In vivo inhibition of cyclooxygenase-2 by a selective phosphorothioated oligonucleotide.

Inhibition of cyclooxygenase-2 (cox-2) is considered to be anti-inflammatory, whereas inhibition of the constitutive isozyme cox-1 causes renal and gastrointestinal toxicity. Therefore, to achieve an optimal anti-inflammatory effect, an inhibitor should be cox-2 selective without inhibiting cox-1. For this purpose, 10 different cox-2-selective phosphorothioated oligonucleotides (S-oligos) were tested to inhibit the cox-2 enzyme selectively in vivo. An aqueous solution of these S-oligos (3 mg/kg body weight) was injected intraperitoneally (i.p.) into male Sprague-Dawley rats with colitis induced by trinitrobenzene sulfonic acid (TNBS). The colonic levels of cox-2 protein, mRNA, myeloperoxidase (MPO), and prostaglandin E2 (PGE2) were increased significantly on day 1 and remained significantly elevated until day 7 post-TNBS administration, whereas cox-1 remained unaltered. Two S-oligos were found to be effective in reducing the level of cox-2 protein selectively without any effect on the cox-1. The effective S-oligo, but not the mismatched control oligo, reduced the tissue levels of PGE2 and MPO activity significantly. The effective S-oligo reduced the level of cox-2 but not the cox-1 mRNA significantly, whereas a mismatched or a sense control oligo did not affect the levels of these isoforms. M-fold analysis demonstrated extensive secondary structure formation in the cox-2 mRNA. These findings demonstrate that only a few selected sites in the cox-2 target mRNA are accessible in vivo, probably because of the presence of secondary structures. Suppression of cox-2 protein, PGE2, and MPO activity by the S-oligo might prove to be an anti-inflammatory property.

Antiinflammatory effects of Cordia myxa fruit on experimentally induced colitis in rats.

Products of certain species of Cordia are reported to have antiinflammatory properties. In the present study we examined the effects of Cordia myxa fruit on experimentally induced colitis in rats. Colitis was induced by intrarectal administration of 4% acetic acid. Colitic, normal, and corresponding control animals were included. Body weight was recorded daily. All the animals were sacrificed 4 days after the fruit treatment. Colitis was monitored histologically and by activity of myeloperoxidase. Glutathione peroxidase, superoxide dismutase, as well as total antioxidant status and concentrations of zinc, copper, manganese, selenium, and iron were assayed in plasma, liver, and colon using standard methods. Histology of the colon of colitic rats showed acute colitis that was confirmed by a significant increase in the myeloperoxidase activity. Colitis was associated with significant decreases in the tissue activities of glutathione peroxidase and superoxide dismutase and lower concentrations of trace elements. Histologic examination and myeloperoxidase activity showed that the fruit treatment reversed the above findings in the inflamed colon, and in liver and plasma of colitic rats. The present results suggest that the observed antiinflammatory effect of the Cordia myxa may be attributed partly to its antioxidant property and to restoration of the levels of trace elements in the inflamed colon, liver, and plasma.

Colitis-induced changes in the level of trace elements in rat colon and other tissues.

Trace elements constitute important prosthetic groups in a number of antioxidant enzymes which neutralize free radicals generated during inflammatory conditions such as colitis. However, the status of trace elements in colitis remains to be found. In the present study the concentrations of zinc, copper, manganese and selenium in the colon, liver and serum of rats with acetic acid (HAc)- or trinitrobenzenesulfonic acid (TNBS)-induced colitis were measured using atomic absorption spectrophotometer. Myeloperoxidase and glutathione peroxidase activities were measured spectrophotometrically. Our results show that the selenium concentration was significantly decreased by 33 and 37.5% in the colon and 69 and 78% in liver by HAc and TNBS treatment, respectively. Similarly the zinc concentration in the colon was decreased by 21 and 28% by HAc- and TNBS-induced colitis as compared to the controls, but manganese and copper, remained unaltered. The serum concentrations of copper, zinc and selenium also remained unaltered during colitis. The weight of HAc-treated rats did not decrease while there was a significant weight loss in the TNBS-treated rats. Myeloperoxidase activity was increased, whereas glutathione peroxidase activity was significantly decreased in the colon inflamed by HAc or TNBS as compared to the controls. These findings suggest that colitis induces a reduction in the tissue levels of trace elements which is independent of the way colitis is induced. Our findings of a reduction in Se and glutathione peroxidase activity together suggest that the reduction in the trace element concentrations is not due to dietary factors or malabsorption. The decrease may severely affect the antioxidant potential of the colon and therefore is a putative factor for the progression of disease.

Studies on the activity of individual plants of an antidiabetic plant mixture.

A blood glucose lowering extract of a mixture of five plants in use by Kuwaiti diabetics was studied for the identification of its active component(s). Only the extracts of myrrh and aloe gums effectively increased glucose tolerance in both normal and diabetic rats. The remaining components, gum olibanum, Nigella sativa seeds and gum assafoetida were without effect.

On the mechanism of the hypoglycaemic effect of a plant extract.

The efficacy of a hypoglycaemic plant extract, in common use by Kuwaiti diabetic individuals, was evaluated using both streptozotocin-induced diabetic and normal rats. A significant decrease in blood glucose concentration was demonstrated on glucose tolerance tests, as compared to untreated animals. The sum of the fasting, 1 and 2 h blood glucose values, decreased from 18.5 +/- 0.72 to 13.6 +/- 0.62 mmol/l (p less than 0.001) and from 58.6 +/- 2.83 to 44.5 +/- 3.12 mmol/l (p less than 0.005) in normal and diabetic animals treated for 1 week, respectively. Treatment with the extract was not found to significantly alter insulin levels or intestinal glucose absorption. The mode of action of the hypoglycaemic preparation remains to be elucidated.