*3.11. Anti-Inflammatory Activity*

RA administration (40 mg/kg) in a rat model of sciatic nerve chronic constriction injury (CCI)-induced neuropathic pain reduced spinal inflammatory markers, such as matrix metallopeptidase 2 (MMP2), prostaglandin E2 (PGE-2), IL-1β, and COX-2 [126]. In addition, RA administration (75, 150, and 300 mg/kg) in hepatocellular carcinoma (HCC) for 10 days reduced inflammatory and angiogenic factors levels, including TNFα, IL-6, IL-1β, TGF-β, and VEGF. Moreover, it also decreased NF-κB and p65 expression in the xenograft microenvironment [127].

On the other hand, RA (IC50 = 14.25 μM) inhibited LPS-induced NO production in RAW 264.7 cells. It also repressed LPS-induced pro-inflammatory cytokines expression, including INF-β, MCP-1, iNOS, IL-1β, IL-6, IL-10, and NF-κB activation. In dependent and independent pathways, down-regulation of iNOS by RA was due to myeloid di fferentiation primary response gene 88 (MyD88). Additionally, RA triggered HO-1 expression through inducing Nrf2 activity [92,128].

RA (5, 10, and 20 mg/kg) also inhibited Th2 cytokines in BAL fluid, increased inflammatory cells, ameliorated hyper airway responsiveness (AHR), and reduced total IgE and Ova-specific IgE concentrations in a murine model of asthma (female BALB/c mice). In upper airways, RA reduced the number of mucus hypersecretion and inflammatory cells. It seems that RA protective e ffects might be mediated by p38 phosphorylation, JNK, and ERK suppression. Additionally, RA pretreatment provoked the reduction of Ym2, CC chemokine receptor 3 (CCR3), CCL11 (eotaxin), AMCase, and E-selectin mRNA expression in lung tissues [129]. In SPI, RA noticeably increased antioxidant status and reduced oxidative stress levels in Wistar rats post-SCI. It also improved inflammatory mechanisms through pro-inflammatory cytokines reduction and NF-κB down regulation [69]. RA (10, 25, and 50 mg/kg) also remarkably decreased the serum transaminases (ALT and AST) and LDH concentration in liver ischemia-reperfusion rats. Furthermore, it reduced multiorgan dysfunction markers (lung, liver, and kidney) through metalloproteinase-9 and NF-κB modulating [130]. RA also displayed both peripheral and central antinociceptive e ffects and anti-inflammatory activity against chronic and acute inflammation [83,131–133]. In Freund's complete adjuvant (FCA)-induced arthritic rats, RA attenuates inflammation [134].

RA also decreased blocked TNFα-induced NF-κB activation and cytotoxicity, oxygen-glucose deprivation (OGD)-induced apoptosis, and high-mobility group box1 (HMGB1) expression in SH-SY5Y cells. It also decreased brain edema, reduced NF-κB activation and HMGB1 expression, and attenuated histopathological damage at a dose of 50 mg/kg [135]. RA also considerably lowered allergic asthma through a significant decrease in the number of leukocytes/eosinophils, of mucus present in the respiratory tract, eosinophil peroxidase activity, and IL-4 and histopathological changes in lung BAL fluid [117,136]. RA-derived water and ethanol extract also markedly inhibited LPS-stimulated PGE-2 and NO production in a dose-dependent manner in RAW 264.7 mouse macrophages [137].
