Characterization of Prostaglandin G/H Synthase 1 and 2 in rat, dog, monkey, and human gastrointestinal tracts
Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Quebec, Canada. Gastroenterology
(Impact Factor: 16.72).
09/1996; 111(2):445-54. DOI: 10.1053/gast.1996.v111.pm8690211
In the gastrointestinal tract, prostaglandins are implicated as important mediators of normal physiological processes. Prostaglandin G/H synthase (PGHS) is the first enzyme leading to the formation of prostaglandins. Two forms exist: the constitutive PGHS-1 and the inducible PGHS-2 isoforms. The purpose of this study was to examine the expression of PGHS-1 and -2 in gastrointestinal tissues.
PGHS-1 and -2 expression and activity were examined in rat, dog, monkey, and human gastrointestinal tracts by immunoblot and biochemical assays.
PGHS-1 but not PGHS-2 protein was identified in all gastrointestinal tissues. PGHS-1 protein varied throughout the gastrointestinal tracts; interspecies differences were also noted. Immunohistochemical studies showed PGHS-1 staining of rat endothelial cells in all gastrointestinal regions; PGHS-2-specific staining was noted in a subset of macrophages in 3 of 22 rats examined. Elevated activity was shown in tissues expressing greater concentrations of PGHS-1 protein. Indomethacin, a nonsteroidal anti-inflammatory drug that inhibits both isoforms, inhibited prostaglandin synthesis, whereas NS-398, a selective PGHS-2 inhibitor, showed little or no inhibition of prostaglandin synthesis in gastrointestinal tissues.
These results indicate that prostaglandins produced in normal gastrointestinal tissue and required for normal physiological functioning are derived from the PGHS-1 isoform.
Available from: Barbara Rolando
- "COX enzyme can exist in two isoforms called COX-1 and COX-2 respectively. ASA is able to inhibit both, with a marked preference for COX-1 isoform which plays a fundamental role in maintaining gastrointestinal mucosa integrity (Blobaum and Marnett, 2007; Kargman et al., 1996). One approach to overcome the problem of ASA gastrotoxicity was the design of aspirin-nitric oxide (NO) donor hybrids (Bondarage and Janero, 2001; Koc and Kucukguzel, 2009). "
Available from: Sender Jankiel Miszputen
- "These effects of NSAIDs are associated with a deficiency of endogenous prostaglandins (Pgs) due to the inhibition of cyclooxygenase (COX) activity. COX exists in two isoforms; COX-1 is constitutively expressed in various tissues, whereas COX-2 is generally expressed at very low levels in most tissues but is rapidly up-regulated in response to growth factors and cytokines such as tumour necrosis factor alpha (TNF-a) (Feng et al. 1993; Kargman et al. 1996; O'Neill and Ford-Hutchinson 1993; Singer et al. 1998). More recently, COX-2 has been implicated in several distinct cellular mechanisms, such as angiogenesis, proliferation and the prevention of apoptosis (Dempke et al. 2001). "
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ABSTRACT: Crohn's disease (CD) is associated with gut barrier dysfunction. Besides the baseline barrier defect, a subgroup of patients also expresses an intestinal barrier hyperresponsiveness to nonsteroidal anti-inflammatory drugs. On the other hand, the anti-tumour necrosis factor alpha (TNF-α) treatment has brought benefits to these patients. Thus, this study aimed to evaluate the effect of lumiracoxib, a selective-cyclooxygenase-2 (COX-2) inhibitor, and Etanercept (ETC), a TNF-α antagonist on the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis. A total of 47 Wistar rats were randomized into seven groups, as follows: (1) Sham: sham induced-colitis; (2) TNBS: nontreated induced-colitis; (3) Lumiracoxib control; (4) Lumiracoxib-treated induced-colitis; (5) ETC control; (6) ETC-treated induced-colitis; (7) Lumiracoxib-ETC-treated induced-colitis. Rats from groups 6 and 7 presented significant improvement of macroscopic and histopathological damages in the distal colon. The gene expression of COX-2 mRNA, as well of TNF-α mRNA, decreased significantly in groups 6 and 7 compared to the TNBS nontreated and lumiracoxib-treated groups. The treatment only with lumiracoxib did not reduce the inflammation on TNBS-induced experimental colitis. ETC attenuated the damage seen in the colon and reduced the inflammation caused by TNBS. Our results suggest that down-regulation of TNF-α and COX-2 resulted in a decrease in inflammation caused by TNBS and thus provided some protection from the colonic damage caused by TNBS.
Available from: Rina Amatya
- "COX has been recognized as the first enzyme in the formation of prostaglandin (PG) and thromboxane (TX) from arachidonic acid at the site of inflammation or after infection . COX-1 isozyme is expressed constitutively in many tissues, whereas COX-2 isozyme is expressed only at the site of inflammation . "
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ABSTRACT: We demonstrated that hydrophobic derivatives of the nonsteroidal anti-inflammatory drug (NSAID)flufenamic acid (FA), can be formed into stable nanometer-sized prodrugs (nanoprodrugs) that inhibit the growth of glioma cells, suggesting their potential application as anticancer agent. We synthesized highly hydrophobic monomeric and dimeric prodrugs of FA via esterification and prepared nanoprodrugs using spontaneous emulsification mechanism. The nanoprodrugs were in the size range of 120 to 140 nm and physicochemically stable upon long-term storage as aqueous suspension, which is attributed to the strong hydrophobic interaction between prodrug molecules. Importantly, despite the highly hydrophobic nature and water insolubility, nanoprodrugs could be readily activated into the parent drug by porcine liver esterase, presenting a potential new strategy for novel NSAID prodrug design. The nanoprodrug inhibited the growth of U87-MG glioma cells with IC(50) of 20 μM, whereas FA showed IC(50) of 100 μM, suggesting that more efficient drug delivery was achieved with nanoprodrugs.
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