## 2 Pomergnate Health-Promoting Properties
### Antiviral Activities  
The hydrolysise tannins of pomegranate, including puncalin (13), puncalagin (9), gallic acid (18), and ellagic acid (8), have antiviral properties capable of modulating respiratory infections and influenza. The antiviral properties of the polyphenic extract of pomegranate are due to the inhibition of influenza virus RNA replication [117; 123]. Similarly, phenols in the skin inactivate viruses through direct structural damage and indirect intercellular inhibition of viral replication. The virucidal effects of pomegranate phenolic compounds imply their interaction with the antigenic glycoprotein, hemagglutinin, present on the surface of some viruses (es. influenza viruses), which produce a loss of red blood cell agglutination [124]. In particular, [PERSON] et al. argued that puncalagin (9) is the effective component of pomegranate polyphenol extract able to block replication of the virus RNA, inhibit agglutination of chicken red blood cells (RBCs) by the virus of influenza H3N2, and have viricidal activity. They also investigated the potential synergistic effect of pomegranate polyphenol extract and oseltamivir (a well-known antiviral agent), outlining that oseltamivir in association with pomegranate polyphenol extract amplificated its anti-influenza power [125]. [PERSON] et al. in 2010 confirmed and implemented these data, strengthening that the direct anti-influenza activity of pomegranate polyphenols (PPs) is principally an outcome of PP-induced virion structural damage. Indeed, these components of pomegranates quickly block the influenza virus through a direct effect on the viral particle. They also suggested that this action might be separate from effects on hemagglutinin (HA) function. Moreover, they demonstrated the efficacy of pomegranate PPs against H1N1 and H3N2 influenza viruses and against the reassort H5N1 virus rg-VN/04 [126]. Furthermore, another study attributed to puncalagin the power to reduce the viral cytopathic effect on rhabdomyosarcoma cells, calculating an IC\({}_{50}\) value of 15 \(\upmu\)g/mL. This effect was also assessed in vivo, noticing a decrease of mortality in mice treated with a lethal dose of enterovirus 71 [126]. [PERSON] et al. focused on the potential effect against hepatitis C virus (HCV) of the ellagitannins extracted from pomegranate (_Punica granatum_) fruit peel. In particular, pure compounds puncalagin, puncalin, and ellagic acid exhibited in vitro the capability of blocking the HCV NS3/4A protease activity in a concentration-dependent manner with IC\({}_{50}\) values of less than 0.1 mM (for puncalagin and puncalin), whereas IC\({}_{50}\) for ellagic acid was achieved at 1.0 mM. These data were confirmed through in silico studies and observing a consistent reduction of HCV replication in cell culture systems. Data ex vivo pointed out the optimal bioavailability and the toxicity absence of these compounds [127]. In addition, a good activity of pomegranate extract toward adenovirus has been found. The IC\({}_{50}\) and CC\({}_{50}\) (50% cytotoxicity concentration) were estimated on HeLa cells with values of \(165\pm 10.1\) and \(18.6\pm 6.7\upmu\)g/mL, respectively, whereas the selectivity index (SI, calculated as the ratio of CC\({}_{50}\) and IC\({}_{50}\)) on adenovirus amounted to 8.9 [128]. In their analysis, [PERSON] et al. investigated the co-administration effects of pomegranate rind extract in conjunction with zinc (II) salts in order to challenge herpes simplex virus HSV-1 and its acidovir-resistant. Data showed a potentiation factor by up to 5.5-fold. Regarding acidovir-resistance, pomegranate rind extract exhibited an EC\({}_{50}\) value amounting to 0.02 \(\upmu\)g mL\({}^{-1}\), whereas acyclovir displayed no activity [129]. Given the several reported studies that have proven the antiviral effects of pomegranate, [PERSON] and [PERSON] surmised the possible inhibitory effect of _Punica granatum_ against Herpes simplex virus-2 (HSV-2).