title: The antifibrotic and fibrolytic properties of date fruit extract via modulation of genotoxicity, tissue-inhibitor of metalloproteinases and nuclear factor- kappa B pathway in a rat model of hepatotoxicity.
abstract: BACKGROUND
  Hepatic fibrosis and its end point; cirrhosis, are the major cause of liver failure and death in patients with chronic liver disease. Therefore, the need for an effective treatment is evident. This study was designed to assess the potential effects of aqueous extract of date fruits, either flesh (DFE) or pits (DPE), on oxidative DNA damage and liver inflammation induced by carbon tetrachloride (CCl4) and whether they are related to inhibition of nuclear factor-κB pathway. In addition, the fibrolytic potential was evaluated via measuring matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases -1 and -2.
  
  
  METHODS
  Rats were divided into the following groups: normal control, model control (CCl4only), CCl4+ DFE, CCl4+ DPE and CCl4+ coffee. Coffee was used as a positive control. Fibrosis was induced by chronic administration of CCl4(0.4 ml/kg) 3× a week for 8 weeks, and rats were treated with 6 ml/kg/day of DFE or DPE for 8 weeks. Liver homogenate was prepared for evaluation of oxidative stress, DNA damage, inflammatory and fibrolytic markers. Data are analyzed using one-way analysis of variance followed by a Tukey-Kramer post hoc test.
  
  
  RESULTS
  Both DFE and DPE significantly attenuated CCl4-induced oxidative damage as indicated by reducing lipid, protein and DNA oxidation in addition to increasing the levels of hepatic catalase activity. Both extracts blocked the accumulation of collagen I in the liver and ameliorated the increased expression of collagen III and α-smooth muscle actin suggesting suppression of profibrotic response induced by CCl4. DFE and DPE also upregulated the expression of heme oxygenase-1 and attenuated the nuclear factor-κB activation and cycloxygenase-2 expression reflecting their anti-inflammatory potential. Additionally, both flesh and pits extracts attenuated the increase in the tissue inhibitor of metalloproteinases -1 and -2 suggesting their fibrolytic activity.
  
  
  CONCLUSIONS
  Our data suggest that DFE or DPE can prevent liver fibrosis by suppressing genotoxicity and nuclear factor-κB inflammatory pathway and by promoting collagen degradation.
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11495, Kingdom of Saudi Arabia. halafetoh@yahoo.com.|Department of Biochemistry, College of Pharmacy, Mansoura University, 35516, Mansoura, Egypt. halafetoh@yahoo.com.
authors: Hala
authors: H
authors: Attia
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11495, Kingdom of Saudi Arabia.
authors: Nouf
authors: N
authors: Al-Rasheed
authors: Anatomy Department, Faculty of Medicine, King Saud University, Riyadh, 11495, Kingdom of Saudi Arabia.
authors: Raeesa
authors: R
authors: Mohamad
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11495, Kingdom of Saudi Arabia.
authors: Nawal
authors: N
authors: Al-Rasheed
authors: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11495, Kingdom of Saudi Arabia.
authors: Maha
authors: M
authors: Al-Amin
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D005638:Fruit / Q000737:chemistry; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D065749:Phoeniceae / Q000737:chemistry*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D010936:Plant Extracts; D020011:Protective Agents; D019714:Tissue Inhibitor of Metalloproteinases; D002251:Carbon Tetrachloride; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2
keywords: 8-hydroxy deoxyguanosine; Cycloxygenase-2; Date Fruits; Liver fibrosis; Matrix metalloproteinase; Nuclear factor-kappa B