## 3 Health Benefits of Rosmarinic Acid
### Antioxidant Activity  
RA exhibited free radicals scavenging activity in hepatic stellate cells (HSCs) as a result of its antioxidant effects by boosting GSH synthesis and participating in NF-\(\kappa\)B-dependent inhibition of MMP-2 activity. It also has the ability to reverse activated HSCs to quiescent cells and ultimately inhibits MMP-2 activity. RNA interference-imposed knockdown of NF-\(\kappa\)B abolished MMP-2 down-regulation by RA. NF-\(\kappa\)B inactivation mediated by RA could be blocked by the diphenyleneiodonium chloride, a potent inhibitor of NADH/NADPH oxidase. Moreover, transfection of dominant-negative (DN) mutant JNK, p38\(\alpha\) kinase, or extracellular signal-regulated kinases 2 (ERK2) had no such effect. At once, RA suppresses lipid peroxidation (LPO) and ROS generation, whereas in HSC-T6 cells it increases cellular GSH. Additionally, it significantly increases Nrf2 translocation and catalytic subunits from glutamate cysteine ligase (GCLc) expression but was not able to modulate GCL (GCLm) subunits and antioxidant response element (ARE)-mediated luciferase activity. GClc up-regulation mediated by RA is inhibited by shRNA-induced Nrf2 knockdown. The knocking down of Nrf2 abolished RA-mediated inhibition of ROS [16; 62]. On the other hand, lycopene and RA administration reduced elevated blood urea nitrogen, renal malondialdehydedehyde (MDA), proapoptotic protein (Bax) immuno-expression, serum creatinine, inducible nitric oxide synthase (iNOS), and autophagic marker protein (LC3/B) levels induced by gentamicin. This combination also increased the reduced SOD, an antiapoptotic protein (Bcl2) immuno-expression, GPx, and GSH levels and ameliorated gentamicin-induced histopathological changes. Moreover, it also evidenced a greater protective effect than corresponding monotherapy [63]. The in vivo antioxidant defense system consists of antioxidant enzymes including CAT, GPx, SOD, and nutritional antioxidants. Any disturbance in normal antioxidant defense system triggers several diseases, including diabetes, cancer, atherosclerosis, and degenerative diseases [64]. In experimental animals, carbon tetrachloride (CCI\({}_{4}\)) induced neurotoxicity, whereas CCl\({}_{4}\) skin absorption, inhalation,and ingestion increased lipid peroxidation and reduced protein and antioxidant enzymes contents. This molecule produces free radicals in the lungs, heart, blood cells, and kidney. Under aerobic conditions, CCl4 is converted into highly reactive trichloromethyl radicals through the action of the cytochrome P450 system [65]. Brain amyloid-\(\beta\) (A\(\beta\)) accumulation is a hallmark of Alzheimer's disease (AD) and has an important role in cognitive dysfunction [66]. At a dose of 0.25 mg/kg, RA significantly enhanced cognitive function and object discrimination and recognition test. Furthermore, RA decreased the time to reach the platform and increased the number of crossings over the removed platform, when compared with A\(\beta\)25-35-induced group in Morris water maze test; moreover, it reduced NO and MDA levels in kidney, brain, and liver [67]. RA also suppresses AD development by reducing amyloid \(\beta\) aggregation by increasing monoamine secretion in mice [68]. RA also prevented oxidative stress in C6 glial cells by increasing cell viability and inhibiting lipid peroxidation. It also decreased H\({}_{2}\)O\({}_{2}\)-induced COX-2 and iNOS expression at the transcriptional level and down-regulated COX-2 protein expression and iNOS in C6 glial cells treated with RA [67]. It significantly reduced oxidative stress and increased antioxidant status in Wistar rats post-spinal cord injury (SCI). RA also facilitated the inflammatory process through pro-inflammatory post-SCI and down-regulated NF-kB [69]. It also exerted a significant cytoprotective effect through covering the intercellular ROS in HaCat keratinocytes. RA also increased CAT, SOD, heme oxygenase-1 (HO-1), and transcription factor Nrf2 expression and activity, markedly reduced by UVB radiation [70].