Aspirin’s Active Metabolite Salicylic Acid Targets High Mobility Group Box 1 to Modulate Inflammatory Responses

Choi, Hyong Woo; Tian, Mingxing; Song, Fei; Véneréau, Emilie; Preti, Alessandro; Park, Sang Wook; Hamilton, Keith; Swapna, G.V.T.; Manohar, Murli; Moreau, Magali; Agresti, A; Gorzanelli, Andrea; Marchis, Francesco De; Wang, Huang; Antonyak, Marc A.; Micikas, Robert J.; Gentile, Daniel R.; Cerione, Richard A.; Schroeder, Frank C.; Montelione, Gaetano T.; Bianchi, Marco E.; Klessig, Daniel F.

doi:10.2119/molmed.2015.00148

Cited by 90 publications

(100 citation statements)

References 40 publications

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“…In order to gain insight into the mechanisms of down-regulation, we hypothesized that salicylic acid may directly bind to CDK2 causing a conformation change. Such a scenario is also supported by reports in literature which suggest that salicylic acid indeed interacts with cellular proteins [18, 44, 45]. We further hypothesized that, salicylic acid bound CDK2 may still associate with cyclin A2 to form a triad of CDK2/salicylic acid/cyclin A2 complex, the formation of this un-natural complex may lead to degradation of these proteins by the 26S proteasomes.…”

Section: Resultssupporting

confidence: 73%

“…While the identification of the aspirin-mediated acetylation targets has recently gained momentum [15, 16] after our initial reports [12] [14], identification of direct binding targets for salicylic acid has been under-explored [13]. Till date, salicylic acid has been shown to bind directly and interact with three cellular proteins in human cells: IκB kinase (IKK) β, a component of the NF-κB complex [18], AMP-activated protein kinase [44] and High Mobility Group Box1 proteins [45]. We hypothesized that, salicylic acid being a small molecule with hydroxyl (−OH) and carboxyl (−COOH) functional groups, potentially could directly bind/interact with additional cellular proteins and affect their functions.…”

Section: Discussionmentioning

confidence: 99%

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Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention

Dachineni

Kumar

et al. 2016

Molecular Cancer Research

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Data emerging from the past 10 years have consolidated the rationale for investigating the use of aspirin as a chemopreventive agent; however, the mechanisms leading to its anti-cancer effects are still being elucidated. We hypothesized that aspirin’s chemopreventive actions may involve cell cycle regulation through modulation of the levels or activity of cyclin A2/cyclin dependent kinase-2 (CDK2). In this study, HT-29 and other diverse panel of cancer cells were used to demonstrate that both aspirin and its primary metabolite, salicylic acid, decreased cyclin A2 (CCNA2) and CDK2 protein and mRNA levels. The down regulatory effect of either drugs on cyclin A2 levels was prevented by pretreatment with lactacystin, an inhibitor of proteasomes, suggesting the involvement of 26S proteasomes. In-vitro kinase assays showed that lysates from cells treated with salicylic acid had lower levels of CDK2 activity. Importantly, three independent experiments revealed that salicylic acid directly binds to CDK2. Firstly, inclusion of salicylic acid in naïve cell lysates, or in recombinant CDK2 preparations, increased the ability of the anti-CDK2 antibody to immunoprecipitate CDK2, suggesting that salicylic acid may directly bind and alter its conformation. Secondly, in 8-anilino-1-naphthalene-sulfonate (ANS)-CDK2 fluorescence assays, pre-incubation of CDK2 with salicylic acid, dose-dependently quenched the fluorescence due to ANS. Thirdly, computational analysis using molecular docking studies identified Asp145 and Lys33 as the potential sites of salicylic acid interactions with CDK2. These results demonstrate that aspirin and salicylic acid down-regulate cyclin A2/CDK2 proteins in multiple cancer cell lines, suggesting a novel target and mechanism of action in chemoprevention. Implications Biochemical and structural studies indicate that the anti-proliferative actions of aspirin are mediated through cyclin A2/CDK2.

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Section: Resultssupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention

Dachineni

Kumar

et al. 2016

Molecular Cancer Research

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“…Pinitol has anti-diabetes effects and improves metabolic disease, which was confirmed by clinical data and basic research2425262728. This discovery indicates the potential, novel use of UC to treat diabetes.…”

Section: Discussionmentioning

confidence: 62%

“…Additional studies are still required to confirm whether the anti-inflammation activity of UC is mediated by regulating the Nrf2 pathway. The UC-mediated regulation of Nrf2 and anti-oxidation effects might be correlated with the levels of flavonoids, triterpene and betaine, while the COX-2 enzyme activity and anti-inflammation effects may be related to flavonoids and salicylic acid2425. These activities of UC may be relevant to the traditional uses of UC: detoxification, detumescence and the treatment of traumatic injuries.…”

Section: Discussionmentioning

confidence: 99%

Improving the Concentrations of the Active Components in the Herbal Tea Ingredient, Uraria crinita: The Effect of Post-harvest Oven-drying Processing

Chao¹,

Dai

Cheng³

et al. 2017

Sci Rep

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Uraria crinita is widely used as a popular folk drink; however, little is known about how the post-harvest operations affect the chemical composition and bioactivity of UC. We assessed three drying methods (Oven-drying, Air-drying, Sun-drying), as well as the Oven-drying temperature using metabolomics approaches and bioactivity assays. The samples processed at 40 degree show a greater effect on the levels of estrogen receptor-alpha activity and nuclear factor erythroid 2–related factor 2 activity, anti-oxidative activity, and cyclooxygenase-2 inhibition compared with the other samples. A multivariate analysis showed a clear separation between the 40 degree Oven-dried samples and the other samples, which is consistent with the results of bioactivity assay. These results are ascribed to at least two-fold increase in the concentrations of flavonoids, spatholosineside A and triterpenoids in the oven-dried samples compared with the other groups. The proposed Oven-drying method at 40 degree results in an improved quality of UC.

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“…We recently discovered that HMGB1 binds salicylic acid (SA); this suppresses both reduced HMGB1’s chemo-attractant activity and disulfide bond-containing HMGB1’s ability to induce the expression of pro-inflammatory cytokine genes and COX-2 [16]. The SA-binding sites on HMGB1 were identified in the HMG-box domains by NMR studies and confirmed by mutational analysis.…”

Section: Introductionmentioning

confidence: 99%

DAMPs, MAMPs, and NAMPs in plant innate immunity

2016

Self Cite

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BackgroundMulticellular organisms have evolved systems/mechanisms to detect various forms of danger, including attack by microbial pathogens and a variety of pests, as well as tissue and cellular damage. Detection via cell-surface receptors activates an ancient and evolutionarily conserved innate immune system.ResultPotentially harmful microorganisms are recognized by the presence of molecules or parts of molecules that have structures or chemical patterns unique to microbes and thus are perceived as non-self/foreign. They are referred to as Microbe-Associated Molecular Patterns (MAMPs). Recently, a class of small molecules that is made only by nematodes, and that functions as pheromones in these organisms, was shown to be recognized by a wide range of plants. In the presence of these molecules, termed Nematode-Associated Molecular Patterns (NAMPs), plants activate innate immune responses and display enhanced resistance to a broad spectrum of microbial and nematode pathogens. In addition to pathogen attack, the relocation of various endogenous molecules or parts of molecules, generally to the extracellular milieu, as a result of tissue or cellular damage is perceived as a danger signal, and it leads to the induction of innate immune responses. These relocated endogenous inducers are called Damage-Associated Molecular Patterns (DAMPs).ConclusionsThis mini-review is focused on plant DAMPs, including the recently discovered Arabidopsis HMGB3, which is the counterpart of the prototypic animal DAMP HMGB1. The plant DAMPs will be presented in the context of plant MAMPs and NAMPs, as well as animal DAMPs.

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Aspirin’s Active Metabolite Salicylic Acid Targets High Mobility Group Box 1 to Modulate Inflammatory Responses

Cited by 90 publications

References 40 publications

Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention

Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention

Improving the Concentrations of the Active Components in the Herbal Tea Ingredient, Uraria crinita: The Effect of Post-harvest Oven-drying Processing

DAMPs, MAMPs, and NAMPs in plant innate immunity

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