Low molecular-weight gel fraction of Aloe vera exhibits gastroprotection by inducing matrix metalloproteinase-9 inhibitory activity in alcohol-induced acute gastric lesion tissues.

CONTEXT: Aloe has been used for the prevention and cure of various diseases and symptoms including burns, injuries, oedema and pain. OBJECTIVE: This study determines the specific inhibitory activity of matrix metalloproteinase (MMP)-9 induced by the low molecular-weight gel fraction of Aloe vera (L.) Burm.f. (lgfAv) on alcohol-induced acute gastric lesions. MATERIALS AND METHODS: We examined the protective effects of oral (p.o.) administration of lgfAv (molecular weight cutoff <50.0 kDa, 150.0 mg/kg body weight) in a Balb/c mouse model of alcohol-induced acute gastritis for 1 h exposure. By measuring ulcer index, we compared the antiulcerative activity of the fraction. mRNA expression and immunohistochemical analysis of various biomarkers were performed. RESULTS: The lgfAv-treated mice exhibited drastically fewer ulcer lesions than the untreated control mice did. It featured that lgfAv lessened the ulcer lesions than their relevant controls. Moreover, the transcriptional level of MMP-9 was completely alleviated by lgfAv treatment in alcohol-treated gastritis-induced mice. DISCUSSION: The transcriptional level of MMP-9 was significantly alleviated by lgfAv treatment of the model. However, reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry experiments revealed that lgfAv treatment in mucosal tissues had the potential to inhibit the mRNA and protein expression levels of MMP-9, respectively. The protein expression of MMP-9 was closely associated with lgfAv-induced gastroprotection against alcohol-induced gastric lesions. CONCLUSIONS: The present findings suggest that lgfAv has the potential to alleviate alcohol-induced acute gastric lesions, which is mediated in part, mainly by the suppression of the mRNA expression of MMP-9.

Olive (Olea europaea) leaf methanolic extract prevents HCl/ethanol-induced gastritis in rats by attenuating inflammation and augmenting antioxidant enzyme activities.

Gastritis is preponderantly characterized by inflammation of the lining epithelial layer and the chronic gastritis is considered as a pre-cancer lesion. For many centuries olive (Olea europaea) leaf has been used for its putative health potential, nonetheless, to date, the gastroprotective effects of olive leaves have not been studied yet. Hence, in this study we investigated whether olive leaf extract (OLE) could protect gastric mucosa against HCl/ethanol-induced gastric mucosal damage in rats. Hcl/ethanol administration caused significant damage to the gastric mucosa, as confirmed by gastric ulcer index and histological evaluation. However, this damage was largely prevented by pre-administering 20mg/kg omeprazole or 100mg/kg OLE. Interestingly, the damage was completely prevented by pre-administering 200 and 300mg/kg OLE. Moreover, OLE attenuated the inflammatory response by decreasing nuclear factor-κB (NF-κB), cycloxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α) expressions, and down-regulating inducible nitric oxide synthase (iNOS) and interleukin-1ß (IL-1ß) in gastric mucosa. The gastroprotective mechanism of OLE involved the promotion of enzymatic and nonenzymatic molecules (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione reduced form), promoting nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression, halting lipid peroxidation and preventing the overproduction of nitric oxide. Together, our findings clearly demonstrated that OLE could prevent HCl/ethanol-induced gastritis by attenuating inflammation and oxidant/antioxidant imbalance. Indeed, OLE could potentially be useful as a natural therapy for gastritis.

PDK1 in NF-κB signaling is a target of Xanthium strumarium methanolic extract-mediated anti-inflammatory activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Xanthium strumarium L. (Asteraceae) has traditionally been used to treat bacterial infections, nasal sinusitis, urticaria, arthritis, chronic bronchitis and rhinitis, allergic rhinitis, edema, lumbago, and other ailments. However, the molecular mechanisms by which this plant exerts its anti-inflammatory effects are poorly characterized. Here we studied the immunopharmacological activities of the methanolic extract of the aerial parts of this plant (Xs-ME) and validated its pharmacological targets. MATERIALS AND METHODS: To evaluate the anti-inflammatory activity of Xs-ME, we employed lipopolysaccharide (LPS)-treated macrophages and an HCl/EtOH-induced mouse model of gastritis. We also used HPLC to identify the potentially active anti-inflammatory components of this extract. The molecular mechanisms of its anti-inflammatory activity were studied by kinase assays, reporter gene assays, immunoprecipitation analysis, and overexpression of target enzymes. RESULTS: The production of nitric oxide (NO) and prostaglandin E2 (PGE2) were both suppressed by Xs-ME. Moreover, orally administered Xs-ME ameliorated HCl/EtOH-induced gastric lesions. Furthermore, this extract downregulated the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 and reduced the nuclear levels of NF-κB. Signaling events upstream of NF-κB translocation, such as phosphorylation of AKT and the formation of PDK1-AKT signaling complexes, were also inhibited by Xs-ME. Moreover, Xs-ME suppressed the enzymatic activity of PDK1. Additionally, PDK1-induced luciferase activity and Akt phosphorylation were both inhibited by Xs-ME. We also identified the polyphenol resveratrol as a likely active anti-inflammatory component in Xs-ME that targets PDK1. CONCLUSION: Xs-ME exerts anti-inflammatory activity in vitro and in vivo by inhibiting PDK1 kinase activity and blocking signaling to its downstream transcription factor, NF-κB.

PMK-S005 Alleviates Age-Related Gastric Acid Secretion, Inflammation, and Oxidative Status in the Rat Stomach.

BACKGROUND/AIMS: The aim of this study was to evaluate the effect of the synthetic S-allyl-L-cysteine (SAC) PMK-S005 on gastric acid secretion, inflammation, and antioxidant enzymes in aging rats. METHODS: The rats were divided into four groups at 31 weeks of age and were continuously fed a diet containing a vehicle control, PMK-S005 (5 or 10 mg/kg), or lansoprazole (5 mg/kg). Gastric acid secretion and connective tissue thickness of the lamina propria were evaluated at 74 weeks and 2 years of age. Tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and COX-2 levels were measured by using enzyme-linked immunosorbent assays (ELISAs) or Western blot assays. Levels of antioxidant enzymes, including heme oxyganase 1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO-1), were also measured. RESULTS: As the rats aged, gastric acid secretion significantly decreased, and the connective tissue of the lamina propria increased. However, 74-week-old rats in the PMK-S005 group exhibited greater levels of gastric acid secretion than those of the control and lansoprazole groups. The increase of TNF-α, IL-1ß, and COX- 2 expression in 74-week and 2-year-old control rats were inhibited by PMK-S005. In addition, the decrease in HO-1 and NQO-1 protein expression that occurred with aging was inhibited by PMK-S005 in the 74-week-old rats. CONCLUSIONS: These results suggest that PMK-S005 has therapeutic potential as an antiaging agent to ameliorate age-related gastric acid secretion, inflammation, and oxidative stress in the stomach.

Effect of some natural products either alone or in combination on gastritis induced in experimental rats.

Gastritis, an inflammatory state in gastric mucosa, can be induced experimentally in various ways. The present study considered the iodoacetamide model (Iodo). Omega-3 fatty acids (fish oil), black seed oil, and curcuminoids (natural products) in addition to omeprazole (synthetic proton-pump inhibitor) were tested. Supplementation of 0.1% iodoacetamide to drinking water of experimental rats for two consecutive weeks resulted in: (i) increased serum nitric oxide (NO) and gastrin, and decreased pepsinogen, (ii) depletion of gastric mucosal glutathione (GSH), and (iii) increased gastric mucosal lipid peroxidation (MDA), but failed to affect gastric mucosal myeloperoxidase (MPO) activity. Histological examination showed marked neutrophilic infiltration after 1 week of iodoacetamide administration and shedding of apical cell layer with pale edematous vacuolated gastric gland cells and thickening of muscularis mucosa after 2 weeks of iodoacetamide intake. Individual administration of omega-3 fatty acids 12 mg/kg, black seed oil 50 mg/kg, and curcuminoids 50 mg/kg body weight orally daily for 3 weeks decreased MDA, gastrin, and NO, and normalized mucosal GSH but failed to affect serum pepsinogen level. Combined administration of these natural products for 3 weeks normalized MPO activity, and other effects were nearly the same as with individual use. Omeprazole administration 30 mg/kg body weight orally daily for 3 weeks induced a similar response except for an observed increase in serum gastrin and pepsinogen levels.

[Molecular mechanisms of cytoprotective action of the plant proanthocyanidins in gastric lesions].

The molecular defence mechanisms against ethanol- and stress-induced (WRS) gastric lesions under the action of plant proanthocyanidins from grapefruit-seed extract (GSE) were investigated. Pre-treatment with GSE (8-64 mg/kg/day) in dose-dependent manner attenuated gastric lesions induced by 100% ethanol and WRS; the doses of GCE reducing these lesions by 50% (ID50) were 28 and 36 mg/kg/day, respectively and this protective effect was similar to that obtained with PGE2 analogue. Lesions reduction was also accompanied by improvement of gastric blood flow, antiradical action, increased mucosal generation of PGE2, antioxidant activity.

Decrease of ornithine decarboxylase activity in premalignant gastric mucosa and regression of small intestinal metaplasia in patients supplemented with high doses of vitamin E.

The effect of high doses of vitamin E (Vit.E; 400 units/ day) on ornithine decarboxylase (ODC) activity and regression of small intestinal metaplasia (SIM) was studied in a 1-year double-blind intervention trial. Biochemical and morphological parameters were estimated in 14 evaluable SIM patients of 18 in the Vit.E group and in 16 of 18 intestinal metaplasia patients enrolled in control group (placebo). In the control group, there were no statistically significant changes in Vit.E content in blood plasma, ODC activity, and the rate of SIM in multiple biopsies from antrum gastric mucosa. In the Vit.E group, after 6 and 12 months of intervention, the initial content of Vit.E in blood plasma increased from 6.4 +/- 0.9 up to 17.0 +/- 1.8 and 21.2 +/- 2.3 micrograms/ml, respectively, and the initial abnormally high activity of ODC, 62.6 +/- 7.8 units, decreased by 53 and 65%, respectively. Histological analysis of multiple biopsies, taken from the gastric antrum of patients supplemented with Vit.E, revealed that in 8 of 14 patients (57%) after 6 months and in 10 of 14 patients (71%) after 12 months, no signs of SIM were observed; gastroscopic dye procedure confirmed the regression of SIM in these cases and showed the presence of only small isolated stained areas identified as SIM.

Effect of omeprazole on Helicobacter pylori urease activity in vivo.

BACKGROUND: Detection of Helicobacter pylori infection in clinical routine is based either on the direct visualization of the bacterium in gastric biopsies by histology or microbiology or on the demonstration of urease activity in gastric biopsies and by the labelled-urea breath test (UBT). Omeprazole has a strong inhibitory effect on H. pylori urease activity in vitro, but its effect in vivo and thus its influence on urease-based diagnostic procedures has not been investigated systematically. AIM: To investigate whether omeprazole is able to inhibit H. pylori urease activity in vivo and, if so, at which doses. PATIENTS: Eighteen patients with H. pylori associated chronic gastritis were studied. METHODS: H pylori diagnosis was based on histology, rapid urease test and culture from antral biopsies. Following a positive H. pylori diagnosis patients received omeprazole 20mg (n = 6), 40mg (n = 6) and 80mg (n = 6) once daily for 5 days and 13C-UBT was performed on day 1, 3 and 5, 30min after each omeprazole administration. The 13C-UBT was performed with 200ml 0.1 N citric acid as test drink and 75mg 13C-urea. Breath samples were collected before and 30 min after 13C-urea administration. RESULTS: A significant inhibition of urease activity was observed only under high dose omeprazole administration (80 mg/day), and the 13C-UBT turned negative in three (50%) of these patients after 5 days therapy. CONCLUSION: Short-term omeprazole administration reduces H. pylori urease activity only at doses as high as 80 mg/day. A direct inhibition of enzyme activity as well as a reduction in the number of viable H. pylori bacteria may be responsible for this omeprazole-mediated reduction in urease activity. Urease-based diagnostic procedures for H. pylori are not suitable for patients under omeprazole therapy depending on the dose and duration of therapy.

Murine autoimmune gastritis and the gastric H,K-ATPase: insights from a new model and autoantibody detection system.

Human type A chronic gastritis or autoimmune gastritis (AIG) is associated with gastric H,K-ATPase-specific autoantibodies (HKAb). The pathogenic role of the HKAb and the triggering autoantigen(s) are unknown. In a mouse model, neonatal thymectomy (nTx) induces AIG, which is likely T cell mediated, although HKAb are always present. Our aim is to study the role of the H,K-ATPase in the initiation of AIG. The direct involvement of the H,K-ATPase in the onset of AIG is suggested by the following findings. AIG appears at the age of 1 month in susceptible BALB.D2 mice, i.e. the time at which H,K-ATPase expression reaches adult levels. A new HKAb assay system based on immunoprecipitation of native H,K-ATPase expressed in Xenopus oocytes has revealed that the early lesion is already associated with low titers of HKAb. Injection of gastric membranes, rich in H,K-ATPase, into neonatal BALB.D2 mice without adjuvant induces a persisting AIG. This new model for AIG will provide the means to identify which H,K-ATPase subunit triggers AIG.