**4.3.1 Antiinflammatory activity**

Epidemiological evidence points that many cancers arise from sites of infection, chronic irritation and inflammation (Rakoff-Nahoum, 2006; Heber, 2008). The inflammatory response result in persistent oxidative stress orchestrates tumour microenvironment to microbial infection and mediates tissue repair and regeneration, which may occur due to infectious or non-infectious tissue damage.

Pomegranate and the selected chemical constituents isolated from juice, peel, and seed have been found to have a large range of effects: (i) inhibition of Cyclooxygenase-2 (COX-2) expression and ultimately eicosanoid biosynthesis (Schubert et al., 1999; Shukla et al., 2008); (ii) synergistic suppression of inflammatory cytokine expression (Adams et al., 2006); (iii) inhibition of matrix MMPs (Okamoto et al., 2004; Ahmad et al., 2005; Aslam et al., 2006).

In view of the antioxidant, anticarcinogenic and antiinflammatory properties of pomegranate phenolics and/or its derived metabolites, one could hypothesize that pomegranate and/or its derived metabolites have a beneficial effect on inflammation. Larrosa et al. (2010) evaluated the effects of pomegranate intake and its main microbiotaderived metabolite urolithin-A (UROA) on colon inflammation in a dextran sodium sulfate (DSS)-induced colon inflammation rat model and to assess whether UROA is the main antiinflammatory compound. In addition, they examined the effect of the inflammation on the phenolic metabolism. DSS (5%) was administered for the five last days to Male Fisher rats, fed with 250 mg/kg day pomegranate extract or 15 mg/kg day UROA for 25 days. In both groups inflammation markers (iNOS, COX-2, PTGES and PGE2 in colonic mucosa) were decreased, the gut microbiota was modulated and the G1 to S cell cycle pathway was upregulated. UROA group showed various down-regulated pathways, including that of the inflammatory response. Pomegranate extract, but not UROA, decreased oxidative stress in plasma and colon mucosa. Only UROA preserved colonic architecture. The normal formation of urolithins in pomegranate extract-fed rats was prevented during inflammation suggesting UROA could be the most active anti-inflammatory compound derived from pomegranate ingestion in healthy subjects, whereas in colon inflammation, the effects could be due to the nonmetabolized ellagitannin-related fraction.

Structure–activity relationships of natural products have been found to influence the various pharmacological functions. *In vitro* and *in vivo* antiinflammatory effects of *Punica granatum* Linne, a high phenolic content fruit, widely used as an antipyretic analgesic in Chinese culture, were investigated by Lee et al. (2010). Pomegranate has shown potential nitric oxide (NO) inhibition in liposaccaharide (LPS)-induced RAW 264.7 macrophage cells, with significant decrease in carrageenan-induced mice paw edema. Hydrolysable tannins, punicalagin, punicalin, strictinin A, and granatin B, inhibited NO production and inductible nitric oxide synthase (iNOS) expression in RAW 264.7 cells. Granatin B showed the strongest iNOS and COX-2 inhibitory effects, and exhibited these effects in the inhibition of paw swelling and the prostaglandin (PG) E2 level in carrageenan-induced mice.

Inflammatory disorders are due to excessive production of pro-inflammatory mediators such as TNFa, GM-CSF, IL-1, IL-6, IL-8, leukotriene B4 and PAF, the activity of inflammatory cells such as neutrophils, monocytes and macrophages, and excessive production of reactive oxygen species (ROS) (Nathan, 2006). Bachoual et al. (2011) investigated the effect of pomegranate peel aqueous extract (PPAE) on human neutrophil reactive oxygen species (ROS) production *in vitro* and on LPS-induced lung inflammation *in vivo* in mice. PPAE, in a concentration-dependent manner, inhibited luminol-amplified chemoluminescence of resting neutrophils and N-formyl-methionylleucyl- phenylalanine (fMLF)- or phorbol myristate acetate (PMA)-stimulated neutrophils. On the contrary, had no significant effect on superoxide anion generation, suggesting that it does not directly inhibit NADPH oxidase activity or activation pathways, or scavenge superoxide anions. *In vivo* studies showed that PPAE also attenuated LPS-induced lung inflammation in mice. Consequently PPAE found to inhibit neutrophil myeloperoxidase activity and attenuates LPS-induced lung inflammation in mice.
