## 3 Results
### Ability of Caryophyllane sesquiterpenes to Modulate Macrophage Function
\begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Caryophyllane** & **Immune System** & **Stimulation** & **Concentration of** & & \\
**Sesquiterpene** & **Cells/Cell Model** & **Stimulation** & **Test Compound** & **Outcome** & **References** \\ \hline \multirow{6}{*}{\(\alpha\)-Humulene} & Macrophages/ & LPS a & \multirow{2}{*}{755, 1555} & \multirow{2}{*}{\(\downarrow\) NO} & \multirow{2}{*}{[32]} \\  & RAW 264.7 & [1 ug/mL] & & & \\ \cline{1-1} \cline{2-6}  & Macrophages/primary & & & & \\ \cline{1-1} \cline{2-6}  & splenocytes from & & & & \\ \cline{1-1} \cline{2-6}  & BALB/c mice & & & & \\ \cline{1-1} \cline{2-6}  & Lymphocytes/MLNs & OVA & & & \\ \cline{1-1} \cline{2-6}  & & [50 ug/mL] & & & \\ \hline \hline \end{tabular}  
* increase; \(\downarrow\) reduction; RAW 264.7 murine monocyte/macrophage cell line; Akt protein kinase B; p21 protein 21; MAPK mitogen-activated protein kinases; TNF Tumor necrosis factor; PGE2 prostaglandin E2; IL interleukin; LPS lipopolysaccharide; BALB/c mice albino, immunological laboratory-breat of the house mouse; Th T helper; M2-MPs BALB/c mice bone marrow-derived M2 macrophage; MCP-1 monocyte chemoattractant protein-1; M-CSF macrophage-colomy stimulating factor; CS7 BL/6 inbred mouse strain; NO nitric oxide; iNOS inducible nitric oxide synthase; Arg-1 arginase-1; GSH glutathione; BV2 murine microglial cell line; A\(\beta_{1-2}\) beta amyloid peptide; TLR Toll-like receptor 4; IDH lactate dehydrogenase; Nf-kB nuclear factor Kappa B; COX-2 cyclooxygenase; 2; THP-1 human leukemia monocyte cell line; VCAM-1 vascular cell adhesion molecule-1; HUVECs primary human umbilical vein endothelial cells; Erk 1/2 extracellular receptor kinases \(\frac{1}{2}\); JNK 1/2 c-Jun N-terminal kinase; MAPK p38 mitogen-activated protein kinases p38; EAE experimental autoimmune encephalomyelitis; MO53-55 Myelin oligodendrocyte glycoprotein 35–55; IFN\(\gamma\) interferon-\(\gamma\); MLNs draining lymph nodes (mediastl) derived cultures, isolated from OVA-immunized BALB/c mice; OVA ovalbumin.
* LPS undefined source; b LPS from _E. coli_ (026;B6; LPS E. coli_ 058;B5; M TNF-c concentration not reported.  
\end{table} 
Table 1: Cont. induced by middle and higher concentrations of \(\beta\)-caryophyllene, can stimulate the PPAR-\(\gamma\) pathway and thus further contribute to the protective activity of \(\beta\)-caryophyllene [40]. \(\beta\)-caryophyllene also showed modulatory effects on microglial activity in in vitro models of Alzheimer's disease by counteracting the toxic effects of A\(\beta_{1-42}\) soluble oligomers, known to be responsible for direct neurotoxicity and for indirect neuroinflammation. [PERSON] and colleagues [42] showed that \(\beta\)-caryophyllene (10, 25, and 50 \(\upmu\)M) was able to protect BV2 microglial cells from A\(\beta_{1-42}\) (20 \(\upmu\)M) injury by lowering the release of LDH and inflammation, through the impairment of TLR4/Nf-kB signaling, involved in brain inflammatory response. Indeed, it inhibited the iNOS and cyclooxygenase-2 (COX-2) enzymes and their products and the gene expression of pro-inflammatory cytokines (TNF-\(\alpha\), IL-6, and IL-18); moreover, a decreased expression of TLR4, involved in the progression of [PERSON]'s disease, and M1 polarization [40], along with a reduced Nf-kB activity, due to the inhibition of \(\mathrm{k}\mathrm{B}\alpha\) phosphorylation and degradation, were found too [42]. \begin{table}
\begin{tabular}{c c c c c} \hline
**Caryophyllane** & **Animal Model/** & **Test Compound Dose** & **Outcome** & **References** \\
**Sesquietpene** & **Immun Cells** & **(Administration Route)** & & \\ \hline High-fat diet and & & & \(\downarrow\) macrophages in tumor tissue & \\  & B16 Flo10 bearing & 0.15-0.3\% of diet (per os) & \(\downarrow\) macrophages in the & [35] \\  & CS7 BL/6 mice/macrophages & & & lymphmode & \\ \hline LPS-fat-induced atherosclerosis & & & & \\  & CS7 BL/6 mice/macrophages & 10 mg/kg (i.p.)