Pannexin1 drives multicellular aggregate compaction via a signaling cascade that remodels the actin cytoskeleton.

Pannexin 1 (Panx1) is a novel gap junction protein shown to have tumor-suppressive properties. To model its in vivo role in the intratumor biomechanical environment, we investigated whether Panx1 channels modulate the dynamic assembly of multicellular C6 glioma aggregates. Treatment with carbenoxolone and probenecid, which directly and specifically block Panx1 channels, respectively, showed that Panx1 is involved in accelerating aggregate assembly. Experiments further showed that exogenous ATP can reverse the inhibitive effects of carbenoxolone and that aggregate compaction is sensitive to the purinergic antagonist suramin. With a close examination of the F-actin microfilament network, these findings show that Panx1 channels act as conduits for ATP release that stimulate the P(2)X(7) purinergic receptor pathway, in turn up-regulating actomyosin function. Using a unique three-dimensional scaffold-free method to quantify multicellular interactions, this study shows that Panx1 is intimately involved in regulating intercellular biomechanical interactions pivotal in the progression of cancer.

Efficacy of a whey protein concentrate on the inhibition of stomach ulcerative lesions caused by ethanol ingestion.

The purpose of this research was to test the ability of a whey protein concentrate (WPC) to inhibit gastric mucosal ulcerative lesions caused by oral administration to rats of absolute ethanol. Acute administration (single doses) of WPC resulted in 41% inhibition of the ulcerative lesion index (ULI), and 73% inhibition was obtained with repetitive doses. In a 10-days subchronic treatment study, the inhibition was 64%, all relative to a saline treatment (negative control). Alkylation of sulfhydryl compounds by subcutaneous injection of N-ethylmaleimide essentially eliminated the WPC protection. Treating the rats with an intraperitoneal injection of butathionine sulfoximine, which inhibits glutathione synthesis, reduced WPC protection to 35% and 52% for single and double doses, respectively. Taken as a whole, the results indicate that WPC does protect gastric mucosa from ethanol damage and that the protection depends on sulfhydryl compounds present in the WPC, including its capacity to stimulate glutathione synthesis.

Effect of carbenoxolone on the biological activity of nitric oxide: relation to gastroprotection.

1. The interactions between carbenoxolone and nitric oxide (NO) were examined by investigating their effects on human platelet aggregation, on rat aortic strips precontracted by phenylephrine and on protection of rat gastric mucosa against ethanol-induced injury. 2. Carbenoxolone (100-300 microM) caused a significant and concentration-dependent potentiation of rat peritoneal neutrophil (RPN)- 3-morpholino-syndnonimine (SIN-1)- or iloprost-induced inhibition of platelet aggregation. Higher concentrations (500 microM) of carbenoxolone alone markedly inhibited platelet aggregation. Pretreatment with carbenoxolone (100-300 microM) antagonized the reversal of the RPN- or SIN-1-induced antiaggregatory effect by oxyhaemoglobin (10 microM). 3. Rat aortic strips with intact endothelium precontracted by phenylephrine (0.1-0.3 microM) were relaxed by carbenoxolone (100-300 microM) in a concentration-dependent manner. Relaxations were abolished by mechanical removal of the endothelium or by incubation with methylene blue (10 microM) or NG-nitro-L-arginine (L-NNA, 100 microM). Sodium nitroprusside (10 nM)-induced relaxations of endothelium-denuded rat aortic strips were potentiated by carbenoxolone (100 microM). . The carbenoxolone (200 mg kg-1, p.o.)-induced gastroprotection against ethanol was antagonized by L-NNA (5-40 mg kg-1) in a dose-dependent manner. Pretreatment of rats with indomethacin (10 mg kg-1, s.c.) increased the effect of L-NNA. 5. The results suggest that the activity of carbenoxolone in the experimental systems tested is due to phosphodiesterase inhibition, although radical scavenging properties of the drug could contribute to some of the effects observed. In the rat gastric mucosa both increased prostaglandin levels and effects on the NO system could contribute to the protective action of carbenoxolone.

Cytoprotective action of carbenoxolone sodium on ethanol-induced gastric lesions in rats and its inhibition by indomethacin.

Carbenoxolone produced a marked and dose-related inhibition of ethanol-induced gastric lesions in rats. This cytoprotective action was inhibited progressively and significantly by increasing doses of indomethacin. The evidence presented confirms previous suggestions that prostaglandin(s) are involved in the cytoprotective action of carbenoxolone.

The influence of amiloride on the therapeutic and metabolic effects of carbenoxolone in patients with gastric ulcer. A double-blind controlled trial.

Patients with benign gastric ulcer were treated for four weeks with carbenoxolone sodium as Biogastrone tablets 100 mg three times a day, and if the ulcers were not healed at 4 weeks treatment was continued for a further 4 weeks. Fifty two patients entered the trial, and 12 were withdrawn. In 17 patients who were randomly allotted double-blind additional dummy tablets 16 of their ulcer healed completely endoscopically, whereas of the 23 patients given additional amiloride 5 mg three times a day only 14 ulcers healed, a significant reduction in ulcer healing. The clinical (weight gain and oedema) and metabolic (hypertension, hypokalaemia and hypernatraemia) side-effects were reduced by the active amiloride therapy, but serum carbenoxolone levels were not affected. Thus the potassium-retaining diuretic amiloride, like the aldosterone antagonist spironolactone, markedly reduces both the ulcer-healing and the metabolic side-effects of carbenoxolone sodium, and should not be used together with it in the treatment of peptic ulcer.