{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T08:53:10Z","timestamp":1768985590152,"version":"3.49.0"},"reference-count":62,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2019,2,3]],"date-time":"2019-02-03T00:00:00Z","timestamp":1549152000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008725","name":"Agencia Nacional de Investigaci\u00f3n e Innovaci\u00f3n","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:sec><jats:title>Background and purpose<\/jats:title><jats:p>Atherosclerosis is characterized by chronic low\u2010grade inflammation with concomitant lipid accumulation in the arterial wall. Anti\u2010inflammatory and anti\u2010atherogenic properties have been described for a novel class of endogenous nitroalkenes (nitrated\u2010unsaturated fatty acids), formed during inflammation and digestion\/absorption processes. The lipid\u2010associated antioxidant \u03b1\u2010tocopherol is transported systemically by LDL particles including to the atheroma lesions. To capitalize on the overlapping and complementary salutary properties of endogenous nitroalkenes and \u03b1\u2010tocopherol, we designed and synthesized a novel nitroalkene\u2010\u03b1\u2010tocopherol analogue (NATOH) to address chronic inflammation and atherosclerosis, particularly at the lesion sites.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental approach<\/jats:title><jats:p>We synthesized NATOH, determined its electrophilicity and antioxidant capacity and studied its effects over pro\u2010inflammatory and cytoprotective pathways in macrophages <jats:italic>in vitro<\/jats:italic>. Moreover, we demonstrated its incorporation into lipoproteins and tissue both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>, and determined its effect on atherosclerosis and inflammatory responses <jats:italic>in vivo<\/jats:italic> using the Apo E knockout mice model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results<\/jats:title><jats:p>NATOH exhibited similar antioxidant capacity to \u03b1\u2010tocopherol and, due to the presence of the nitroalkenyl group, like endogenous nitroalkenes, it exerted electrophilic reactivity. NATOH was incorporated <jats:italic>in vivo<\/jats:italic> into the VLDL\/LDL lipoproteins particles to reach the atheroma lesions. Furthermore, oral administration of NATOH down\u2010regulated NF\u2010\u03baB\u2010dependent expression of pro\u2010inflammatory markers (including IL\u20101\u03b2 and adhesion molecules) and ameliorated atherosclerosis in Apo E knockout mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and implications<\/jats:title><jats:p><jats:italic>In toto<\/jats:italic>, the data demonstrate a novel pharmacological strategy for the prevention of atherosclerosis based on a creative, natural and safe drug delivery system of a non\u2010conventional anti\u2010inflammatory compound (NATOH) with significant potential for clinical application.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14561","type":"journal-article","created":{"date-parts":[[2018,12,27]],"date-time":"2018-12-27T07:19:08Z","timestamp":1545895148000},"page":"757-772","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A novel 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