Punica granatum (pomegranate)
Pomegranate fruit [PF, Figure 1(A)] has been used for centuries to confer health benefits in many cultures. It is native to semitropical Asia and is now being cultivated in Afghanistan, India, China, Russia, Japan and the United States [Palaniswamy, 2003]. Modern use of PF-derived products includes treatment of AIDS [Lee and Watson, 1998], cancer [Kim et al. 2002], cosmetic use [Moayadi, 2004], allergic symptoms [Watanabe and Hatakoshi, 2002], cardiovascular conditions [Aviram and Dornfeld, 2003], oral hygiene [Kim and Kim, 2002] and as ophthalmic ointment [Bruijn et al. 2003]. Edible parts of the PF are composed of 80% juice and 20% seed [Singh et al. 2002b]. PF itself is a rich source of two types of polyphenolic compounds: anthocyanins (such as delphinidin, cyanidin, and pelargonidin) and hydrolyzable tannins (such as punicalin, pedunculagin, punicalagin, gallagic, and ellagic acid esters of glucose), which account for 92% of the antioxidant activity of the whole fruit [Singh et al. 2002b]. Anthocyanins are potent antioxidants, provide the brilliant color of the pomegranate juice, and their administration is reported to significantly decrease the malondialdehyde, hydroperoxide levels, lipid peroxidation and also enhance the activities of catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase in the liver [Sudheesh and Vijayalakshmi, 2005; Gil et al. 2000; Seeram and Nair, 2002]. Punicalagin has been shown to downregulate the expression of IL-2 from anti-CD3/anti-CD28-stimulated murine splenic CD4+ T cells and suppress mixed leukocyte reaction without exhibiting cytotoxicity to the cells via inhibition of nuclear factor of activated T cells [Lee et al. 2008]. This suggests that PF could be a potential candidate for the therapeutics of immune pathologies. We reported that pomegranate fruit extract (PFE)-derived bioavailable compounds suppress COX-2 enzyme activity and IL-1β-induced prostaglandin E2 (PGE2) and nitric oxide (NO) production in OA chondrocytes [Shukla et al. 2008a]. We showed the inhibitory effects of PFE on IL-1β-induced proteoglycan breakdown in cartilage explants in vitro [Ahmed et al. 2005]. We also studied the efficacy of PFE in suppressing joint inflammation and damage using a collagen-induced arthritis mouse model. Consumption of PFE potently delayed the onset and reduced the incidence of collagen-induced arthritis in mice. Histopathology of the arthritic joints from PFE-fed mice demonstrated reduced joint infiltration by the inflammatory cells, and the destruction of bone and cartilage was alleviated with the decrease level of IL-6 [Shukla et al. 2008b]. Activation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB is intimately associated with the increased expression of critical mediators of inflammation involved in OA pathogenesis, including the expression of IL-6 and IL-8 [Marcu et al. 2010; Firestein and Manning, 1999]. We recently showed that inhibition of IL-6 and IL-8 by PFE in PMACI (phorbol-12-myristate 13-acetate plus calcium inophore A23187)-stimulated KU812 cells was mediated by inhibition of NF-κB, cJun-N-terminal kinases (JNKs) and the extracellular regulated kinase (ERK)–MAPK pathway [Rasheed et al. 2009a]. We also showed that PFE (6.25–25 mg/liter) inhibits the IL-1β-induced expression of MMP-1, MMP-3 and MMP-13 mRNA and proteins in OA chondrocytes, which was mediated by inhibiting the activation of p38-MAPK and JNK, thereby reducing the available pool of activated c-Jun and activating transcription factor 2 [Ahmed et al. 2005]. Our recent study showed that PFE inhibits the IL-1β-induced activation of MKK3 and the p38α-MAPK isoform and DNA binding activity of the runt-related transcription factor 2 in human chondrocytes [Rasheed et al. 2010]. These results provide an important insight into the molecular basis of the reported cartilage protective and arthritis inhibitory effects of pomegranate [Rasheed et al. 2010].
Repeated administration of high doses of PFE or its constituents ellagitannin and punicalagin to rats resulted in no toxicity in the dosages commonly used in traditional medicine systems [Cerdá et al. 2003]. An acute supplementation with PFE containing 330 mg of punicalagins and 22 mg of ellagic acid in 11 healthy volunteers led to the detection of ellagitannin metabolites, including ellagic acid, urolithin A, hydroxyl urolithin A, urolithin B, urolithin A glucuronideet and dimethyl ellagic acid glucuronide in plasma after 2–24 h [Mertens-Talcott et al. 2006]. In healthy human volunteers who consumed 180 ml of a commercially available pomegranate juice containing 25 mg of ellagic acid, ellagic acid was detected at a maximum concentration of 32 ng/ml in the plasma after 1 h [Seeram et al. 2004]. We also showed that ellagic acid becomes bioavailable 2 h after oral ingestion of PFE [Shukla et al. 2008b]. Ellagic acid has been reported to inhibit the activation of NF-κB and the production of inflammatory mediators [Choi and Yan, 2009].
Overall, these data indicate that consumption of PF may be beneficial and of value in developing adjunct preventive and/or therapeutic approaches to the prevention and treatment of OA. However, clinical trials showing the benefit of pomegranate fruit or its extracts on inflammation and OA are lacking. Based on published evidence, further in vivo evaluation and clinical testing for the efficacy of PF in OA are needed [Khalifé and Zafarullah, 2011].