The first natural product described as LO

The first natural product described as 5-LO inhibitor was the polyphenol nordihydroguaiaretic blue nitro from the Mexican dessert plant Larrea divaricata in 1981 (Bokoch and Reed, 1981), short after the initial identification of 5-LO in 1979 (Borgeat and Samuelsson, 1979). Long time before mPGES-1 was discovered in 1999 as crucial enzyme for production of PGE2 at inflammatory sites (Jakobsson et al., 1999), natural products were described that blocked both formation of 5-LO products and of PGs (particularly PGE2), such as curcumin (Huang et al., 1991). In 2009, myrtucommulone A (MC-A), a non-prenylated acylphloroglucinol from the leaves of myrtle (Myrtus communis), was documented as the first natural product that in addition to suppressing 5-LO (Feisst et al., 2005) also inhibited mPGES-1 (Koeberle et al., 2009e). Subsequently, five additional acylphloroglucinols of natural origin were identified as dual mPGES-1/5-LO inhibitors: (I) garcinol (camboginol) from the fruit rind of Guttiferae species (Koeberle et al., 2009d), (II) arzanol, a heterodimeric phloroglucinyl α-pyrone from Helichrysum italicum (Bauer et al., 2011), (III) hyperforin from the herb Hypericum perforatum (St. John's wort) (Albert et al., 2002; Koeberle et al., 2011), (IV) acrovestones which are acetophenone dimers from Acronychia pedunculata (Svouraki et al., 2017), and (V) the chalcone xanthohumol from Humulus lupulus (hop plant) (Forino et al., 2016). Of interest, some of these compounds were already recognized before to block cellular formation of PGE2 and LTs but the proposed molecular modes of actions (e.g., COX inhibition) were ambiguous and speculative lacking experimental proof. Up to date, almost a docent of additional structural classes of natural products that dually inhibit mPGES-1 and 5-LO were discovered and, together with the acylphloroglucinols, will be reviewed below. As described in Section 3, 5-LO inhibitors are essentially classified according to their mode of 5-LO inhibition (Werz et al., 2017), whereas mPGES-1 inhibitors are rather distinguished based on structural features, i.e., as being either acidic or non-acidic compounds (Koeberle et al., 2016). The dual mPGES-1/5-LO inhibitors from natural origin reported here are classified as (I) acylphloroglucinols, (II) phenolic compounds and (III) non-phenolic acidic structures, and they are presented in Table 1.
Conclusion
Funding sources Research activities of the authors related to the subject of this article were kindly supported by the Deutsche Forschungsgemeinschaft (SFB1127 ChemBioSys, SFB1278 Polytarget, RTG 1715, KO4589/7-1) and by the Free State of Thuringia and the European Social Fund (2016 FGR 0045).
Value of the data
Data Here we present immunohistochemical and qPCR data showing that lipoxygenases-5 and -12 are also activated during acetaminophen-induced liver damage[1]. The lipoxygenase-5 appeared to be weakly expressed in the normal liver parenchyma (Fig. 1A, 40× magnification), but at 48h acetaminophen administration consistently enhanced its expression in the damaged livers[2], primarily around the centrilobular veins (Fig. 1B, 40× magnification). The lipoxygenase-12 also appeared to stain weakly the normal liver parenchyma (Fig. 1C, 40× magnification), whereas acetaminophen administration enhanced, but only modestly, its expression at 48h (Fig. 1D, 40× magnification), especially around the centrilobular veins[3]. The expression pattern of lipoxygenase-12 overlapped with that observed for the lipoxygenase-5 in the damaged liver. When the expression of lipoxygenase-5 and -12 was examined in the control and acetaminophen-treated livers, we found that at 48h, the expression of both lipoxygenases was up-regulated, but significant differences were found only for lipoxygenase-5 (Fig. 1E and F).
Experimental design, materials and methods
Statistical analysis The data are displayed as mean (X)±SE from at least three independent experiments. Statistical analysis was performed with the statistical package Gnumeric Spreadsheet (Gnome Foundation, Orinda, CA, USA). Planned pairwise comparisons between groups were performed by using Student׳s t-tests; p<0.05 was the criterion of significance.