title: Ellagitannins of the fruit rind of pomegranate (Punica granatum) antagonize in vitro the host inflammatory response mechanisms involved in the onset of malaria.
abstract: BACKGROUND
  The sun-dried rind of the immature fruit of pomegranate (Punica granatum) is presently used as a herbal formulation (OMARIA, Orissa Malaria Research Indigenous Attempt) in Orissa, India, for the therapy and prophylaxis of malaria. The pathogenesis of cerebral malaria, a complication of the infection by Plasmodium falciparum, is an inflammatory cytokine-driven disease associated to an up-regulation and activity of metalloproteinase-9 and to the increase of TNF production. The in vitro anti-plasmodial activity of Punica granatum (Pg) was recently described. The aim of the present study was to explore whether the anti-malarial effect of OMARIA could also be sustained via other mechanisms among those associated to the host immune response.
  
  
  METHODS
  From the methanolic extract of the fruit rind, a fraction enriched in tannins (Pg-FET) was prepared. MMP-9 secretion and expression were evaluated in THP-1 cells stimulated with haemozoin or TNF. The assays were conducted in the presence of the Pg-FET and its chemical constituents ellagic acid and punicalagin. The effect of urolithins, the ellagitannin metabolites formed by human intestinal microflora, was also investigated.
  
  
  RESULTS
  Pg-FET and its constituents inhibited the secretion of MMP-9 induced by haemozoin or TNF. The effect occurred at transcriptional level since MMP-9 mRNA levels were lower in the presence of the tested compounds. Urolithins as well inhibited MMP-9 secretion and expression. Pg-FET and pure compounds also inhibited MMP-9 promoter activity and NF-kB-driven transcription.
  
  
  CONCLUSIONS
  The beneficial effect of the fruit rind of Punica granatum for the treatment of malarial disease may be attributed to the anti-parasitic activity and the inhibition of the pro-inflammatory mechanisms involved in the onset of cerebral malaria.
authors.affiliation: Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, Via Balzaretti, 9 - 20133 Milano, Italy. mario.dellagli@unimi.it
authors.forename: Mario
authors.initials: M
authors.lastname: Dell'agli
authors.forename: Germana V
authors.initials: GV
authors.lastname: Galli
authors.forename: Michela
authors.initials: M
authors.lastname: Bulgari
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Basilico
authors.forename: Sergio
authors.initials: S
authors.lastname: Romeo
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhattacharya
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.forename: Enrica
authors.initials: E
authors.lastname: Bosisio
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D001681:Biological Assay; D004610:Ellagic Acid / Q000494:pharmacology*; D005638:Fruit; D005786:Gene Expression Regulation / Q000187:drug effects; D006420:Hemeproteins / Q000032:analysis; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy; D029561:Lythraceae / Q000737:chemistry*; D016779:Malaria, Cerebral / Q000188:drug therapy; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B / Q000187:drug effects / Q000502:physiology; D008517:Phytotherapy; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation
chemical_list: D000962:Antimalarials; D006420:Hemeproteins; D047348:Hydrolyzable Tannins; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D010936:Plant Extracts; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D004610:Ellagic Acid; C020753:hemozoin; C115642:punicalagin; D020780:Matrix Metalloproteinase 9