Potentialities of Dandelion (Taraxacum Mongolicum Hand.-Mazz.) Flower Extracts on Gastric Protection against Helicobacter Pylori and Characterization of its Bioactive Constituents.

OBJECTIVES: Dandelion has been shown to exert anti-inflammatory and anti-bacterial effects. Our study aimed to identify the effect and mechanism of dandelion flower extracts on H. pylori-induced gastritis and screen for novel antimicrobial substances. METHODS: Anti-H. pylori activities of water extracts(WEDF) and ethanol extracts (EEDF) of dandelion flowers were performed with disk diffusion method assay, MIC, and MBC. The H. pylori-induced model was constructed to examine the gastroprotective of EEDF using RUT, pathological analysis, and ELISA. RESULTS: EEDF exhibited better anti- H. pylori and urease inhibition activities than WEDF. In vivo studies, EEDF can reduce the adhesion of H. pylori to the gastric mucosa, alleviate gastric damage, and concurrently reduce the levels of TNF-α and IL-6 in gastric tissues. The six phenolic compounds showed urease inhibition effect (IC50: 2.99±0.15 to 66.08±6.46 mmol/mL). Among them, chlorogenic acid, caffeic acid, and luteolin also had anti-H. pylori activity (MIC: 64-256 µg/mL). CONCLUSION: EEDF exhibited anti-H. pylori, gastroprotective and anti-inflammatory effects. Chicoric acid and luteolin may be the main active compounds of dandelion flowers to exert anti-H. pylori, and worthy of further investigation.

A Novel Multilayer Natural Coating for Fed-State Gastric Protection.

Several nutraceutical products require gastric protection against the hostile environment in the stomach. Currently marketed synthetic and semi-synthetic coatings suffer from major shortcomings such as poor gastric protection, slow-release response to pH change, and the use of artificial ingredients. The challenge of coating natural products is further exacerbated by the relatively high gastric pH in the fed state. In this work, a novel natural enteric coating is presented as a breakthrough alternative to current solutions. Two coating systems were devised: (i) a triple-layer coating that comprises a wax layer embedded between two alginate-based coatings, and (ii) a double-layer coating, where an overcoat of organic acids (fumaric or citric acid) is applied to an alginate-based coating. The multi-layer architecture did not impact the pH-responsive nature of the coating even when more biologically relevant Krebs bicarbonate buffer of lower buffer capacity was used. Interestingly, the gastric protection barrier of organic acid-based coating remained resistant at elevated gastric pH 2, 3, or 4 for 2 h. This is the first report of using an alginate-based coating to provide gastric protection against fed-state stomach conditions (pH 2-4). Being biodegradable, naturally occurring, and with no limit on daily intake, the reported novel coating provides a superior platform to current coating solutions for pharmaceutical and nutraceutical products.

Efficacy and Safety of Novel Aspirin Formulations: A Randomized, Double-Blind, Placebo-Controlled Study.

Low-dose aspirin represents the best option in the secondary prevention of coronary artery disease, but its extensive use in primary prevention is limited by the occurrence of gastric mucosal lesions and increased risk of bleeding. We investigated the safety profile of a novel sublingual aspirin formulation in 200 healthy volunteers, randomly assigned to ten (n = 20 each) different 7-day once-daily treatment regimens. Gastric mucosal injury based on the modified Lanza score (MLS), the histopathology of gastric mucosa and the serum determination of thromboxane B2 (TXB2) and urinary 11-dehydro-TXB2 levels were evaluated at basal as well as after 7 days of each placebo or aspirin treatment regimen. In Groups A and B (placebo-oral and sublingual, respectively), no changes in MLS and in gastric mucosal micro-vessel diameter were found at day 7. In contrast, in Groups C and D (oral standard aspirin-100 and 50 mg daily, respectively), the median MLS was significantly increased. Very few changes were found in Groups E and F (standard sublingual aspirin-100 and 50 mg, respectively). Groups G and H (oral administration of micronized collagen-cogrinded aspirin) showed gastric protection compared to Groups C and D. Moreover, Groups I and L (sublingual collagen-cogrinded aspirin-100 and 50 mg, respectively) showed a significant reduction (Group I) or total abolition (Group L) of gastric mucosal lesions and no difference compared to the standard one in serum TXB2 and urinary 11-dehydro-TXB2 levels. In conclusion, our data show that the new formulation leads to a better safety profile compared to standard aspirin, representing a better therapeutic option for extended use in primary and secondary prevention of cardiovascular diseases.

Effects of the diphenylheptane extract of Alpinia officinarum rhizomes on ethanol-induced gastric ulcers in mice.

OBJECTIVES: Experimental studies have revealed that Alpinia officinarum Hance (Zingiberaceae) exhibits a gastrointestinal protective effect. The present study aimed to investigate the effects of diphenylheptanes (DPHs) extracted from A. officinarum rhizomes on ethanol-induced gastric ulcers in BALB/c mice. MATERIALS AND METHODS: A total of 60 female BALB/c mice were divided into six groups as follows: negative control, which received sodium carboxymethyl cellulose; positive control, which received ethanol; treatment control, which received ethanol+ranitidine; ethanol+high dose of DPHs; ethanol+medium dose of DPHs; ethanol+low dose of DPHs. Different doses of DPHs were administered orally once daily for seven consecutive days before the animals were subjected to ethanol-induced gastric ulcers. RESULTS: Various doses of DPHs significantly reduced Gastric ulcers index when compared with the positive control. DPHs treatments and treatment control increased the activity of superoxide dismutase; decreased the levels of inflammatory mediators, malondialdehyde, motilin, and gastrin; decreased the activity of inducible nitric oxide synthase and cyclooxygenase-2; and inhibited the expression of Toll-like receptor 4, myeloid differentiation factor 88, and nuclear factor-κB at the protein and mRNA levels. In addition, DPHs inhibited the expression of transient receptor potential vanilloid 1, calcitonin gene-related peptide, and increased the expression of substance P at the protein and mRNA levels. CONCLUSION: The protective effect of DPHs extracted from A. officinarum rhizomes against ethanol-induced gastric damages in mice suggests that the extract can be used as an auxiliary supplement for the prevention and treatment of gastric ulcers.

An innovative wax-based enteric coating for pharmaceutical and nutraceutical oral products.

In this work, a novel enteric coating based on natural waxes and alginate was reported. Initially, theophylline tablets were coated with emulsified ceresin wax in heated aqueous alginate solution using a fluidised bed coating technology. A coating level of 10% proved sufficient to prevent tablets from uptaking gastric medium (<5%) and produced a delayed release profile that complies to the pharmacopeial criteria of enteric coating release. Then, a wide range of emulsions based on other natural waxes (white beeswax, yellow beeswax, cetyl palmitate, carnauba wax or rice bran wax) yielded coatings with similar disintegration times and release profiles. Interestingly, the ceresin-based coating showed a superior performance at inhibiting acid uptake and enabling highly pH-responsive drug release in comparison to different commercially available GRAS enteric coating products (Eudraguard® Control, Swanlac® ASL10, and Aquateric™ N100). The coating was stable for 6 months at 30 °C and 65% RH. This innovative approach of applying hot O/W emulsion of natural waxes yielded an aesthetically attractive and stable coating with gastric protection and pH-sensitive release properties. The novel coating can be an efficient and promising alternative to overcome the shortcomings of current GRAS grade enteric coating products.

The Tumor Suppressor TFF1 Occurs in Different Forms and Interacts with Multiple Partners in the Human Gastric Mucus Barrier: Indications for Diverse Protective Functions.

TFF1 is a protective peptide of the Trefoil Factor Family (TFF), which is co-secreted with the mucin MUC5AC, gastrokine 2 (GKN2), and IgG Fc binding protein (FCGBP) from gastric surface mucous cells. Tff1-deficient mice obligatorily develop antropyloric adenoma and about 30% progress to carcinomas, indicating that Tff1 is a tumor suppressor. As a hallmark, TFF1 contains seven cysteine residues with three disulfide bonds stabilizing the conserved TFF domain. Here, we systematically investigated the molecular forms of TFF1 in the human gastric mucosa. TFF1 mainly occurs in an unusual monomeric form, but also as a homodimer. Furthermore, minor amounts of TFF1 form heterodimers with GKN2, FCGBP, and an unknown partner protein, respectively. TFF1 also binds to the mucin MUC6 in vitro, as shown by overlay assays with synthetic 125I-labeled TFF1 homodimer. The dominant presence of a monomeric form with a free thiol group at Cys-58 is in agreement with previous studies in Xenopus laevis and mouse. Cys-58 is likely highly reactive due to flanking acid residues (PPEEEC58EF) and might act as a scavenger for extracellular reactive oxygen/nitrogen species protecting the gastric mucosa from damage by oxidative stress, e.g., H2O2 generated by dual oxidase (DUOX).

The TFF Peptides xP1 and xP4 Appear in Distinctive Forms in the Xenopus laevis Gastric Mucosa: Indications for Different Protective Functions.

The gastric secretory trefoil factor family (TFF) peptides xP1 and xP4 are the Xenopus laevis orthologs of mammalian TFF1 and TFF2, respectively. The aim of this study was to analyze the molecular forms of xP1 and xP4 in the X. laevis gastric mucosa by FPLC. xP1 mainly occurred in a monomeric low-molecular-mass form and only a minor subset is associated with the mucus fraction. The occurrence of monomeric xP1 is unexpected because of its odd number of cysteine residues. Probably a conserved acidic residue flanking Cys55 allows monomeric secretion. Furthermore, Cys55 is probably post-translationally modified. For the first time, we hypothesize that the free thiol of monomeric xP1-and probably also its mammalian ortholog TFF1-could have a protective scavenger function, e.g., for reactive oxygen/nitrogen species. In contrast, xP4 mainly occurs in a high-molecular-mass form and is non-covalently bound to a mucin similarly as TFF2. In vitro binding studies with radioactively labeled porcine TFF2 even showed binding to X. laevis gastric mucin. Thus, xP4 is expected to bind as a lectin to an evolutionary conserved sugar epitope of the X. laevis ortholog of mucin MUC6 creating a tight mucus barrier. Taken together, xP1 and xP4 appear to have different gastric protective functions.

Characterization of a food-based enteric coating for capsules and its compatibility with an alternative sealing method.

Efficiency of a new protein-based enteric coating for capsules was studied. Coating physical-chemical properties were compared to those obtained from a well-known methacrylate-based enteric coating (Eudragit). Swelling in simulated gastric fluid (SGF) was 20 times higher than for Eudragit films. Mechanical properties (elastic modulus, elongation and puncture strength at break) were comparable to those measured from a standard Eudragit formulation. Pilot-scale coating trials were performed following three methods: using a standard spray-gun configuration, using a HPC-based seal-coat prior to enteric coating and using an "inverted" spray-gun configuration. The effect of these methods on capsules sealing and in vitro gastric performance was studied. In vitro tests were performed following the two USP official methods: disintegration and dissolution. Inverted gun configuration and HPC-sealing showed the highest sealing efficiency and the best in vitro performance. Capsules with a weight gain of 14-16% generally passed all USP tests (no disintegration evidence after 60 min in SGF; release below 10% after 2h of experiments in SGF). However, in some cases, slight differences between results obtained from dissolution and disintegration tests were pointed out. This work demonstrates the potential of a protein-based enteric coating and underlines the importance of capsules sealing.

Role of gastric acid inhibition, prostaglandins and endogenous-free thiol groups on the gastroprotective effect of a proteolytic fraction from Vasconcellea cundinamarcensis latex.

OBJECTIVES: The aim of this study was to extend our knowledge about the mechanism involved in the gastroprotective effect of P1G10, a proteolytic fraction rich in cysteine proteinases from Vasconcellea cundinamarcensis (syn. Carica candamarcensis) latex, which demonstrated gastric healing and protection activities in rats. METHODS: Wistar rats were submitted to gastric lesions by indomethacin and treated with P1G10 (10 mg/kg). Free thiol groups and prostaglandin E2 content were measured in gastric mucosal and gastrin levels in blood samples. To evaluate the participation of nitric oxide (NO) or proteolytic activity of P1G10 on its gastroprotective effect, animals were treated with an inhibitor of NO production (L-NAME) or the fraction inhibited by iodoacetamide, respectively. Gastric secretion study (acidity and pepsin activity) was also performed. KEY FINDINGS: P1G10 (10 mg/kg) inhibited the occurrence of gastric lesions by indomethacin, restored the free thiol groups content on gastric mucosa and increased moderately prostaglandin E2 levels (34%). Furthermore, the treatment decreased the gastrin levels (95%), suggesting a possible modulation of secretory activity. This effect was accordant with attenuation of gastric acidity (42%) and pepsin activity (69%) seen in animals subjected to pyloric ligation. The inhibition of NO production or the proteolytic activity of P1G10 does not affect the gastroprotective effect. CONCLUSIONS: These results can explain the gastroprotective activity of P1G10 and serve a basis for further studies of this active principle.

Anti-ulcer activity of Synadenium grantii latex

Synadenium grantii Hook f., Euphorbiaceae, is popularly known as leitosinha or janaúba. The diluted latex (18 drops/L of water) is commonly used in the south of Brazil to treat gastric disturbances. This study evaluated phytochemical screening and toxicity using Artemia salina Leach of crude bark extract and also latex. The toxicity and the anti-ulcer activity of S. grantii latex were also tested in rats. Phytochemical results showed presence of tannins, terpenes, unsaponificable substances, coumarins and anthraquinones in the crude bark extract and terpenes in the latex. Gas chromatography-mass spectrometry (GC-MS) analysis demonstrated the presence of diterpene tigliane esters in the latex, identified as 12-deoxyphorbol-13-(2-metilpropionate) and phorbol 12,13,20-triacetate. The toxicity results using A. salina presented CL50 26.58μg/mL and CL50 778.66μg/mL, for the latex and the crude bark extract respectively. The toxicological hepatic parameters of the diluted latex were not different to the control group (p<0.05). The eosinophils cells showed an increase in both the diluted and pure latex groups. The pure latex showed gastric protection of 90% (p<0.05) and the diluted latex showed 6% compared to the negative control. Therefore, our data indicate that S. grantii latex, under research conditions presented gastric protection. Pure latex showed more toxicity than the diluted latex.

Avaliação da atividade protetora gástrica do extrato hidroalcoólico da semente de girassol em ratas / Evaluation of the gastroprotective activity of hydroalcoholic extract of sunflower seed in rats

JUSTIFICATIVA E OBJETIVOS: Avaliar a proteção gástrica do extrato hidroalcoólico da semente de girassol (EHSG) em relaçãoao estresse, ao uso de indometacina e etanol. MÉTODO: Foi realizado um estudo experimental envolvendo 90 ratas (Rattus norvegicus albinus), da linhagem Wistar, fêmeas, com peso corporal médio de 150-230 g, divididos em 18 grupos distintos os quais receberam os seguintes tratamentos: EHSG:250 mg/kg, 500 mg/kg, 1000 mg/kg e 2000 mg/kg; etanol 0,5mL; cimetidina 60 mg/kg; indometacina 20 mg/kg; água 1 mL. Os dados foram analisados utilizando o programa Grand PadPrism 5 com aplicação de testes estatísticos considerando o nível de significância de 5%. RESULTADOS: O EHSG apresenta proteção contra as lesões gástricas em ratas, nas doses de 250 e 1000 mg, tanto no modelo pelo estresse, quanto na indução por etanol e indometacina. CONCLUSÃO: Os dados obtidos no presente estudo mostram que o EHSG apresenta proteção gástrica em determinadas doses.

BACKGROUND AND OBJECTIVES: To evaluate the gastric protection hidroalcoólico extract the sunflower seed (EHSG) in relation to stress, the use of indomethacin and ethanol. METHOD: We conducted an experimental study involving 90 rats (Rattus norvegicus albinos), Wistar, females, mean body weight of 150-230 g were divided into 18 distinct groups which received the following treatments: EHSG: 250mg/kg , 500 mg/kg, 1000 mg/kg and 2000 mg/kg; 0.5 mL ethanol, cimetidine 60 mg/kg, 20 mg/kg indomethacin; 1 mL water. Data were analyzed using the GrandPad Prism 5 with application of statistical tests, the significance level of 5%. RESULTS: The EHSG has protective against gastric injury in rats at doses 250 mg and 1000, both in the model by stress, as in the induction by ethanol and indomethacin. CONCLUSION: The data obtained in this study show that has EHSG gastric protection in certain doses.

Avaliação da atividade protetora gástrica do extrato de raspa de juá / Assessment of gastric protective of rasp juá extract

JUSTIFICATIVA E OBJETIVOS: Avaliar a possível atividade gastroprotetora do extrato de raspa de juá (Ziziphus joazeiro) em relação ao estresse, ao uso de indometacina e etanol; verificar a acidez (pH) gástrica por meio da ligadura pilórica (resíduo gástrico puro e com adição de água) e comparar as diferenças dos valores do pH em ambos os modelos. MÉTODO: Foram utilizados 120 ratos (cinco em cada grupo), da espécie Rattus norvegicus albinus, com peso de 150 a 230 g, divididos em 24 grupos distintos, os quais receberam os seguintes tratamentos: extrato de raspa de juá: 250, 500, 1000 e 2000 mg/kg, etanol 0,5 mL; cimetidina (60 mg/kg); indometacina (20 mg/kg); água (1 mL); ligadura de piloro (água; cimetidina e extrato de raspa de juá). Os dados foram analisados pelo programa Grand Pad Prism 5 com aplicação de testes estatísticos. RESULTADOS: O extrato de raspa de juá nas doses de 250, 1000 e 2000 mg/kg sugeriu proteção gástrica no estresse. No modelo de indução de úlcera gástrica por etanol, as doses de 250 e 2000 mg/kg apresentaram proteção gástrica. No grupo do extrato de raspa de juá e indometacina as doses de 250, 1000 e 2000 mg/kg também sugeriram proteção gástrica. Em relação ao valor de pH, o resíduo gástrico, quando verificado puro, é mais ácido que pelo modelo da adição da água, significando que este modelo aumenta o pH, comprovando assim que o modelo do resíduo gástrico puro é mais indicado. CONCLUSÃO: Os dados obtidos no presente estudo mostraram que o extrato de raspa de juá apresentou provável proteção gástrica em determinadas doses.

BACKGROUND AND OBJECTIVES: To evaluate the possible gastroprotective activity of the extract of scrapings juá (Ziziphus joazeiro) by stress, indomethacin and ethanol; check the acidity (pH) through the gastric pylorus ligation (gastric residue pure and with added water) and compare differences in pH values in both models. METHOD: A total of 120 rats (5 in each group), Rattus norvegicus albinus, weighing 150-230 g were divided into 24 distinct groups, which received the following treatments: extract scrapings juá (250, 500 mg, 1000 and 2000 mg/kg), ethanol (0.5 mL), cimetidine (60 mg/kg), indomethacin (20 mg/kg), water (1 mL); ligation of pylorus (water, cimetidine and extract scrapings juá). The data were analyzed by Grand Pad Prism 5 with application of statistical tests. RESULTS: The extract of scrapings juá at doses 250, 1000 and 2000 mg/kg suggested gastric protection in stress. In the model of gastric ulcer induced by ethanol, the dosages of 250 and 2000 mg/kg showed gastric protection. In the group of extract scrapings juá and indomethacin dosages of 250, 1000 and 2000 mg/kg also suggested gastric protection. Regarding the pH, the gastric residue, occurred when pure, is more acidic than the model of the addition of water, meaning that this model increases the pH, thus proving that the model of pure gastric residue is indicated. CONCLUSION: The data obtained in this study show that the extract of scrapings has juá likely gastric protection in certain doses.

Avaliação da atividade protetora gástrica do extrato hidroalcoólico da semente de girassol / Evaluation of the gastroprotective activity of the hydroalcoholic extract of sunflower seeds

JUSTIFICATIVA E OBJETIVOS: Avaliar quantitativa e qualitativamente a provável proteção gástrica do extrato hidroalcoólico da semente de girassol (EHSG) em relação ao estresse, ao uso de indometacina e etanol; bem como verificar a acidez (pH) gástrica por meio da ligadura pilórica (resíduo gástrico puro e com adição de água) e comparar as diferenças dos valores do pH em ambos os modelos. MÉTODO: Foram estudados 120 ratos (5 em cada grupo) da espécie Rattus norvegicus albinus, com peso de 150-230g, divididos em 24 grupos distintos, os quais receberam os seguintes tratamentos: EHSG: 250 mg/kg, 500 mg/kg, 1000 mg/kg e 2000 mg/kg; etanol 0,5 mL; cimetidina 60 mg/kg; indometacina 20 mg/kg; água 1 mL; ligadura de piloro (água; cimetidina e EHSG). Os dados foram analisados utilizando o programa Grand Pad Prism 5 com aplicação de testes estatísticos considerando o nível de significância de 5%.RESULTADOS: O EHSG nas doses 250 e 1000 mg/kg sugeriu proteção contra as lesões gástricas no estresse. No modelo de indução de úlcera gástrica por etanol, as doses de 250 e 1000 mg/kg apresentaram provável proteção gástrica. No grupo utilizando EHSG 250 mg/kg e indometacina a dose de 250 mg/kg também sugere proteção gástrica. Em relação ao valor de pH, o resíduo gástrico, quando verificado puro, é mais ácido que pelo modelo da adição da água, significando que este último modelo está aumentando o pH, comprovando assim que o modelo do resíduo gástrico puro é mais indicado e prático. CONCLUSÃO: Os dados obtidos no presente estudo mostram que o EHSG apresenta provável proteção gástrica em determinadas doses.(AU)

BACKGROUND AND OBJECTIVES: To evaluate quantitatively and qualitatively the probable gastric protection of hydroalcoholic extract from sunflower seed (EHSG) in relation to stress, the use of indomethacin and ethanol; check the acidity (pH) through the gastric pylorus ligation (gastric residue pure and with added water), and compare differences in pH values in both models. METHOD: A total of 120 rats (5 in each group) of the type Wistar rats weighing 150-230g were divided into 24 distinct groups, which received the following treatments: EHSG: 250 mg/kg, 500 mg/kg, 1000 mg/kg and 2000 mg/kg, 0.5 mL ethanol, cimetidine 60 mg/kg, indomethacin 20 mg/kg, 1 mL water, ligation of pylorus (water, cimetidine and EHSG). The data were analyzed using the Grand Pad Prism 5 with application of statistical tests considering the significance level of 5%.RESULTS: The EHSG at doses 250 and 1000 mg/kg suggested protection against gastric lesions in stress. In the model of gastric ulcer induced by ethanol, the doses of 250 and 1000 mg/kg showed probable gastric protection. Group using EHSG 250 mg/kg and indomethacin dose of 250 mg/kg also suggests gastric protection. Regarding the pH, the gastric residue, occurred when pure, is more acidic than the model of the addition of water, meaning that the latter model is increasing the pH, thus proving that the model of pure gastric residue is more appropriate and more practical. CONCLUSION: The data obtained in this study show that has likely EHSG gastric protection in certain doses.(AU)

Central and peripheral vagal mechanisms involved in gastric protection against ethanol injury.

Activation of medullary thyrotropin-releasing hormone (TRH), at a dose subthreshold to increase gastric acid secretion, protects the gastric mucosa against ethanol injury through vagal cholinergic pathways in urethane-anaesthetized rats. Peripheral mediators involve the efferent function of capsaicin-sensitive splanchnic afferents leading to calcitonin gene-related peptide (CGRP)- and nitric oxide (NO)-dependent gastric vasodilatory mechanisms. In addition, gastric prostaglandins participate in gastric protection through mechanisms independent of the stimulation of gastric mucosal blood flow and mucus secretion. Medullary TRH has physiological relevance in the vagal-dependent adaptive gastric protection induced by mild (acid or ethanol), followed by strong, irritants. Additional neuropeptides, namely peptide YY (PYY), somatostatin analogues, CGRP and adrenomedullin, also act in the brainstem to induce a vagal-dependent gastric protection against ethanol through interactions with their specific receptors in the medulla. Central PYY and adrenomedullin act through vagal cholinergic prostaglandins and NO pathways, while somatostatin analogue acts through vagal non-adrenergic, non-cholinergic vasoactive intestinal peptide and NO mechanisms. Although their biological relevance is still to be established, these peptides provide additional tools to investigate the multiple vagal-dependent mechanisms which increase the resistance of the gastric mucosa to injury.