## 2 Sesquietpene Lactones with Significant In Vivo Activity
### Alantolactone
Alantolactone (**1**) acts as an alkylating agent leading to inhibition of key enzymes and proteins, and as an apoptosis inducer in cancer cells at mitochondrial level by interacting with cytochrome c. It promotes overproduction of reactive oxygen species (ROS) due to specific caspase activation, by inhibiting autophagic deregulation, among other processes. Beyond its anticancer activity, compound **1** also exhibits interesting anti-inflammatory activity. [PERSON] et al. [51] used the DSS-induced colitis mouse model to test alantolactone (**1**) anti-inflammatory activity. A 50 mg/kg dose reversed colitis symptoms (bloody diarrhea, colon shortening and weight loss), besides significantly reducing pro-inflammatory cytokine TNF-\(\alpha\) expression (to about half that of positive control) and IL-6 (by over 2.5 times compared to positive control) [51]. [PERSON] et al. [41], showed that a 10 mg/kg (b.w.) dose of alantolactone (**1**) significantly improved neurological function and reduced cerebral edema in a traumatic brain injury mouse model. This neuroprotective effect was attributed to alantolactone's capacity to inhibit the NF-\(\kappa\)B inflammatory pathway and the cytochrome c/caspase-mediated apoptosis pathways [41]. To the best of our knowledge, no other authors have elaborated on this interesting double action: the fact that alantolactone (**1**) can simultaneously activate apoptotic pathways in cancer cells and inhibit these pathways in a cerebral edema model. [PERSON] et al. [52] described the neuroprotective effect of alantolactone (**1**) using amyloid \(\beta\)25-35-induced ex vivo neuronal cell death and scopolamine-induced amnesia in mouse models meant to emulate conditions common to neurodegenerative conditions like Alzheimer's disease. A 1 uM alantolactone (**1**) treatment increased cortical neuron viability to almost baseline control readings, and 1 mg/kg (b.w.) significantly decreased scopolamine-induced cognitive impairments. It is a interesting to note that this particular neuroprotective effect is attributed to a drop in ROS levels. High ROS concentrations are associated with the neurodegenerative damage of Alzheimer's disease. Again, alantolactone (**1**) exhibits a double action: it raises ROS levels to induce apoptosis in murine models of neurodegenerative damage. The interesting advances with alantolactone (**1**) derivatives are also worth mentioning. [PERSON] et al. [53] assayed three of the 17 thiol derivatives synthesized, at 10 mg/kg (b.w.) doses, in mice showing that they have in vivo anti-inflammatory activity comparable to alantolactone (**1**). The novel compounds shared alantolactone's anti-inflammatory mechanisms. Another noteworthy study involving alantolactone (**1**) derivatives was published in 2018 by [PERSON] et al. [54], testing 44 derivatives for their ability to inhibit induced pulmonary fibrosis in mice. The results showed that 2 of these compounds are particularly active at 100 mg/kg (b.w. ), reducing the fibrotic area by more than 60%. This is achieved by inhibition of the TGF-\(\beta\)1 pathway of myofibblast differentiation. It should be noted that no toxic effects were observed for either compound in the chronic toxicity test (seven days), using a dose of 2 g/kg (b.w.) administered orally. Finally, a patent involving an alantolactone (**1**) spiro-isoxazoline derivative was filed in June 2019 (US patent N\({}^{\circ}\) 20190185487) for the development and production of these compounds that exhibit significant anti-inflammatory activity. One factor which contributes to making alantolactone (**1**) very interesting as a future medicine is its low toxicity. In work by [PERSON] et al. [55], Kunming mice treated with 100 mg/kg (b.w.) alantolactone (**1**) showed no significant signs of hepatotoxicity or nephrotoxicity, in line with the previously cited work by [PERSON] et al. [38].