# \(\beta\)-Caryophyllene: A Sesquiterpene with Countless Biological Properties
## 2 Biological properties of \(\beta\)-caryophyllene
### \(\beta\)-Caryophyllene and Inflammatory Diseases  
Acute inflammation is a body defence mechanism against various factors, which may evolve in chronic inflammation, resulting in pathological disease [81]. After the acute reaction, monocytes remain in the inflammation site, where they secrete cytokines and chemokines and stimulate macrophages, amplifying the inflammatory response. As for neuroinflammation, the main phlogistic mediators are interleukins IL-1\(\beta\), IL-6, and TNF-\(\alpha\), which increase NF-kB (nuclear factor kappa B) expression, prostaglandandins and leukotrienes, synthesized by cyclooxygenase (COX) and 5-lipoxygenase (LOX) [82]. An in vitro study on macrophages of RAW267.4 [83] mice has revealed that BCP, administered in association to other two natural molecules, baicalin (**10**) and (+)-catechin (**11**) (Figure 4), at relatively low doses, suppresses the proliferation of these cells involved in inflammation [52]. Figure 4: Structures of the baicalin (**10**) and (+)-catechin (**11**). The three substances act synergically, since they separately do not exert any significant activity. Their effect is achieved through the cell cycle arrest phase G2/M and the modulation of various intracellular pathways, such as PI3K/Akt, extracellular signal-regulated kinases(ERK)/MAPK, and calcium homeostasis. In particular, the decrease of the expression of Akt, MAPK p38 and p44/42, and caspase-3 activation, an important step of apoptosis, have been observed. In addition to these effects, the expression of COX-1 and COX-2 diminishes, and so the activity of the protein p65 of NF-kB family does [52]. According to a recent study, BCP exerted powerful results against the negative effects of dyslipidemia and vascular inflammation in mice [53]. In fact, it has been revealed that the treatment with the sesquiterpene, at the dose of 30 mg/kg, prevents the increase of adiposity index, glycemia and insulinemia due to a high fat-diet. It also helps dyslipidemia and reduces all atherogenic risk indexes, even if it does not modify body weight. BCP reduces oxidative stress, by decreasing the concentration of NO and malondialdehydehyde (MDA), a by-product of lipid peroxidation, and by increasing the level of the endogenous antioxidant glutathione [84]. The phytocannabinoid is able to suppress mediators involved both in inflammation and atherosclerosis, such as TNF-\(\alpha\) and NF-\(\kappa\)B. In this way, it leads to the inhibition of VCAM1 [53], a vascular cell adhesion protein, which promotes the adhesion of white cells of the vascular endothelium and favours atherosclerosis, confirming what was reported in other in vitro researches [54]. BCP normalizes the ratio between endothelial (eNOS) and inducible (iNOS) nitric oxide synthase within the aorta. The latter is activated in the phlogistic process and in the atherosclerosis following the oxidative stress-induced NF-\(\kappa\)B activation. Further, iNOS produces a high amount of nitric oxide, which interacts with ROS, generating peroxpritrites, which amplify the oxidative stress. Furthermore, BCP attenuates the formation of foam cells and the deposition of collagen, which plays a crucial role in the formation and progression of vulnerable atherosclerotic plaques, and protects the integrity of elastic lamina. All these effects are attributable to direct action of BCP, as agonist of cannabinoid receptors CB2, other than of PPAR-\(\gamma\) receptors (receptors activated by peroxisome proliferatorator-activated receptors), involved in the reduction of blood levels of total cholesterol, low density lipoprotein (LDL) and very low density lipoprotein (VLDL), in the inhibition of vascular inflammation and synthesis of adhesion molecules and in the rebalancing of nitric oxide concentration and nitric oxide synthase isoforms. Moreover, it would seem that BCP is also an agonist of PPAR-\(\alpha\) receptors, reduces fat mass and triglycerides and increases high density lipoprotein (HDL).