] have been shown to allosterically enhance the Adenosine A1 Receptor agonist binding. We report a thermodynamic analysis of the agonist affinity obtained at human Adenosine A1 Receptors, in the presence and absence of LUF 5468 and LUF 5484. Moreover, an analysis of the temperature dependence for association and dissociation rates of N6-cyclohexylAdenosine (CHA) binding was performed in the absence and presence of LUF 5484. Thermodynamic data were obtained by affinity measurements performed at different temperatures followed by van’t Hoff analysis. The results indicate that the agonist binding is always totally entropy-driven, and that the modulators contribute to decrease the ΔG° , ΔH°  and ΔS°  values. It is concluded that the enhancers are able to increase the non-bonded interactions of the binding site with agonists as CHA, N6-cyclopentlylAdenosine (CPA), 2′-methyl-N6-cyclopentylAdenosine (MeCPA) and 2-chloro-2′methyl-N6-cyclopentylAdenosine (MeCCPA).

Laura H Heitman – One of the best experts on this subject based on the ideXlab platform.

  • long residence time Adenosine A1 Receptor agonists produce sustained wash resistant antilipolytic effect in rat adipocytes
    Biochemical Pharmacology, 2019
    Co-Authors: Yi Yun, Adriaan P Ijzerman, Jianmin Chen, Rongfang Liu, Wenbing Chen, Chunji Liu, Ruoqi Wang, Zhongzhi Hou, Ying Sun, Laura H Heitman
    Abstract:

    Abstract Elevated circulating free fatty acid (FFA) level is closely linked to the pathogenesis of insulin resistance and type 2 diabetes mellitus. Activation of the Adenosine A1 Receptor (A1R) inhibits lipolysis in adipocytes and hence reduces the concentration of FFA, which represents a potential target for the development of antilipolytic agents. We aimed to assess the binding affinity as well as target binding kinetics of A1R agonists and further delineate a possible relationship with their antilipolytic effect in adipocytes. Radioligand binding assays were performed to determine the affinity and kinetics of three representative A1R agonists, namely CPA, LUF6944 and LUF6941, on the rat A1R. Functional responses to these agonists were examined in both a recombinant cell system and physiologically relevant rat adipocytes. The three A1R agonists displayed similar affinity while divergent target binding kinetics on the rat A1R. Irrespective of equilibrium binding affinity, temporal analysis of Receptor signaling demonstrated persistent functional responses for the long residence time agonist, despite removal of excess agonist, in both a recombinant cell system and in rat adipocytes. By contrast, such effect was less pronounced or even lost for agonists with medium or short Receptor residence time, respectively. Our results indicate that ligand Receptor binding kinetics rather than their affinity or potency play an essential role in regulating cellular responses. The long residence time A1R agonist produces a sustained wash-resistant antilipolytic effect in rat adipocytes and thus may represent a potential antilipolytic alternative for further investigation.

  • agonists for the Adenosine A1 Receptor with tunable residence time a case for nonribose 4 amino 6 aryl 5 cyano 2 thiopyrimidines
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Julien Louvel, Johannes Brussee, Dong Guo, Marta Agliardi, Tamara A M Mocking, Roland Kars, Tan Phat Pham, Lizi Xia, Henk De Vries, Laura H Heitman
    Abstract:

    We report the synthesis and evaluation of previously unreported 4-amino-6-aryl-5-cyano-2-thiopyrimidines as selective human Adenosine A1 Receptor (hA1AR) agonists with tunable binding kinetics, this without affecting their nanomolar affinity for the target Receptor. They show a very diverse range of kinetic profiles (from 1 min (compound 52) to 1 h (compound 43)), and their structure–affinity relationships (SAR) and structure–kinetics relationships (SKR) were established. When put in perspective with the increasing importance of binding kinetics in drug discovery, these results bring new evidence of the consequences of affinity-only driven selection of drug candidates, that is, the potential elimination of slightly less active compounds that may display preferable binding kinetics.

Vickram Ramkumar – One of the best experts on this subject based on the ideXlab platform.

  • Adenosine A1 Receptor protects against cisplatin ototoxicity by suppressing the nox3 stat1 inflammatory pathway in the cochlea
    The Journal of Neuroscience, 2016
    Co-Authors: Tejbeer Kaur, Leonard P. Rybak, Vikrant Borse, Sandeep Sheth, Kelly Sheehan, Sumana Ghosh, Srinivasan Tupal, Sarvesh Jajoo, Debashree Mukherjea, Vickram Ramkumar
    Abstract:

    Cisplatin is a commonly used antineoplastic agent that produces ototoxicity that is mediated in part by increasing levels of reactive oxygen species (ROS) via the NOX3 NADPH oxidase pathway in the cochlea. Recent studies implicate ROS generation in mediating inflammatory and apoptotic processes and hearing loss by activating signal transducer and activator of transcription (STAT1). In this study, we show that the Adenosine A1 Receptor (A1AR) protects against cisplatin ototoxicity by suppressing an inflammatory response initiated by ROS generation via NOX3 NADPH oxidase, leading to inhibition of STAT1. Trans-tympanic administration of the A1AR agonist R-phenylisopropylAdenosine (R-PIA) inhibited cisplatin-induced ototoxicity, as measured by auditory brainstem responses and scanning electron microscopy in male Wistar rats. This was associated with reduced NOX3 expression, STAT1 activation, tumor necrnecrosistor-α (TNF-α) levels, and apoptosis in the cochlea. In vitro studies in UB/OC-1 cells, an organ of Corti immortalized cell line, showed that R-PIA reduced cisplatin-induced phosphorylation of STAT1 Ser727 (but not Tyr701) and STAT1 luciferase activity by suppressing the ERK1/2, p38, and JNK mitogen-activated protein kinase (MAPK) pathways. R-PIA also decreased the expression of STAT1 target genes, such as TNF-α, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced cisplatin-mediated apoptosis. These data suggest that the A1AR provides otoprotection by suppressing NOX3 and inflammation in the cochlea and could serve as an ideal target for otoprotective drug therapy. SIGNIFICANCE STATEMENT Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. Its use results in significant and permanent hearing loss, for which no US Food and Drug Administration-approved treatment is currently available. In this study, we targeted the cochlear Adenosine A1 Receptor (A1AR) by trans-tympanic injections of the agonist R-phenylisopropylAdenosine (R-PIA) and showed that it reduced cisplatin-induced inflammation and apoptosis in the rat cochlea and preserved hearing. The mechanism of protection involves suppression of the NOX3 NADPH oxidase enzyme, a major target of cisplatin-induced reactive oxygen species (ROS) generation in the cochlea. ROS initiates an inflammatory and apoptotic cascade in the cochlea by activating STAT1 transcription factor, which is attenuated by R-PIA. Therefore, trans-tympanic delivery of A1AR agonists could effectively treat cisplatin ototoxicity.

  • induction of Adenosine A1 Receptor expression by pertussis toxin via an Adenosine 5 diphosphate ribosylation independent pathway
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: Sarvesh Jajoo, Sandeep C. Pingle, Yuko Sekino, Debashree Mukherjea, Vickram Ramkumar
    Abstract:

    Pertussis toxin ADP ribosylates Gi and Go transducing proteins and functionally uncouples Adenosine A1 Receptor (A1AR) from its effectors. We hypothesized that this loss in Receptor coupling could lead to de novo A1AR synthesis by the cell in a futile attempt to re-establish normal Receptor function. To test this hypothesis, we used hamster ductus deferens tumor (DDT1 MF-2) cells, a cell culture model for studying A1AR, and showed that pertussis toxin (100 ng/ml) produced a time-dependent loss in A1AR-Gi interaction and abolished A1AR activation of extracellular signal-regulated kinase 1/2. Interestingly, pertussis toxin increased the expression of A1AR, as measured by real-time polymerase chain reaction, immunocytochemistry, and [3H]cyclopentyl-1,3-dipropylxanthine (DPCPX) binding, suggesting a compensatory response to Gi protein inactivation. DDT1 MF-2 cells exposed to pertussis toxin demonstrated nuclear factor κB (NF-κB) activation within 30 min of exposure, a time point that preceded the loss of function of the A1AR. Inhibition of NF-κB attenuated the increase in A1AR induced by pertussis toxin. Cells exposed to B-oligomer subunit of pertussis toxin, devoid of significant ADP ribosyltransferase activity, showed increased A1AR protein expression, preceded by activation of NF-κB. B-Oligomer increased intracellular Ca2+ in DDT1 MF-2 cells. Chelation of intracellular Ca2+ with 1,2-bis(2-aminophenoxy)ethane– N , N , N ′, N ′-tetraacetic acid or inhibition of protein kinase C (PKC) with bisindolylmaleimide hydrochloride reduced the activation of NF-κB and [3H]DPCPX binding. We conclude that pertussis toxin promotes de novo A1AR synthesis by activating NF-κB through an ADP ribosylation-independent mechanism involving intracellular Ca2+ release and PKC activation.

  • Osmotic diuretics induce Adenosine A1 Receptor expression and protect renal proximal tubular epithelial cells against cisplatin-mediated apoptosis.
    The Journal of biological chemistry, 2004
    Co-Authors: Sandeep C. Pingle, Snigdha Mishra, Adriana Marcuzzi, Satyanarayan Bhat, Yuko Sekino, Leonard P. Rybak, Vickram Ramkumar
    Abstract:

    Osmotic diuretics are used successfully to alleviate acute tubutubular necrnecrosis (ATN) produced by chemotherapeutic agents and aminoglycoside antibiotics. The beneficial action of these agents likely involves rapid elimination of the nephrotoxic agents from the kidney by promoting diuresis. Adenosine A1 Receptor (A1AR) subtype present on renal proximal tubular epithelial and cortical collecting duct cells mediates the antidiuretic and cytoprotective actions of Adenosine. These Receptors are induced by activation of nuclear factor (NF)-kappaB, a transcription factor reported to mediate hyperosmotic stress-induced cytoprotection in renal medullary cells. In this study, we tested the hypothesis that induction of the A1AR in renal proximal tubular cells by NF-kappaB contributes to the cytoprotection afforded by osmotic diuretics. Exposure of porcine renal proximal tubular epithelial (LLC-PK1) cells to mannitol or NaCl produced a significant increase in A1AR. This increase was preceded by Adenosine release and NF-kappaB activation. Expression of an IkappaB-alpha mutant, which acts as a superrepressor of NF-kappaB, abrogated the increase in A1AR. Cells exposed to mannitol demonstrated increased reactive oxygen species (ROS) generation, which was attenuated by inhibiting xanthine oxidase with allopurinol. Allopurinol attenuated both the increase in A1AR expression and NF-kappaB activation produced by osmotic diuretics, indicating a role of Adenosine metabolites in these processes. Treatment of LLC-PK1 cells with cisplatin (8 microm) resulted in apoptosis, which was attenuated by mannitol but exacerbated by selective A1AR blockade. Administration of mannitol to mice increases A1AR expression and activation of NF-kappaB in renal cortical sections. Taken together, these data provide novel mechanisms of nephroprotection by osmotic diuretics, involving both activation and induction of the A1AR, the latter mediated through activation of a xanthine oxidase pathway leading to ROS generation and promoting activation of NF-kappaB.