# \(\beta\)-Caryophyllene: A Sesquiterpene with Countless Biological Properties
## 2 Biological properties of \(\beta\)-caryophyllene
### \(\beta\)-Caryophyllene and Inflammatory Diseases
This happens through the binding of BCP to cannabinoid receptors CB2-R, which activates PGC1-\(\alpha\) (coactivator 1 of the peroxisome gamma proliferatorator) and allows the interaction among PPAR-\(\gamma\) and various transcriptional factors, such as PPAR-\(\alpha\), increasing the expression of enzymes with the function of oxidizing fat acids, above all in the liver. The comparison with the thiazoltionedione pioglitazone (**12**) (Figure 5), a PPAR-\(\gamma\) agonist used for the treatment of type 2 diabetes and atherosclerosis, has shown that BCP is more effective than the drug for all the parameters, except for the glutathione levels. In addition, the sesquiterpene does not induce body weight gain, the main side effect of pioglitazone [53]. BCP is beneficial in a model of bilateral carotid artery occlusion and reperfusion (BCCAO/R) in Wistar rats. This study has demonstrated that a single dose of BCP prevents plasmatic and  
Figure 5: Structure of the pioglitazone. tissue modifications induced by carotid obstruction and reperfusion [55]. It increases tissue levels of endocannabinoids (anandamide, 2-arachidonovglyycerol, palmitoylethanolamide, oleylethanolamide) and cannabinoid receptors CB1 and CB2, reducing anandamide blood concentrations. Furthermore, it preserves the tissue levels of the essential fatty acid docosahexaenoic acid (DHA), increases PPAR-\(\alpha\) expression, and decreases lipoperoxidation damage [55]. BCP effects have been studied in a rat model of rheumatoid arthritis, characterized by inflammatory response. BCP and copaiba oil (the sesquiterpene accounts for about 37% of the oil) have the same ability to reduce paw edema, popliteal lymph nodes weight and myeloperoxidase plasmatic activity. BCP, unlike copaiba oil, decreases also the activity of hepatic myeloperoxidase and leukocytes, both the blood ones and those present in the joints. The anti-inflammatory activity is slightly greater in copaiba oil than in BCP, probably because of the presence of other molecules with synergism effect. Neither the oil nor the single molecule are able to modify secondary injuries and body weight in rats. Both are capable, at high doses, to:  
* Reduce carboxylic groups of protein and ROS in the liver, normalizing the levels;
* Increase glutathione levels and reduce lipoperoxidation [56]. Copaiba oil, because of the presence of diterpenes, like kaurenoic acid and hardwickiic acid, is hepatotoxic, reducing the liver functionality due to hepatic cholestasis. In this context, the use of isolated BCP is preferable, since it is hepatoprotective [57]. BCP exerts in vitro [45; 85; 86] and in vivo antioxidant capacities. As regards the mechanism, BCP, at a dose of 430 mg / kg, exhibits antioxidant activity and acts by exerting various functions: radical scavenging ability in particular with respect to hydroxyl radicals, lipid peroxides and superoxide anions; stimulation of the endogenous antioxidant system, highlighted by the increased content of glutathione in the liver, induced by Nrf. A decrease in inflammation, characterized by reduced activity of myeloperoxidase, is a marker of infiltration of polymorphonuclear cells, and diminished expression of COX-2 and cytokines, such as TNF-\(\alpha\), IL-1\(\beta\), IL-6, and consequently, NF-\(\kappa\)B. Also, BCP effects on C57 BL/6J mice have been investigated. The mice, fed with an essential amino acid-deficient diet, are a model of non-alcoholic steatohepatitisitis (NASH), which is a hepatic inflammatory pathology associated to metabolic syndrome predisposing cardio-vascular diseases. In the case of steatohepatitisitis, the organ undergoes histological changes caused by oxidative stress, inflammation and fibrosis. The treatment with BCP reduced inflammation and fibrosis. Moreover, a decrease in alanine-transaminase (ALT) and cytokine expression has been observed, suggesting that the liver has been less damaged.