## 3 Health Benefits of Rosmarinic Acid
### Antidiabetic Activity  
RA supplementation increases the expression of mitochondrial biogenesis key genes, like sirtuin 1 (SIRT-1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1\(\alpha\)), and mitochondrial transcription factor A (TFAM) via activation of AMP-activated protein kinase (AMPK) in the skeletal muscle of insulin-resistant rats as well as in L6 myotubes. It also increased glucose faster and decreased serine IRS-1 phosphorylation, while increasing the glucose transporter type 4 (GLUT4) transfer [37]. In streptozotocin (STZ)-induced diabetic rats, RA exerted a noticeable hypoglycemic effect, whereas in high-fat diet (HFD) fed diabetic rats it increased glucose utilization and ameliorated insulin sensitivity. RA supplementation inverted the STZ- and HFD-induced increase in phosphoenolpyruvate carboxykinase (PEPCK) expression in the liver and the STZ- and HFD-induced decrease in GLUT4 expression in skeletal muscle. RA exerts hypoglycemic effects and improves insulin sensitivity, also increasing GLUT4 expression and decreasing PEPCK expression [38]. In addition, it also reverses memory and learning defects through improving cognition in healthy rats, inhibiting hyperglycemia, lipid peroxidation, and enhancing antioxidant defense system [39]. At a concentration of 10 mg/kg, RA decreased TBARS levels in kidney and liver of STZ-induced diabetic rats. This effect was mainly conferred by its ability to increase superoxide dismutase (SOD) and catalase (CAT) activity and to reverse the decrease in ascorbic acid and of non-protein thiol levels in diabetic rats [40]. RA administration also ameliorated oxidative stress markers in diabetic rats and water consumption and urination. Thus, it was proposed that RA mitigates STZ-induced diabetic manifestations by protecting rat's tissues against  
Figure 3: Mechanism of rosmarinic acid as an anticancer agent. free radicals' damaging effects [15]. At 100 mg/kg, RA significantly increased insulin index sensitivity and reduced blood glucose, advanced glycation end-products, HbA1c, IL-18, TNF\(\alpha\), IL-6, p-JNK, P38 mitogen-activated protein kinase (MAPK), and NF-\(\kappa\)B levels. Moreover, it significantly reduced free fatty acids (FFA), triglycerides, serum cholesterol, AOPPs, lipid peroxides, and protein carbonyls levels in plasma and pancreas of diabetic rats. The reduced activities of CAT, SOD, glutathione _S_-transferases (GST), and glutathione peroxidase (GPx) and the reduced levels of vitamins C and E, ceruloplasmin, and GSH in plasma of diabetic rats were also significantly recovered by RA application. Furthermore, it protects pancreatic \(\beta\)-cells from oxidative stress in HFD-STZ-induced experimental diabetes [41]. The protective effects of RA (30 mg/kg) against hypoglycemia, hyperlipidemia, oxidative stress, and an imbalanced gut microbiota architecture was studied in diabetic rats. The treatment decreased the levels of fasting plasma glucose, total cholesterol, and triglyceride, exhibited an antioxidant and antiglycative effect, showed protective effects against tissue damage and inflammation in the abdominal aorta, increased the population of diabetes-resistant bacteria, and decreased the number of diabetes-sensitive bacteria [12]. RA also reduced diabetes occurrence and preserved normal insulin secretion, ROS, and reactive nitrogen species (RNS) by regulating antioxidant enzymes, and attenuating the pro-inflammatory T helper 2 and T regulatory cells levels [42]. At a concentration of 10 mg/kg, RA treatment significantly reduced lipid peroxidation levels in the hippocampus (28%), cortex (38%), and striatum (47%) of diabetic rats [43]. In Wistar rats, RA administrated orally at 50 mg/kg for 10 weeks in STZ-induced diabetes diminished endothelium-dependent relaxation accompanied by IL-18, TNF-\(\alpha\), preproendothelin-1, and endothelin converting enzyme 1 overexpression. It also provided aortic endothelial function protection against diabetes-induced damage [44].