## 5 Bioactivity of Secondary Metabolites in the _Leontopodium_ Taxa
### Anti-Inflammatory Activity
aluminum_} & Lipophilic extracts of the aerial plant parts & Rat paw & - & reduced the oedema by swelling reduction by 72\% (CO\({}_{2}\)-extract) and 80\% (dichloromethane extract) & [7] \\  & & & (dichloromethane extract) &  
roots. Two bisabolene derivatives caused a reduction in the polymorphonuclear neutrophil leukocytes' accumulation in the inflamed tissue, while a silphiperfolene-type sesquiterpene and a coumarin derivative inhibited the in vitro chemotaxis of these inflammatory cells [3]. Another study reported that some constituents of this \(L\). _alpinum_ roots' extract were potent inhibitors of cyclooxygenase isoenzymes COX-1 and COX-2 [4]. The authors showed that the bisabolene derivates, one lignin and _ent_-kaureanoate acid, exhibited the highest inhibitory activity on the ex vivo LTB synthesis. In the same manner, other authors linked the anti-inflammatory activities in extracts from the aerial organs of \(L\). _leontopodioides_ to phenolic acids with caffeoyl moieties, such as 2,3,4,5-tetracaffeoyl-D-glucaric acid, 3,4-O-dicaffeoylquinic acid and 3, 5-O-dicaffeoylquinic acid [78], which were previously identified in the _Leontopodium_ genus [82; 83]. Some compounds identified in \(L\). _leontopodioides_ were tested as antagonists for C-C chemokine receptor 2b (CCR2b). This receptor is part of the G protein-coupled receptor family, the largest class of cell surface receptors, representing the most important targets for marketed anti-inflammatory drugs [97]. From all tested compounds, tetracaffeoyl-D-glucaric acid, 3,4 di-caffeoylquinic acids and apigenin 3-O-\(\beta\)-glucoside showed antagonism to the CCR2b receptor, suggesting that \(L\). _leontopodioides_ could be used for the treatment of CCR2b-related diseases [101]. In the case of using UV irradiation as a pro-inflammatory trigger, intracellular NO levels were increased without activating the expression of inducible NO synthase (iNOS) but with the transient activation of COX-2 expression [12]. Other authors signalled an increased expression of the two pro-inflammatory marker genes, COX-2 and iNOS [34]. Treatment with \(L\). _alpinum_ callus extracts determined the decrease in COX-2 and iNOS mRNA transcription, with results comparable to dexamethasone. It also had no inhibitory effects on the transcription of other markers specific to the UV-induced inflammatory response, such as TNF-\(\alpha\), IL-6 and IL-1\(\alpha\)[12]. Transcriptomic analysis of RHE irradiated with UV showed that the Alpaflor(r) Edelweiss product was able to rebalance the expression of some pro-inflammatory markers corresponding to the LOX 5 cascade, psoriasis (S100 calcium binding protein A7) and chemokine (CXC motif) ligand 5, which is the key mediator in sunburn signalling [39]. Bacterial LPSs are substances that cause inflammatory reactions and were applied in studies using the Raw 264.7 line to study their involvement in pro-inflammatory cascades. A newly discovered neoligan and luteolin isolated from the aerial parts of \(L\). _leontopodioides_ exhibited inhibitory activities on NO production in this experimental model, being more potent inhibitors than N-monomethyl-L-arginine used as a positive control [13]. In the same model system, two _ent_-kaureanoic acid derivatives isolated form \(L\). _longifolium_ roots inhibited the NO production at 63% and 61%, respectively, after treatment with a 5 mg/mL concentration [35]. Extracts of _Leontopodium coreanum_ Nakai appeared to have inhibitory effects on NO production [100], while those of \(L\). _alpinum_ reduced cytokine production (IL-6) with better efficiency than dexamethasone [99]. The chromatographic fingerprints of different \(L\). _leontopodioides_ extracts were used in acute inflammatory studies. The HPLC data showed that six compounds were associated with anti-inflammatory activities on IL-1, nine compounds on IL-6 and two compounds on LTB4 [98], with only chlorogenic acid and ferulic acid inhibiting the production of IL-1 and IL-6. The effect of the \(L\).