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While acute activation of the novel endocannabinoid receptor GPR18 causes hypotension, there are no reports on GPR18 expression in the heart or its chronic modulation of cardiovascular function. In this study, after demonstrating GPR18 expression in the heart, we show that chronic (2 weeks) GPR18 activation with its agonist abnormal cannabidiol (abn-cbd; 100 µg/kg/day; i.p) produced hypotension, suppressed the cardiac sympathetic dominance, and improved left ventricular (LV) function (increased the contractility index dp/dtmax, and reduced LV end diastolic pressure, LVEDP) in conscious rats. Ex vivo studies revealed increased: (i) cardiac and plasma adiponectin (ADN) levels; (ii) vascular (aortic) endothelial nitric oxide synthase (eNOS) expression, (iii) vascular and serum nitric oxide (NO) levels; (iv) myocardial and plasma cyclic guanosine monophosphate (cGMP) levels; (v) phosphorylation of myocardial protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) along with reduced myocardial reactive oxygen species (ROS) in abn-cbd treated rats. These biochemical responses contributed to the hemodynamic responses and were GPR18-mediated because concurrent treatment with the competitive GPR18 antagonist (O-1918) abrogated the abn-cbd evoked hemodynamic and biochemical responses. The current findings present new evidence for a salutary cardiovascular role for GPR18, mediated, at least partly, via elevation in the levels of ADN.

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The purpose of this study was to investigate the anti-cancer property of grape seed extract (GSE) during early stages of developing liver cancer using a two-stage carcinogenic model combining diethylnitrosamine (DEN) and 2-Acetyl Aminofluorene (2-AAF). Administration of GSE at doses 25, 50 and 100 mg/kg per day started at the beginning of promotion periods and continued for 14 weeks. GSE dramatically inhibited pre-neoplastic foci formation as well as significantly decreased the number and the area of placental glutathione-S-transferase in livers of DEN-2AAF-treated rats by approximately 4 & 10 fold deductions, respectively. GSE's effects were associated with induced apoptosis, reduced cell proliferation, decreased oxidative stress and down regulation of histone deacetylase activity and inflammation makers, such as cyclooxygenase 2, inducible nitric oxide synthase, nuclear factor-kappa B-p65 and p-phosphorylated tumor necrosis factor receptor expressions in liver. GSE treatment also decreased the viability of HepG2 cells and induced early and late apoptosis through activating caspase-3 and Bax. Furthermore, GSE induced G2/M and G1/S cell cycle arrest. The present study provides evidence that the GSE's anticancer effect is mediated through the inhibition of cell proliferation, induction of apoptosis, modulating oxidative damage and suppressing inflammatory response.Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death both in developed and under-developed countries 1 . Chronic infection with hepatitis B and C are the main causes of HCC 2 . Other factors that contribute to the formation of HCC include fatty liver disease, iron overload, alcoholism and exposure to environmental carcinogens 3 . One of the most common carcinogens is diethylnitrosamine (DEN), which is widely used in the surrounding of everyday life, in tobacco, smoke, processed food, gasoline, and cosmetics 4 .Chemoprevention of cancer especially by natural compounds is a promising strategy to protect against various stages of cancer development [5][6][7] . Total plant extracts have been of a particular interest mainly because of the synergistic effects of the cocktail of plant metabolites and their multiple points of intervention during chemoprevention 7,8 . The development of pre-neoplastic foci of altered hepatocytes (FAH) was exploited as short-term bioassays to assess the chemopreventive potential of natural products against cancer formation 9 . Thus, inhibiting or suppressing the development of pre-neoplastic FAH by natural products may lead to diminishing the subsequent progression to liver cancer. One particular plant product that has gained much attention is grape seed extract (GSE). Grapes (Vitis vinifera) are rich in polyphenols, with 60-70% of grape polyphenols being found in the seeds, which are available as a nutraceutical agent. The consumer's interest in GSE has been primarily due to its high content of antioxidants in the form of flavonoids, polyphenols and proanthocyanidins 10,11 . GSE has been shown to posses...

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