Editing Aspirin (section)

===Additional mechanisms===
Aspirin has been shown to have at least three additional modes of action. It uncouples [[oxidative phosphorylation]] in cartilaginous (and hepatic) mitochondria, by diffusing from the inner membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons.<ref name="SomasundaramS">{{cite journal | vauthors = Somasundaram S, Sigthorsson G, Simpson RJ, Watts J, Jacob M, Tavares IA, Rafi S, Roseth A, Foster R, Price AB, Wrigglesworth JM, Bjarnason I | title = Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat | journal = Alimentary Pharmacology & Therapeutics | volume = 14 | issue = 5 | pages = 639–50 | date = May 2000 | pmid = 10792129 | doi = 10.1046/j.1365-2036.2000.00723.x | s2cid = 44832283 | doi-access = free | title-link = doi }}</ref> Aspirin buffers and transports the protons. When high doses are given, it may actually cause fever, owing to the heat released from the electron transport chain, as opposed to the antipyretic action of aspirin seen with lower doses. In addition, aspirin induces the formation of NO-radicals in the body, which have been shown in mice to have an independent mechanism of reducing inflammation. This reduced leukocyte adhesion is an important step in the immune response to infection; however, evidence is insufficient to show that aspirin helps to fight infection.<ref>{{cite journal | vauthors = Paul-Clark MJ, Van Cao T, Moradi-Bidhendi N, Cooper D, Gilroy DW | title = 15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation | journal = The Journal of Experimental Medicine | volume = 200 | issue = 1 | pages = 69–78 | date = July 2004 | pmid = 15238606 | pmc = 2213311 | doi = 10.1084/jem.20040566 }}</ref> More recent data also suggest salicylic acid and its derivatives modulate signalling through [[NF-κB]].<ref>{{cite journal | vauthors = McCarty MF, Block KI | title = Preadministration of high-dose salicylates, suppressors of NF-kappaB activation, may increase the chemosensitivity of many cancers: an example of proapoptotic signal modulation therapy | journal = Integrative Cancer Therapies | volume = 5 | issue = 3 | pages = 252–68 | date = September 2006 | pmid = 16880431 | doi = 10.1177/1534735406291499 | doi-access = free | title-link = doi }}</ref> NF-κB, a [[transcription factor]] complex, plays a central role in many biological processes, including inflammation.<ref>{{cite journal | vauthors = Silva Caldas AP, Chaves LO, Linhares Da Silva L, De Castro Morais D, Gonçalves Alfenas RD |date=29 December 2017|title=Mechanisms involved in the cardioprotective effect of avocado consumption: A systematic review|journal=International Journal of Food Properties|volume=20|issue=sup2|pages=1675–1685 |doi=10.1080/10942912.2017.1352601 |issn=1094-2912|quote=...there was postprandial reduction on the plasma concentration of IL-6 and IkBα preservation, followed by the lower activation of NFκB, considered the main transcription factor capable of inducing inflammatory response by stimulating the expression of proinflammatory cytokines, chemokines, and adhesion molecules.|doi-access=free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L | title = Inflammatory responses and inflammation-associated diseases in organs | journal = Oncotarget | volume = 9 | issue = 6 | pages = 7204–7218 | date = January 2018 | pmid = 29467962 | pmc = 5805548 | doi = 10.18632/oncotarget.23208 }}</ref><ref>{{cite journal | vauthors = Lawrence T | title = The nuclear factor NF-kappaB pathway in inflammation | journal = Cold Spring Harbor Perspectives in Biology | volume = 1 | issue = 6 | pages = a001651 | date = December 2009 | pmid = 20457564 | pmc = 2882124 | doi = 10.1101/cshperspect.a001651 }}</ref>

Aspirin is readily broken down in the body to salicylic acid, which itself has anti-inflammatory, antipyretic, and analgesic effects. In 2012, salicylic acid was found to activate [[AMP-activated protein kinase]], which has been suggested as a possible explanation for some of the effects of both salicylic acid and aspirin.<ref>{{cite journal | vauthors = Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG | title = The ancient drug salicylate directly activates AMP-activated protein kinase | journal = Science | volume = 336 | issue = 6083 | pages = 918–22 | date = May 2012 | pmid = 22517326 | pmc = 3399766 | doi = 10.1126/science.1215327 | bibcode = 2012Sci...336..918H }}</ref><ref>{{cite journal |title=Clues to aspirin's anti-cancer effects revealed |journal=New Scientist |date=28 April 2012 |volume=214 |issue=2862 |pages=16 |doi=10.1016/S0262-4079(12)61073-2 }}</ref> The acetyl portion of the aspirin molecule has its own targets. Acetylation of cellular proteins is a well-established phenomenon in the regulation of protein function at the post-translational level. Aspirin is able to acetylate several other targets in addition to COX isoenzymes.<ref>{{cite journal | vauthors = Alfonso LF, Srivenugopal KS, Arumugam TV, Abbruscato TJ, Weidanz JA, Bhat GJ | title = Aspirin inhibits camptothecin-induced p21CIP1 levels and potentiates apoptosis in human breast cancer cells | journal = International Journal of Oncology | volume = 34 | issue = 3 | pages = 597–608 | date = March 2009 | pmid = 19212664 | doi = 10.3892/ijo_00000185 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Alfonso LF, Srivenugopal KS, Bhat GJ | title = Does aspirin acetylate multiple cellular proteins? (Review) | journal = Molecular Medicine Reports | volume = 2 | issue = 4 | pages = 533–7 | year = 2009 | pmid = 21475861 | doi = 10.3892/mmr_00000132 | type = review | doi-access = free | title-link = doi }}</ref> These acetylation reactions may explain many hitherto unexplained effects of aspirin.<ref>{{cite journal | vauthors = Alfonso LF, Srivenugopal KS, Bhat GJ | title = Does aspirin acetylate multiple cellular proteins? (Review) | journal = Molecular Medicine Reports | volume = 2 | issue = 4 | pages = 533–537 | date = 4 June 2009 | pmid = 21475861 | doi = 10.3892/mmr_00000132 | doi-access = free }}</ref>