## 2 Biological Activities of Monoterpenes
### Cyclic Monoterpens  
The cyclic monoterpens **7-12** (Figure 4) have a strong background in biological activities as they are common members of essential oils used in ethnopharmacology [55]. The natural product \(p\)-cymene (**97**, Figure 4) is an aromatic, cyclic monoterpene that has been demonstrated to have antioxidant properties in vivo. A study conducted in diabetes induced Wistar rats demonstrated this compound's ability to upregulate mTOR, AKT, and phospho-AKT enzymes all of which being crucial regulators of oxidative stress [56]. The diabetes induced rats were dosed with either 55 mg/kg of metformin, an approved type II diabetes medication, or 25, 50, 100 mg/kg of \(p\)-cymene. All groups were successful in increasing the expression of these key oxidative stress regulatory enzymes [56]. It is worth noting that although the 25, and 50 mg/kg groups were less effective than metformin, the 100 mg/kg group was able to upregulate these enzymes to a comparable degree as the metformin group [56]. \(d\)-Limonene (**8**, Figure 4) is a chiral, cyclic monoterpene that has been shown to have both anticancer and antioxidant properties. A study conducted in vivo animal models showed this compound's ameliorative effect on chloroform induced cardiotoxicity by lowering oxidative stress, inflammatory and cardiac markers [57]. The study monitored the change in cardiac injury markers whose expression was increased by CCl\({}_{4}\); following two weekly doses of 200 mg/kg of \(d\)-limonene approximately 50% reduction in serum levels of cardiac inflammatory markers IL-6, Hs-CRP, and TNF\(\alpha\) was noted [57]. An independent study observed the effects of \(d\)-limonene in cancer therapy. This work used \(d\)-limonene for its antioxidant effects in a co-treatment study with doxorubicin [58]. The designed nanoparticle delivery system showed a strong decrease in cell viability against HepG2 human liver cancer cell line and a decrease in cytotoxicity of the LX2 normal cells [58]. Unfortunately, there was no further biological evaluation of this treatment system to further support the hypothesis of the mechanism of action with the doxorubicin-_d_-limonene nanoparticle delivery systems. Carvone (**10**, Figure 4) is a chiral, cyclic monoterenoid present in large quantities in caraway and spearmint essential oils that has been isolated identified for its anticancer and anti-oxidative properties. A study on the anticancer effects of carvone on myeloma cells (KMS-5) indicated that this meroterenoid induces apoptosis through inhibition of the p38 MAPK signal transduction pathway [59]. It was found that the IC\({}_{50}\) of carvone against this cell line was 20 \(\upmu\)M [59]. Apoptosis was identified as the mode of action for this treatment by DAPI, AO/EB, and V/PI staining assays carried out at concentration of 20 \(\upmu\)M carvone. Furthermore, western blot analysis demonstrated the decrease in expression of p-P38, a dual regulator of apoptosis, in response to carvone treatment at 20 \(\upmu\)M leading to the conclusion that this compound may inhibit the expression of this regulatory enzyme [59]. An independent study investigated this compound's effects in alleviation of doxorubicin induced cardiotoxicity. The IC\({}_{50}\) value of carvone on the MCF7 cell line was determined to be 14 \(\upmu\)M while in the healthy cell line H9C2 this monoterenoid was nontoxic up to 200 \(\upmu\)M [60]. In vivo analysis of male BALB/c mice was done to evaluate the synergistic effects of carvone during concomitant treatment with doxorubicin. These experiments showed that the myocardial disorganization and degeneration imposed by 20 mg/kg intraperitoneal (i.p) injection of doxorubicin was alleviated when i.p. injection of 75 mg/kg carvone was done one hour prior to doxorubicin treatment [60]. Identical injection of 150 mg/kg carvone resulted in no notable tissue generation upon histological analysis [60]. Cuminaldehyde (**11**, Figure 4) is an aromatic, cyclic monoterenoid with anticancer biological properties.