Gastroprotective activity of Pradosia huberi on experimentally induced gastric lesions in rodents: Role of endogenous sulphydryls and nitric oxide

Pradosia huberi is a medicinal plant very common in the Amazonian forest population. The research interest in this plant is justifiable because of its potential medicinal value in gastritis and gastric ulcer mentioned in local folk medicine. In this paper, we evaluated the acute toxicity and antiulcerogenic effect of a hydroalcoholic extract (HAE) obtained from Pradosia huberi barks in rodents. No acute toxicological sign or symptom was observed in animals treated with the highest dose (5000 mg/kg, p.o.) of Pradosia huberi. In the HCl/EtOH-induced gastric ulcer model, HAE demonstrated significant inhibition of the ulcerative lesion index by 73% (500 mg/kg) and 88% (1000 mg/kg), respectively, in relation to the control value (p < 0.05). The gastric damage induced by absolute ethanol in rats was effectively reduced by 84, 88 and 81% (250, 500 and 1000 mg/kg) when compared with the control group (p < 0.01). In the NSAID-induced lesion model, HAE also showed antiulcerogenic effect with decrease in gastric lesions of 56% (250 mg/kg), 57% (500 mg/kg) and 67% (1000 mg/kg) when compared with animals treated with vehicle (p < 0.05). In the gastric ulcer induced by pylorus ligature model, the administration of HAE by oral and intraduodenal routes inhibited the gastric lesion index by 79 and 52% (500 mg/kg), respectively. HAE administered orally or intraduodenally was able to change gastric juice parameters (pH, volume and acid output) as well as those treated with cimetidine. The treatment with HAE (p.o.) significantly increased gastric volume, the pH values and promoted reduced acid output (1) < 0.01). By comparative effect (intraduodenal and oral route), we observed that HAE was better for local activity in gastric mucosa than in systemic action. HAE also has a non-specific activity when found to be the inhibitor of intestinal motility (p > 0.01). The mechanism of action of HAE did not seem to be related to the NO-inhibitor but showed the participation of endogenous sulphydryl group in the gastroprotective action. (C) 2005 Elsevier B.V.. All rights reserved.

Effect of Mouriri pusa extracts on experimentally induced gastric lesions in rodents: Role of endogenous sulfhydryls compounds and nitric oxide in gastroprotection

Several plants are used in folk medicine to treat gastrointestinal disorders. Mouriri pusa Gardn. (Melastomataceae) is a medicinal plant commonly used in the central region of Brazil against gastric ulcer. Two organic extracts methanolic (MeOH) and dichloromethane (DCM) obtained by sequential extraction from the leaves of Mouriri pusa were evaluated for their ability to protect the gastric mucosa against injuries caused by necrotizing agents (0.3 M HCl/60% EtOH, absolute ethanol, non-steroidal anti-inflammatory drug, stress and pylorus ligature) in mice and rats. The best results were obtained after pretreatment with MeOH extract whereas the DCM extract did not show the same significant antiulcerogenic activity. No acute toxicity was observed in animals treated with 5 g/kg, p.o. of MeOH extract. The mechanism involving the antiulcerogenic action of MeOH extract seemed to be related to NO generation and also suggested the effective participation of endogenous sulfhydryl group in the gastroprotective action. Phytochemical investigation of the MeOH extract of Mouriri pusa yielded tannins, flavonoids and (-)-epicatechin. The presence of these phenolic compounds probably would explain the antiulcerogenic effect of the polar extract of Mouriri pusa leaves. (c) 2006 Elsevier B.V.. All rights reserved.

Evaluation of Strychnos pseudoquina St. Hil. leaves extract on gastrointestinal activity in mice

Strychnos pseudoquina St. Hil. (Loganiaceae) was investigated for its ability to protect the gastric mucosa against injuries caused by non-steroidal anti-inflammatory drugs (piroxicam) and a necrotizing agent (HCl/EtOH) in mice. The MeOH extract and enriched alkaloidic fraction (EAF) provided significant protection in experimental models wheer used at doses of 250 and 1000 mg/kg. In vivo tests were carried out to evaluate for possible toxic effects and no mortality was observed up to the 5 g/kg dose level. Phytochemical investigation led to the isolation of a new indole alkaloid, which elucidated the observed pharmacological effects. © 2005 Pharmaceutical Society of Japan.

Flavonoids with gastroprotective activity

Peptic ulcers are a common disorder of the entire gastrointestinal tract that occurs mainly in the stomach and the proximal duodenum. This disease is multifactorial and its treatment faces great difficulties due to the limited effectiveness and severe side effects of the currently available drugs. The use of natural products for the prevention and treatment of different pathologies is continuously expanding throughout the world. This is particularly true with regards to flavonoids, which represent a highly diverse class of secondary metabolites with potentially beneficial human health effects that is widely distributed in the plant kingdom and currently consumed in large amounts in the diet. They display several pharmacological properties in the gastroprotective area, acting as anti-secretory, cytoprotective and antioxidant agents. Besides their action as gastroprotectives, flavonoids also act in healing of gastric ulcers and additionally these polyphenolic compounds can be new alternatives for suppression or modulation of peptic ulcers associated with H. pylori. In this review, we have summarized the literature on ninety-five flavonoids with varying degrees of antiulcerogenic activity, confirming that flavonoids have a therapeutic potential for the more effective treatment of peptic ulcers.

Anti-nociceptive effects of Carpolobia lutea G. Don (Polygalaceae) leaf fractions in animal models

Leaves from Carpolobia lutea (Polygalaceae) were screened to establish the antiulcer ethnomedicinal claim and to quantitatively isolate, elucidate the active compounds by semi-preparative HPLC. The anti-nociceptive effects of Carpolobia lutea (CL) G. Don (Polygalaceae) organic leaf extracts were tested in experimental models in mice. The anti-nociceptive mechanism was determined using tail-flick test, acetic acid-induced abdominal constrictions, formalin-induced hind paw licking and the hot plate test. The fractions (ethanol, ethyl acetate, chloroform, n-hexane) and crude ethyl acetate extract of CL (770 mg/kg, i.p.) produced significant inhibitions of both phases of the formalin-induced pain in mice, a reduction in acetic acid-induced writhing as well as and an elevation of the pain threshold in the hot plate test in mice. The inhibitions were greater to those produced by indomethacin (5 mg/kg, i.p.). Ethyl acetate fraction revealed cinnamic and coumaric acids derivatives, which are described for the first time in literature. These cinnamalglucosides polyphenols characterised from CL may in part account for the pharmacological activities. These findings confirm its ethnomedical use in anti-inflammatory pain and in pains from gastric ulcer-associated symptoms. © 2011 Springer Basel AG.

Atividade anti-Helicobacter pylori e potencial antioxidante de espécies vegetais do Cerrado brasileiro

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Determinação dos mecanismos de ação envolvidos no efeito antiulcerogênico, antidiarreico e anti-inflamatório da Insulina Vegetal (Cissus sicyoides Linneu) em modelos animais

Pós-graduação em Ciências Biológicas (Farmacologia) - IBB

Deregulation of Annexin-A1 and Galectin-1 Expression in Precancerous Gastric Lesions: Intestinal Metaplasia and Gastric Ulcer

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Antiulcerogenic activity and toxicity of bauhinia holophylla hydroalcoholic extract

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Ulcer healing and mechanism(s) of action involved in the gastroprotective activity of fractions obtained from Syngonanthus arthrotrichus and Syngonanthus bisulcatus

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Role of the different isoforms of cyclooxygenase and nitric oxide synthase during gastric ulcer healing in cyclooxygenase-1 and -2 knockout mice

Traditional NSAIDs, selective cyclooxygenase (COX)-2 inhibitors, and inhibitors of nitric oxide synthase (NOS) impair the healing of preexisting gastric ulcers. However, the role of COX-1 (with or without impairment of COX-2) and the interaction between COX and NOS isoforms during healing are less clear. Thus we investigated healing and regulation of COX and NOS isoforms during ulcer healing in COX-1 and COX-2 deficiency and inhibition mouse models. In this study, female wild-type COX-1(-/-) and COX-2(-/-) mice with gastric ulcers induced by cryoprobe were treated intragastrically with vehicle, selective COX-1 (SC-560), COX-2 (celecoxib, rofecoxib, and valdedoxib), and unselective COX (piroxicam) inhibitors. Ulcer healing parameters, mRNA expression, and activity of COX and NOS were quantified. Gene disruption or inhibition of COX-1 did not impair ulcer healing. In contrast, COX-2 gene disruption and COX-2 inhibitors moderately impaired wound healing. More severe healing impairment was found in dual (SC-560 + rofecoxib) and unselective (piroxicam) COX inhibition and combined COX impairment (in COX-1(-/-) mice with COX-2 inhibition and COX-2(-/-) mice with COX-1 inhibition). In the ulcerated repair tissue, COX-2 mRNA in COX-1(-/-) mice, COX-1 mRNA in COX-2(-/-) mice, and, remarkably, NOS-2 and NOS-3 mRNA in COX-impaired mice were more upregulated than in wild-type mice. This study demonstrates that COX-2 is a key mediator in gastric wound healing. In contrast, COX-1 has no significant role in healing when COX-2 is unimpaired but becomes important when COX-2 is impaired. As counterregulatory mechanisms, mRNA of COX and NOS isoforms were increased during healing in COX-impaired mice.

Apoptosis induction in gastric mucous cells in vitro:lesser potency of Helicobacter pylori than Escherichia coli lipopolysaccharide, but positive interaction with ibuprofen

Non-steroidal anti-inflammatory drugs (NSAIDs) cause peptic ulcer disease, but whether they interact with Helicobacter pylori to promote damage is controversial. Moreover, the reported induction of apoptosis in gastric cells by H. pylori lipopolysaccharide (LPS) (10-9 g /ml) contrasts with studies showing low immunological potency of this LPS. Therefore, the effects of LPS from H. pylori NCTC 11637 and Escherichia coli 0111:B4 on apoptosis in a primary culture of guinea-pig gastric mucous cells were investigated in the presence and absence of the NSAID, ibuprofen. Cell loss was estimated by a crystal violet assay, and apoptosis determined from caspase activity and from condensation and fragmentation of nuclei. Exposure to E. coli LPS for 24 h caused cell loss and enhanced apoptotic activity at concentrations ≥ 10-9 g/ml, but similar effects were only obtained with H. pylori LPS at concentrations ≥10-6 g/ml. Although ibuprofen (250 μM) caused cell loss and apoptosis, addition of either E. coli or H. pylori LPSs further enhanced these effects. In conclusion, LPS and ibuprofen interact to enhance gastric cell loss and apoptosis. In such interactions, E. coli LPS is more potent than that of H. pylori. The low potency of H. pylori LPS may contribute to a chronic low-grade gastritis that can be enhanced by the use of NSAIDs. © W. S. Maney & Son Ltd.

Disparate effects of non-steroidal anti-inflammatory drugs on apoptosis in guinea-pig gastric mucous cells: inhibition of basal apoptosis by diclofenac

Non-steroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in gastrointestinal cancer cell lines. Similar actions on normal gastric epithelial cells could contribute to NSAID gastropathy. The present work therefore compared the actions of diclofenac, ibuprofen, indomethacin, and the cyclo-oxygenase-2 selective inhibitor, NS-398, on a primary culture of guinea-pig gastric mucous epithelial cells. Cell number was assessed by staining with crystal violet. Apoptotic activity was determined by condensation and fragmentation of nuclei and by assay of caspase-3-like activity. Necrosis was evaluated from release of cellular enzymes. Ibuprofen (250 μM for 24 h) promoted cell loss, and apoptosis, under both basal conditions and when apoptosis was increased by 25 μM N-Hexanoyl-D-sphingosine (C6-ceramide). Diclofenac (250 μM for 24 h) reduced the proportion of apoptotic nuclei from 5.2 to 2.1%, and caused inhibition of caspase-3-like activity, without causing necrosis under basal conditions. No such reduction in apoptotic activity was evident in the presence of 25 μM C6-ceramide. The inhibitory effect of diclofenac on basal caspase-3-like activity was also exhibited by the structurally similar mefenamic and flufenamic acids (1–250 μM), but not by niflumic acid. Inhibition of superoxide production by the cells increased caspase-3-like activity, but the inhibitory action of diclofenac on caspase activity remained. Diclofenac did not affect superoxide production. Diclofenac inhibited caspase-3-like activity in cell homogenates and also inhibited human recombinant caspase-3. In conclusion, NSAIDs vary in their effect on apoptotic activity in a primary culture of guinea-pig gastric mucous epithelial cells, and the inhibitory effect of diclofenac on basal apoptosis could involve an action on caspase activity.

Avaliação da atividade anti-Helicobacter pylori e citotóxica in vitro de extratos orgânicos obtidos das folhas de Encholirium spectabile e Syzygium cumini

Helicobacter pylori is a spiral, Gram negative, mobile, and microaerophilic bacteria recognized as a major cause of gastritis, ulcer, gastric cancer, and gastric low grade, B cell, mucosa – associated lymphoid tissue (MALT) lymphoma, constituting an important microorganism in medical microbiology. Its importance comes from the difficulty of treatment because the requirement of multiple drugs use, besides the increasing emergence of resistant and multiresistant strains to antibiotics used in th e clinic. In order to expand safe and effective therapeutic options , chemical studies on medicinal plants by obtaining extracts, fractions, isolated compounds or essential oils with some biological activity has been intensified . Given the above, the objective was to evaluate the inhi bitory activity of organic extracts derived from Syzygium cumini and Encholirium spectabile, with antiulcer history, and the essential oil, obtained from S. cumini, against H. pylori (ATCC 43504) by the disk diffusion method, for qualitative evaluation, an d determination of minimum inhibitory concentration (MIC) using the broth microdilution method, for quantitative analysis. Also was evaluated the extracts in vitro toxicity by a hemolytic assay using sheep red blood cells, and VERO and HeLa cells using the MTT assay to analyze cell viability. The extracts of both plant used in antimicrobial assays did not inhibit bacterial growth, however the essential oil of S. cumini (SCFO) proved effective, showing MIC value of 205 μg/mL (0.024 % dilution of the original oil). In the hemolytic assay, the same oil shows moderate toxicity, by promote 25% hemolysis at 1000 μg/mL. Regarding the cytotoxicity in cell culture, the SCFO, at 260 μg/mL, affected the cell viability around 80% of HeLa and 50% of VERO cells. So the oi l obtained from S. cumini leaves has antimicrobial activity against H. pylori and cytotoxicity potential, suggesting a source of new molecule drug candidates, since new stages of toxicity in vitro and in vivo, as well, chemical characterization be evaluate d. Moreover, the development of a prospective drug delivery system can result in a prototype to be used in preclinical tests.

Anti-Helicobacter pylori activity and oxidative burst inhibition by the naphthoquinone 5-methoxy-3,4-dehydroxanthomegnin from Paepalanthus latipes

Helicobacter pylori is a bacterium recognized as the major cause of chronic gastritis and peptic ulcers. Infection by H. pylori induces inflammatory responses and pathological changes in the gastric microenvironment. The host Keywords: immune cells (especially neutrophils) release inflammatory mediators and large 5-methoxy-3,4-dehydroxanthomegnin amounts of reactive oxygen species (ROS), which are associated with an increased Helicobacter pyloririsk of developing gastric cancer. In this study, we evaluated the anti-H. pylori and oxidative burst antioxidantactivitiesofa1,4-naphthoquinone-5-methoxy-3,4-dehydroxanthomegnin. Paepalanthus latipes The antimicrobial activity was assessed using a spectrophotometric microdilution technique, and antioxidant activity was assessed by noting the effect of 5-methoxy3,4-dehydroxanthomegnin on the neutrophil oxidative burst using luminol-and lucigenin-amplified chemiluminescence. The results showed that 5-methoxy-3,4dehydroxanthomegnin is a potent anti-H. pylori compound (MIC 64 µg/mL and MBC 128 µg/mL) and a strong antioxidant. 5-Methoxy-3,4-dehydroxanthomegnin decreased luminol- and lucigenin-amplified chemiluminescence, with ED50 values of 1.58±0.09 µg/mL and 5.4±0.15 µg/mL, respectively, reflecting an inhibitory effect on the oxidative burst. These results indicate that 5-methoxy-3,4-dehydroxanthomegnin is a promising compound for the prevention and treatment of diseases caused by H. pylori infection, such as gastritis, peptic ulceration, and gastric cancer, because reactive oxygen intermediates are involved in the pathogenesis of gastric mucosal injury induced by H. pylori infections.