# Forest Volatile Organic Compounds and Their Effects on Human Health: A State-of-the-Art Review
## 3 Results
### Evidence about the General Effects of Forest VOCs on Health
#### 3.4.1 Immune System and Inflammation  
A recent review synthesized available evidence on the immune function enhancing effects of essential oils and, in particular, results of studies about forest bathing were discussed, thus suggesting that even 2-h-long forest walks can be associated with a significant increase in Natural Killer (NK) cell count and activity and can augment the number of cytolytic molecules expressing cells, with such variations lasting for many days after the experience, both in healthy subjects and in individuals with cancer-related pain [61]. Some studies included in this review also showed an effect of forest bathing on serum levels of IL-8, IL-6, and TNF\(\kappa\)[61]. These findings confirmed the main results of preclinical laboratory experiments [62]. As with all studies about forest bathing, the suggestion that the mechanism for the observed health benefits is due to the inhalation of forest BVOCs must be balanced by the possible role of mediators like other sensory or non-sensory stimulators [63].  
A review of preclinical studies analyzed available evidence regarding the effects of the most common volatile terpenoids found among BVOCs on inflammation and concluded that these compounds might act as inhibitors of pro-inflammatory mediators such as NO, TNF-\(\alpha\), and PGE2, thus modulating signal transduction pathways involving transcription factors like NF-kB and the mitogen-activated protein kinase (MAPK) [4]. Moreover, some terpenoids can directly interact with TRP receptors (implicated in nociception and inflammatory responses), reduce oxidative stress, and stimulate cell autophagy. The authors reported that, although these activities are not limited to forest bathing and can be exploited through skin applications or oral intake of essential oils, the contact during forest bathing may be safer, although less beneficial [4]. In any case, only a small number of preclinical studies have investigated the role of total extracts of forest BVOCs: volatile compounds extracted from hinoki wood essential oil have been reported to increase in vitro the natural killer (NK) cell activity by enhancing the expression of cytolytic enzymes [64]; also, an extract obtained from pinecones has been found to protect bovine mammary epithelial cells, stimulated with lipopolysaccharide(LPS), from oxidative stress after downregulating cyclooxygenase-2 (COX-2) expression [65]. On the other hand, single terpen (\(\alpha\)-phellandrene, 1,8 cineole, linalool, and \(\beta\)-caryophyllene) have been successfully used as pre-treatment to reduce the levels of interleukins, TNF-\(\alpha\), and iNOS in cellular and animal inflammatory-induced models [66; 67; 68; 69]. Furthermore, mitogen-activated protein kinase (MAPK) signal transduction pathways (e.g., JNK and p38) can be inhibited by myrcene, limonene, and borneol [70; 71]. Interestingly, \(\beta\)-caryophyllene has been shown to bind the peripheral receptor for cannabinoids (CB2R) and modulate the immune function [72; 73]. Additionally, terpene treatment is able to reduce nucleus translocation, phosphorylation, and expression levels of NF-kB [4] and Nrf [74; 75; 76], the main transcriptional factors regulating levels of pro-inflammatory mediators. Moreover, many studies have demonstrated some BVOCs' (i.e., myrcene, linalool, 1,8 cineole, \(\alpha\)- and \(\gamma\)-terpinene) antioxidant properties such as the decrease of Reactive Oxygen Species (ROS), Matrix Metallo-Proteinase (MMP), and Nitric Oxide (NO) production [77; 78; 79; 80]. Finally, inhibition of neuro-inflammation has been shown in vitro for 1,8-cineole [81] and \(\beta\)-caryophyllene [82; 83] and in in vivo animal models for d-limonene [84] and linalool [85].