Comfrey was proven effective for the treatment of, e.g., acute upper and lower back pain, gonarthrosis, or for patients with blunt injuries ( Koll et al., 2004 Predel et al., 2005 Grube et al., 2007 Giannetti et al., 2010). Today, the efficacy and safety of comfrey root extract ointment has been substantiated by several randomized clinical trials and non-interventional studies. Several cellular mechanisms have been proposed in order to explain their mode of action, including the targeting of different intracellular signaling pathways triggered by NF-κB, AP-1, PPAR, Nrf2, and MAPKs ( Chen et al., 2017 Tasneem et al., 2019). Phenolic compounds have been reported to exert anti-inflammatory effects both in vitro and in vivo ( Chen et al., 2018). Native in Europe, it has been used for centuries for the treatment of a variety of painful muscle and joint complaints ( Staiger, 2012 Frost et al., 2013). Symphytum officinale (Boraginaceae), well known as comfrey, represents a plant with an impressive record of medicinal use. These results provide a first mechanistic insight into the mode of action of a century-old popular herbal medicine. Furthermore, our biochemical studies provide evidence that comfrey inhibits NF-κB signaling at two stages: it dampens not only the activation of IKK1/2 and the subsequent IκBα degradation, but also interferes with NF-κB p65 nucleo-cytoplasmatic shuttling and transactivation. Both preparations inhibit the activation of NF-κB, a transcription factor of central importance for the expression of these and other pro-inflammatory genes. The extract, and especially its mucilage-depleted fraction, impair the interleukin-1 (IL-1) induced expression of pro-inflammatory markers including E-selectin, VCAM1, ICAM1, and COX-2. Here, we show that a hydroalcoholic extract of comfrey root impairs the development of a pro-inflammatory scenario in primary human endothelial cells in a dose-dependent manner. However, the molecular basis of its action remained elusive. Today, its topical use is based on its analgesic and anti-inflammatory effects, which have been substantiated by modern clinical trials. Symphytum officinale, commonly known as comfrey, constitutes a traditional medicinal plant with a long-standing therapeutic history, and preparations thereof have been widely used for the treatment of painful muscle and joint complaints, wound and bone healing, and inflammation. Experimental details are given in the Supplementary Text. DP: declustering potential EP: entrance potential CE: collision energy, PI: product ion, DI: daughter ion. In particular, globoidnan A (6) and rosmarinic acid (5) exhibit the highest concentrations of 20.02 mg/100 g and 14.03 mg/100 g of dried extract. The quantitative results highlight that compounds are present in concentration ranges of 0.42–20.02 mg/100 g. Globoidnan A (6) was characterized in the MS/MS spectrum by an intense peak - at m/z 311 due to the neutral loss of a caffeic acid unit. MS/MS fragmentation pattern of rosmarinic acid (5) originated a main fragment ion - at m/z 161, due to the loss of a caffeic acid unit and water molecule. Protocatechuic acid (2), p-hydroxybenzoic acid (3), and caffeic acid (4) showed a very simple fragmentation pattern where the base peak was produced by the neutral loss of 44 Da corresponding to the carboxylic group. For this reason, this transition was selected for MRM experiments. Allantoin (1) in the MS/MS spectrum was characterized by the loss of 60 Da corresponding to the urea unit, originating an intense peak at m/z 97. The amount (per mg/100 g of dried extract) of each selected compound and the MRM transition selected for each compound is shown. LC/ESI/triple quadrupole(QqQ)/MS using a very sensitive and selective mass tandem experiment such as Multiple Reaction Monitoring (MRM) is considered one of the most suitable techniques for quantification of metabolites ( Masullo et al., 2016). (B) In order to determine the amount of the main compounds occurring in the ethylacetate fraction of comfrey roots, a quantitative determination by LC-MS was carried out. Noteworthy, compounds 1–5 were previously isolated in comfrey roots ( Grabias and Swiatek, 1998 Trifan et al., 2018) while this is the first report of globoidnan A (6). In this way, allantoin (1), protocatechuic acid (2), p-hydroxybenzoic acid (3), caffeic acid (4), rosmarinic acid (5), and globoidnan A (6) were identified. The HPLC profile showed peaks corresponding to the main compounds which were collected and structurally elucidated by NMR spectroscopy. (A) The ethylacetate fraction of comfrey roots was analyzed by HPLC-UV. officinale root extract and quantification of its main compounds.
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