Anti-Inflammatory Action of Isorhamnetin

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Dear Editor, A recent paper from Kynhwa Seo and colleagues in the latest issue of this journal reported that isorhamnetin, n ame l y ( 3 , 5 , 7 t r i h y d r o x y 2 ( 4 h y d r o x y 3 methoxyphenyl)chromen-4-one or quercetin-3methylether), a 3′-O-methylated metabolite of quercetin, reduced inducible nitric oxide synthase (iNOS) expression and NO production [1]. Isorhamnetin is able to increase the nuclear translocation of Nrf2 in a doseand time-dependent manner, hence the anti-oxidant response element (ARE) reporter gene activity, the expression and synthesis of proteins such as heme-oxygenase (HO-1) and cysteine lygase, and the increase in intracellular glutathione (GSH) level [2]. The expression of HO-1, via ERK/Nrf2 signaling pathway, is induced also by quercetin (2-(3,4dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one) [3], a fact that would suggest a major role of OH-flavone ring, compared to the methoxyl group, in the Nrf2-mediated anti-oxidant and anti-inflammatory activities of isorhamnetin. In a recent paper of mine, I suggested that the O-methylated group should increase plasma bioavailability of a flavonoid, and –OCH3 lacking flavone-sharing molecules are rapidly metabolized as they undergo glucuronidation and sulfation [4, 5]. In this context, isorhamnetin should deserve higher attention than quercetin. The authors suggested a role for isorhamnetin in the inhibition of cyclooxygenase-2 (COX-2) expression, in order to explain the anti-inflammatory action of the O-3′methylated flavonoid [1]. Other flavonoids, such as wogonin (5,7-dihydroxy-8-methoxy-2-phenyl-4H-chromen-4-one) and acacetin (5,7-dihydroxy-2-(4methoxyphenyl)chromen-4-one), two flavones bearing a methoxyl group, showed an inhibitory activity towards COX-2 expression [6–8]. The inhibitory effect on COX-2 by flavone-ring bearing phytochemicals has been commonly described elsewhere. Flavones without an – OCH3 group are able to affect COX-2 or iNOS expression, and reports demonstrating that flavonoids inhibit COX-2 activity were previously published [9]. A past report showed that isorhamnetin and quercetin 3′-O-sulphate are major plasma metabolites from the more widely diffused quercetin and that these metabolites, unlike quercetin, are enzymatic inhibitors of COX-2 activity [10]. Interestingly, many COX-2 synthetic inhibitors possess a flavone-like backbone [11]. Targeting COX-2 by flavonoids should represent a common hallmark of most polyphenols bearing a flavone backbone, such as flavones. Apigenin showed an anti-inflammatory action against Helicobacter pylori-infected gastric adenocarcinoma cells by affecting NF-κB and COX-2 [12]; luteolin and chrysin inhibited LPS-induced inflammation by inhibiting COX-2 and iNOS expression [13, 14]; scutellarein in Siam weed extract (Chromolaena odorata L.) exhibited an anti-inflammatory action by targeting COX-2 activity [15]. This evidence strongly suggests that many flavone-bearing phytochemicals, such as flavonoids, widely affect COX-2 function, often through ancillary mechanisms involving NF-κB [16]. Flavonoids related to quercetin, such as isorhamnetin or rutin, exhibit the potential to affect the expression of NFE2-related factor 2 (Nrf2) and HO-1 [17]. Isorhamnetin showed an anti-inflammatory action through an anti-oxidant activity [1]. In my opinion, this may represent an interpretation of a more complex pattern, in which isorhamnetin plays a fundamental role, by targeting different pathways. For example, isorhamnetin is able to reduce the inflammatory response by targeting and inhibiting high mobility group box 1 (HMGB1) receptors [17]. In the pulmonary system, binding of HMGB1 to its receptor triggers the production of pro-inflammatory cytokines, chemokines, adhesion molecules, and reactive oxygen species, promoting the development of acute lung injury and acute respiratory distress syndrome. Recent findings have shown that induction of HO-1 protects tissues and cells from extracellular stress by reducing HMGB1 production and HO-1 may mediate the protective effects of peroxisome proliferator-activated 1 Laboratory of Physiopathology of Obesity, Department of Medicine, University of Verona, Italy, LURM est Policlinico GB Rossi, Piazzale AL Scuro 10, 37134 Verona, Italy 2 To whom correspondence should be addressed at Laboratory of Physiopathology of Obesity, Department of Medicine, University of Verona, Italy, LURM est Policlinico GB Rossi, Piazzale AL Scuro 10, 37134 Verona, Italy. E-mail: salvatore.chirumbolo@univr.it