*3.3. Antimicrobial Activity*

Regarding RA antimicrobial activity, it exerted antibacterial e ffects against *Staphylococcus aureus* strains, and the lowest blocking concentration was found to be 0.8 and 10 mg/mL against *S. aureus* and methicillin-resistant *S. aureus* (MRSA), respectively. Moreover, it displayed synergistic e ffects with amoxicillin, ofloxacin and vancomycin antibiotics against *S. aureus*, and only with vancomycin against MRSA. Time-kill analysis showed that using a combination of RA with antibiotics is more effective than using individual antibiotics. Microbial surface components recognizing adhesive matrix molecules (MSCRAMM) adhesion protein expression in MRSA and *S. aureus* was also significantly suppressed by using a combination of RA with vancomycin rather than RA alone [46].

On the other hand, RA administration reduced biofilm formation in a concentration- and time-dependent manner, suggesting that it could be used as an e ffective antimicrobial agen<sup>t</sup> to kill the planktonic cells activity and to reduces the biofilm formation activity in early-stage development [47]. RA also exerts inhibitory e ffects against *Escherichia coli* K-12 and *Staphylococcus carnosus* LTH1502 growth, through decreasing cell counts and cell number [48]. Under acidic conditions, RA was reacted with nitrite ions to give 6,6-nitro and 6-dinitrorosmarinic acids. These compounds were active as HIV-1 integrase inhibitors at sub-molecular levels and inhibited viral replication in MT-4 cells. Without increasing cellular toxicity levels, RA nitration A strongly improved anti-integrase inhibition and antiviral e ffects [49]. Moreover, RA also exerted antimicrobial e ffects against *Enterobacteriaceae* spp., *Pseudomonas* spp., lactic acid bacteria, yeas<sup>t</sup> and mold, and psychotropic counts, as well as fate *Listeria monocytogenes* inculcated in chicken meats [50]. Finally, RA also displayed inhibitory e ffects against *S. aureus* cocktail through inducing morphological changes and reducing viable cells counts and causing morphological changes in cheese and meat samples, such as cell shrinkage and appearance of blabbing-like structures in cell surfaces [51–53].

## *3.4. Cardioprotective Activity*

RA at 25, 50, 10 mg/<sup>L</sup> had the capacity to maintain ATP levels in cells and inhibit the decrease in H/R-induced cell viability, lactate dehydrogenase (LDH) leakage, and excessive ROS. It also inhibited H/R-induced cardiomyocyte apoptosis and down-regulated p-AKt cleaved caspase expression [54].

The endothelial protein C receptor (EPCR) has a prominent role in inflammation and coagulation, whereas its activity is significantly changed by ectodomain cleavage and release as the soluble protein (sEPCR). RA has been found to be a strong anti-inflammatory agent. Monitoring RA e ffects in TNFα, phorbol-12-myristate 13-acetate (PMA), IL-1β and in cecal ligation and puncture (CLP)-mediated EPCR shedding and underlying mechanisms, it was found that RA treatment led to a potent inhibition of PMA, TNFα, and IL-induced EPCR shedding through TACE expression suppression. Furthermore, RA reduced extracellular regulated kinases (ERK) 1/2, PMA-stimulated p38, and c-Jun N-terminal kinase (JNK) phosphorylation. These results support the upcoming use of RA as an anti-sEPCR shedding reagen<sup>t</sup> against IL-1β, TNFα, PMA, and CLP-mediated EPCR shedding [55,56].

RA administration in fructose-fed rats (FFR) significantly enhanced insulin sensitivity, reduced lipid levels, oxidative damage, and a p22phox subunit of nicotinamide adenine dinucleotide phosphate reduced oxidase expression as well as prevented cardiac hypertrophy. RA lowered fructose-induced blood pressure through decreasing angiotensin-converting enzymes activity and endothelin-1 and increasing the level of nitric oxide (NO) [57]. RA also reduced fasting serum levels of vascular cell adhesion molecule 1 (VCAM-1), inter-cellular adhesion molecule 1 (ICAM-1), plasminogen-activator-inhibitor-1 (PAI-1), and increased GPX and SOD levels [58]. RA also intervenes in many important steps of angiogenesis, including adhesion, migration, proliferation, and tube formation of human umbilical vein endothelial cells (HUVEC) in a dose-dependent pattern. It also decreased IL-8 release from endothelial cells, H2O2-dependent vascular endothelial growth factor (VEGF) expression, and intracellular ROS levels [59]. Finally, in H9c2 cardiac muscle cells, RA inhibited apoptosis by decreasing intracellular ROS generation and recovering mitochondria membrane potential [60,61].
