## 2 Sesquietpene Lactones with Significant In Vivo Activity
### Costunolide
Recently, studies have shown that costunolide (**3**) also exhibited anti-osteoarthritic effects [108]. In fact, treatment in rats with osteoarthritis causes attenuation of cartilage degeneration compared to the control osteoarthritis group. The observed effect has been attributed to the inhibitory action of this compound on the Wnt/\(\beta\)-catenin and NF-kB signaling pathways, and on the expression of matrix metalloproteinases [108]. Costunolide (**3**) seems to be also a powerful antiasthmatic [109]. In this work, the researchers treated asthma-induced mice with 10 mg/kg (b.w.) before an immune challenge. Results showed a 61.8% inhibition of asthma-associated eosinophil increase, as well as significantly reducing lung inflammation scores and mucin production [109]. Recently, it has been shown that costunolide (**3**) is an effective inducer of hair growth in mice [110]. For this assay, the researchers implanted mouse dermal cells, treated with 3 mM costunolide (**3**) for two days. Results showed a 2.5-fold increase in induced hair follicles in the implanted treated cells, and topically applied costunolide (**3**) significantly and visibly improved hair growth. The authors claim this might be due to activation by compound **3** of key follicle-cell cycle pathways, including the Wnt/b-catenin, Shh/Gli, and TGF-\(\beta\)/Smad pathways. It is worth mentioning the TGF-\(\beta\)/Smad pathway was also mentioned in previous studies related to anti-inflammatory action of costunolide (**3**) [106]. Costunolide (**3**) derivatives have also proven to be highly interesting, with remarkable in vivo effects. In recent work by [PERSON] et al. in an agro-research context [111], many different functional groups were added to the sesquiterpene backbone, yielding, among others, two amino and two methyl ether derivatives with strong herbicidal activity. The etiolated wheat coleoptile assay indicated treatment with these costunolide (**3**) derivatives had dose-dependent growth inhibition responses equivalent to a widely used synthetic herbicide used as positive control. These results show there is potential for some of these derivatives as bio-herbicides, but further studies are necessary. There was also another interesting result of this work which the authors did not address, but is worth pointing out: two tested thiol derivatives boosted coleoptile growth instead of inhibiting it, with one compound increasing coleoptile length by \(\sim\)30% with a 30 uM treatment. The general implication of these results is that costunolide (**3**) modification can be powerful and versatile, capable of yielding diametrically opposed bioactive compounds depending on the functional group added. In conclusion, costunolide (**3**) is a highly multitalented and potent bioactive compound. Similar to other sesquiterpene lactones such as the previously discussed alantolactone (**1**), much of its potential for future drug development lies in its anticancer and anti-inflammatory effects. It is interesting that there appears to be more work done with costunolide (**3**) derivatives than alantolactone (**1**) derivatives,which in general suggests greater interest of the scientific community in costunolide (**3**) as opposed to alantolactone (**1**). With so many relevant publications in 2019 alone, we expect to see costunolide (**3**) research ramping up to a pre-clinical stage very soon.