Tamarix aphylla derived metabolites ameliorate indomethacin-induced gastric ulcers in rats by modulating the MAPK signaling pathway, alleviating oxidative stress and inflammation: In vivo study supported by pharmacological network analysis.

Nature has proven to be a treasure resource of bioactive metabolites. In this regard, Tamarix aphylla (F. Tamaricaceae) leaves crude extract was investigated for its gastroprotective effect against indomethacin-induced damage to the gastric mucosa. Additionally, phytochemical investigation of the methanolic extract afforded eight flavonoids' derivatives (1-8). On pharmacology networking study, the isolated compounds identified 123 unique targets where only 45 targets were related to peptic ulcer conditions, these 45 targets include 11 targets specifically correlate to gastric ulcer. The protein-protein interaction defined the PTGS2 gene as one of the highly interacted genes and the complete pharmacology network defined the PTGS2 gene as the most represented gene. The top KEGG signaling pathways according to fold enrichment analysis was the EGFR tyrosine kinase inhibitor resistance pathway. As a result, these findings highlighted the significance of using T. aphylla leaves crude extract as an anti-gastric ulcer candidate, which provides a safer option to chemical antisecretory medicines, which are infamous for their negative side effects. Our findings have illuminated the potent anti-inflammatory and antioxidant effects of T. aphylla, which are likely mediated by suppressing IL-1ß, IL-6, TNF-α, and MAPK signaling pathways, without compromising gastric acidity.

Ferulic acid nanoemulsion as a promising anti-ulcer tool: in vitro and in vivo assessment.

OBJECTIVE: Ferulic acid (FA) is a promising nutraceutical molecule which exhibits antioxidant and anti-inflammatory properties, but it suffers from poor solubility and bioavailability. In the presented study, FA nanoemulsions were prepared to potentiate the therapeutic efficacy of FA in prevention of gastric ulcer. METHODS: FA nanoemulsions were prepared, pharmaceutically characterized, and the selected nanoemusion was tested for its ulcer-ameliorative properties in rats after induction of gastric ulcer using ethanol, by examination of stomach tissues, assessment of serum IL-1ß and TNF-α, assessment of nitric oxide, prostaglandin E2, glutathione, catalase and thiobarbituric acid reactive substance in stomach homogenates, as well as histological and immunohistochemical evaluation. RESULTS: Results revealed that the selected FA nanoemulsion showed a particle size of 90.43 nm, sustained release of FA for 8 h, and better in vitro anti-inflammatory properties than FA. Moreover, FA nanoemulsion exhibited significantly better anti-inflammatory and antioxidant properties in vivo, and the gastric tissue treated with FA nanoemulsion was comparable to the normal control upon histological and immunohistochemical evaluation. CONCLUSION: Findings suggest that the prepared ferulic acid nanoemulsion is an ideal anti-ulcer system, which is worthy of further investigations.

Aqueous extract of the bark of Uncaria tomentosa, an amazonian medicinal plant, promotes gastroprotection and accelerates gastric healing in rats.

ETHNOPHARMACOLOGICAL IMPORTANCE: Uncaria tomentosa Willd. DC., is used in the Amazonian region of South America, wherein ethnic groups use the plant to treat diseases, including gastric disorders. However, despite its widespread popular use, this species has yet to be assessed for its anti-ulcer effects. AIM OF THE STUDY: In this study, we aimed to evaluate the in vivo gastroprotective and gastric healing activities of an aqueous extract of the bark of Uncaria tomentosa (AEUt) and sought to gain an understanding of the pharmacological mechanisms underlying these biological effects. MATERIALS AND METHODS: To verify the gastroprotective properties rats were treated with AEUt (30, 60, or 120 mg/kg) prior to inducing gastric ulceration with ethanol or piroxicam. Additionally, the involvement of nitric oxide, non-protein sulfhydryl compounds (NP-SH), α-2 adrenergic receptors, and prostaglandins was investigated. Furthermore, a pylorus ligature model was employed to investigate the antisecretory activity of AEUt. The gastric healing effects of AEUt (60 mg/kg) were examined in rats in which ulceration had been induced with 80% acetic acid, whereas the quality of healing was evaluated in mice with interleukin-induced recurrent ulcers. We also evaluated the in vivo thickness of the gastric wall using ultrasonography. Moreover, the levels of reduced glutathione (GSH) and malondialdehyde (MDA) were evaluated in ulcerated mucosa, and we determined the activities of the enzymes myeloperoxidase (MPO), N-acetyl-ß-D-glycosaminidase, superoxide dismutase, catalase, and glutathione S-transferase. In addition, we assessed the effects of AEUt on cell viability and subjected the AEUt to phytochemical analyses. RESULTS: Administration of the AEUt (60 or 120 mg/kg) prevented ethanol- and piroxicam-induced ulceration, which was also confirmed histologically. Moreover, we observed that pre-treatment with NEM and indomethacin abolished the gastroprotective effects of AEUt, thereby indicating the involvement of NP-SH and prostaglandins in these protective effects. In addition, we found that the administration of AEUt had no appreciable effects on the volume, acidity, or peptic activity of gastric juice. Furthermore, the AEUt (60 mg/kg) accelerated the gastric healing of acetic acid-induced ulcers by 46.2% and ultrasonographic findings revealed a reduction in the gastric wall thickness in this group. The gastric healing effect of AEUt was also accompanied by a reduction in MPO activity. The AEUt (60 mg/kg) also minimized ulcer recurrence in mice exposed to IL-1ß and was associated with the maintenance of GSH levels and a reduction in MDA contents. We deduce that the biological effects of AEUt could be associated with the activities of polyphenols and the alkaloids isomitraphylline and mitraphylline, identified as predominant constituents of the AEUt. Furthermore, we found no evidence to indicate that AEUt would have any cytotoxic effects. CONCLUSION: Collectively, our findings provide compelling evidence indicating the therapeutic efficacy of U. tomentosa. Our data indicate that compounds in AEUt confer gastroprotection and that this preventive effect of AEUt was accompanied by gastric healing and a reduction in gastric ulcer recurrence. Moreover, we provide evidence to indicate that the gastroprotective and gastric healing effects involve the antioxidant system and anti-inflammatory responses that contribute to preserving the gastric mucosa.

Protective Effect of Mormodica balsamina Leaf Extract on the Gastric Morphology of Experimental Rats Against Ethanol Induced Gastric Ulcers / Efecto Protector de los Extractos de Hojas de Mormodica balsamina en la Morfología Gástrica de Ratas Experimentales Contra Úlceras Gástricas Inducidas por Etanol

SUMMARY: Mormodica balsamina is a valuable medicinal plant that is used to treat wounds and inflammation; its leaves are also used as an antibiotic and in the treatment of stomach pain. This study was conducted to determine the anti-ulcer activity of methanolic leaf extract of Mormodica balsamina on ethanol-induced ulcer in albino rats. A total of 32 rats were used for the study. Groups I and II served as the baseline and negative controls respectively, while groups III-VII served as the test groups. Group I was untreated, while group II received 1ml/kg body weight of the vehicle (2 % DMSO). Three test groups (III - V) received methanol extracts (75 mg, 150 mg, 300 mg/kg body weight respectively) while the other three test groups (VI - VIII) received aqueous extracts (75 mg, 150mg, 300 mg/kg body weight respectively) via oral gavage for seven days prior to ulcer induction. The rats were sacrificed, stomachs excised and ulcers scored. Histological sections were produced and examined. Findings revealed that M. balsamina extracts protected the rats' gastric epithelia from ethanol induced ulceration to varying degree with the high dose (150 and 300 mg/kg) of both extracts offering the best preservation (42 % and 50 % ulcer protective index respectively) when compared to untreated animals. Histological findings correlated with calculated ulcer indices, with treated animals having less severe gastric mucosal lesions. In conclusion, extracts of M. balsamina may possess reasonable antiulcer activities in rats against ethanol induced gastric ulcer.

Mormodica balsamina es una valiosa planta medicinal que se utiliza para tratar heridas e inflamaciones; sus hojas también se utilizan como antibiótico y en el tratamiento del dolor de estómago. Este estudio se realizó para determinar la actividad antiulcerosa del extracto metanólico de hojas de Mormodica balsamina sobre la úlcera inducida por etanol en ratas albinas. Se utilizaron un total de 32 ratas para el estudio. Los grupos I y II sirvieron como referencia y controles negativos respectivamente, mientras que los grupos III-VII sirvieron como grupos de prueba. El grupo I no se trató, mientras que el grupo II recibió 1 ml/kg de peso corporal del vehículo (2% de DMSO). Tres grupos de prueba (III - V) recibieron extractos de metanol (75 mg, 150 mg, 300 mg/ kg de peso corporal respectivamente) mientras que los otros tres grupos de prueba (VI - VIII) recibieron extractos acuosos (75 mg, 150 mg, 300 mg/kg de peso corporal respectivamente) por sonda oral durante siete días antes de la inducción de la úlcera. Se sacrificaron las ratas, se extirparon los estómagos y se puntuaron las úlceras. Se realizaron y examinaron secciones histológicas. Los resultados revelaron que los extractos de M. balsamina protegieron el epitelio gástrico de las ratas de la ulceración inducida por etanol en diversos grados, y la dosis alta (150 y 300 mg/kg) de ambos extractos ofreció la mejor conservación (42 % y 50 % de índice de protección contra úlceras, respectivamente) en comparación con los animales no tratados. Los hallazgos histológicos se correlacionaron con los índices de úlcera calculados, y los animales tratados tenían lesiones de la mucosa gástrica menos graves. En extractos de M. balsamina puede poseer actividades antiulcerosas razonables en ratas contra la úlcera gástrica inducida por etanol.

Encapsulation of Dicranopteris linearis extract using cellulose microparticles for antiulcer medication.

Dicranopteris linearis (DL) is a fern in the Gleicheniaceae family, locally known as resam by the Malay community. It has numerous pharmacological benefits, with antiulcer and gastroprotective properties. Peptic ulcer is a chronic and recurring disease that significantly impacts morbidity and mortality, affecting nearly 20 % of the world's population. Despite the effectiveness of peptic ulcer drugs, there is no perfect treatment for the ailment. Encapsulation is an advanced technique that can treat peptic ulcers by incorporating natural sources. This work aims to encapsulate DL extract using different types of cellulose particles by the solvent displacement technique for peptic ulcer medication. The extract was encapsulated using methyl cellulose (MC), ethyl cellulose (EC), and a blend of ethyl methyl cellulose through a dialysis cellulose membrane tube and freeze-dried to yield a suspension of the encapsulated DL extracts. The microencapsulated methyl cellulose chloroform extract (MCCH) has a considerably greater level of total phenolic (84.53 ± 6.44 mg GAE/g), total flavonoid (84.53 ± 0.54 mg GAE/g), and antioxidant activity (86.40 ± 0.63 %). MCCH has the highest percentage of antimicrobial activity against Escherichia coli (2.42 ± 107 × 0.70 CFU/mL), Bacillus subtilis (5.21 ± 107 × 0.90 CFU/mL), and Shigella flexneri (1.25 ± 107 × 0.66 CFU/mL), as well as the highest urease inhibitory activity (50.0 ± 0.21 %). The MCCH particle size was estimated to be 3.347 ± 0.078 µm in diameter. It has been proven that DL elements were successfully encapsulated in the methyl cellulose polymer in the presence of calcium (Ca). Fourier transform infrared (FTIR) analysis indicated significant results, where the peak belonging to the CO stretch of the carbonyl groups of methyl cellulose (MC) shifted from 1638.46 cm-1 in the spectrum of pure MC to 1639.10 cm-1 in the spectrum of the MCCH extract. The shift in the wavenumbers was due to the interactions between the phytochemicals in the chloroform extract and the MC matrix in the microcapsules. Dissolution studies in simulated gastric fluid (SGF) and model fitting of encapsulated chloroform extracts showed that MCCH has the highest EC50 of 6.73 ± 0.27 mg/mL with R2 = 0.971 fitted by the Korsmeyer-Peppas model, indicating diffusion as the mechanism of release.

HPTLC Studies, in silico Docking Studies, and Pharmacological Evaluation of Elaeocarpus ganitrus as a Gastroprotective Agent.

OBJECTIVES: Elaeocarpus ganitrus, a member of the Eleocarpaceae family, is valued in Hinduism and Ayurveda, and is frequently used as a remedy for a variety of illnesses. The plant is reputed to treat a number of stomach issues. The purpose of the study was to produce high-quality scientific data regarding gastroprotective behavior, docking experiments with cholinergic receptors, and HPTLC (with lupeol and ursolic acid). To develop the mechanism of herbal extracts, in vitro anticholinergic and antihistaminic activities were evaluated. Different leaf extracts were treated with various reagents to determine the presence of various metabolites. An examination of the histopathology was conducted to determine the full impact of the extract. METHODS: Methanolic extract was chosen for HPTLC investigations after extraction with various solvents. A mobile phase of toluene, ethylacetate, and formic acid (8:2:0.1) was chosen. Molecular docking was utilized to examine how ursolic acid and lupeol are bound to cholinergic receptors (M3). Different extracts (aqueous and ethanolic) were tested for their ability to provide gastroprotection in Wistar rats at different doses (200 and 400 mg/kg). RESULTS: Phytochemical analysis of different extracts showed the presence of different primary and secondary metabolites. HPTLC data showed the presence of both standards. Docking studies exhibited very good interactions with the M3 receptor. Pharmacological studies revealed that extract-treated groups significantly reduced the ulcer index in all of the models mentioned above. The histopathological analysis clearly supports the biochemical studies, which were conducted utilizing various doses and found to be effective in a dose-dependent manner. The in vitro analysis proved that the abovementioned extracts may act as antagonists of acetylcholine and histamine. CONCLUSION: The data obtained would be valuable for the production of the monograph of the plant and conducting concept-related clinical studies in the future. More investigation is required since the gathered scientific data may lead to new research opportunities.

Evaluation of the gastroprotective and ulcer healing properties by Fridericia chica (Bonpl.) L.G. Lohmann hydroethanolic extract of leaves.

ETHNOPHARMACOLOGICAL RELEVANCE: Fridericia chica (Bonpl.) L.G. Lohmann (Bignoniaceae), is a climber native to Brazil, found in all Brazilian biomes. It is mostly known in Brazil as "carajiru," and home medicines made from the leaves have been used to cure disorders including stomach ulcers and other gastrointestinal disorders. AIM OF THE STUDY: The objective of the study was to investigate the F. chica hydroethanolic extract of leaves (HEFc) preventative and curative antiulcer gastrointestinal efficacy as well as the mechanisms of action using in vivo rodent models. MATERIALS AND METHODS: F. chica was collected in the municipality of Juína, Mato Grosso, and its leaves were used to prepare the extract by maceration technique (70% hydroethanol in the 1:10 ratio, w/v) to obtain the HEFc. The chromatographic analysis of HEFc was carried out by High Performance Liquid Chromatography-Photo Diode Array-Electrospray Ionization-Mass Spectrometry (HPLC-PDA-ESI-MS)- LCQ Fleet™ system. To determine the potential antiulcer potential of HEFc (1, 5 and 20 mg/kg, p.o.), the gastroprotective activity was assessed in various animal models of stomach ulcers caused by acidified ethanol, water constraint stress, indomethacin, (acute), and acid acetic (chronic). Additionally, the prokinetic properties of the HEFC were assessed in mice. The gastroprotective underlying mechanisms were evaluated by the histopathological analysis and determination of gastric secretion (volume, free and total acidity), gastric barrier mucus, activation of PGs, NO, K +ATP channels, α2-adrenoceptor, antioxidant activity (GSH, MPO and MDA), NO and mucosal cytokines (TNF-α, IL-1ß, and IL-10) levels. RESULTS: The chemical composition of HEFc was analyzed and apigenin, scutellarin, and carajurone were identified. HEFc (1, 5 and 20 mg/kg) showed effect against acute ulcers induced by HCl/EtOH with a reduction in the ulcerated area of 64.41% (p < 0.001), 54.23% (p < 0.01), 38.71% (p < 0.01), respectively. In the indomethacin experiment, there was no change in the doses tested, whereas in the water immersion restraint stress ulcer there was a reduction of lesions at doses of 1, 5, and 20 mg/kg by 80.34% (p < 0.001), 68.46% (p < 0.01) and 52.04% (p < 0.01). HEFc increased the mucus production at doses of 1 and 20 mg/kg in 28.14% (p < 0.05) and 38.36% (p < 0.01), respectively. In the pyloric ligation-induced model of gastric ulceration, the HEFc decreased the total acidity in all doses by 54.23%, 65.08%, and 44.40% (p < 0.05) and gastric secretory volume in 38.47% at dose of 1 mg/kg (p < 0,05) and increased the free acidity at the dose of 5 mg/kg by 11.86% (p < 0.05). The administration of EHFc (1 mg/kg) showed a gastroprotective effect possibly by stimulating the release of prostaglandins and activating K+ATP channels and α2-adrenoreceptors. Also, the gastroprotective effect of HEFc involved an increase in CAT and GSH activities, and a reduction in MPO activity and MDA levels. In the chronic gastric ulcer model, the HEFc (1, 5 and 20 mg/kg) decreased the ulcerated area significantly (p < 0.001) at all doses by 71.37%, 91.00%, and 93.46%, respectively. In the histological analysis, HEFc promoted the healing of gastric lesions by stimulating the formation of granulation tissue and consequently epithelialization. On the other hand, regarding the effect of HEFc on gastric emptying and intestinal transit, it was observed that the extract did not alter gastric emptying, but there was an increase in intestinal transit at the dose of 1 mg/kg (p < 0.01). CONCLUSION: These outcomes confirmed the advantages of Fridericia chica leaves for the treatment of stomach ulcers, which are well-known. HEFc was discovered to have antiulcer characteristics through multitarget pathways, which might be related to an increase in stomach defense mechanisms and a decrease in defensive factor. HEFc can be regarded as a potential new antiulcer herbal remedy because of its antiulcer properties, which may be attributed to the mixture of flavonoids, apigenin, scutellarin and carajurone.

Antiulcer Activity of Anthraquinone-Flavonoid Complex of Rumex tianschanicus Losinsk.

The composition of an ethanol extract from the roots of Rumex tianschanicus Losinsk of the Trans-Ili Alatau wild flora was studied in order to determine its antiulcer activity. The phytochemical composition of the anthraquinone-flavonoid complex from (AFC) R. tianschanicus revealed the presence of numerous polyphenolic compounds, the most abundant of which are anthraquinones (1.77%), flavonoids (6.95%), and tannins (13.39%). The use of column chromatography (CC) and thin-layer chromatography (TLC) in conjunction with UV, IR, NMR spectroscopy, and mass spectrometry data allowed the researchers to isolate and identify the major components of the anthraquinone-flavonoid complex's polyphenol fraction: physcion, chrysophanol, emodin, isorhamnetin, quercetin, and myricetin. The gastroprotective effect of the polyphenolic fraction of the anthraquinone-flavonoid complex (AFC) of R. tianschanicus roots was examined in an experimental model of rat gastric ulcer induced by indomethacin. The preventive and therapeutic effect of the anthraquinone-flavonoid complex at a dose of 100 mg/kg was analyzed using intragastric administration per day for 1 to 10 days, followed by a histological examination of stomach tissues. It has been demonstrated that prophylactic and prolonged use of the AFC R. tianschanicus in laboratory animals resulted in significantly less pronounced hemodynamic and desquamative changes in the epithelium of gastric tissues. The acquired results thus offer fresh insight into the anthraquinone and flavonoid metabolite component composition of R. tianschanicus roots, and they imply that the examined extract can be used to develop herbal medicines with antiulcer activity.

Phenolic-rich extract of Nopalea cochenillifera attenuates gastric lesions induced in experimental models through inhibiting oxidative stress, modulating inflammatory markers and a cytoprotective effect.

Nopalea cochenillifera (Cactaceae), popularly known as "palma" or "palma doce", is from Mexico, but it was widely introduced in Brazil through crops. It has been used as food and in traditional medicine and is a good source of phenolic compounds. In this study the phytochemical profile and gastroprotective activity of phenolic-rich extract of N. cochenillifera in acute gastric lesion models induced by ethanol and indomethacin were evaluated. High-performance liquid chromatography coupled with mass spectrometry (HPLC/ESI/MSn) allowed the characterization of 12 compounds such as sugars, phenolics and flavonoids. Among polyphenols, the main peak was assigned to isorhamnetin-3-O-(2'',3''-O-di-rhamnose)-glucoside. The TPC and TFC in the dry extract were 67.85 mg of gallic acid equivalent per g/extract and 46.16 mg quercetin equivalent per g/extract, respectively. In the in vitro MTT assay, the extract showed no cytotoxicity and suppressed ROS levels in LPS-treated RAW 264.7 cells. Preclinical models in rats showed that a dose of 100 mg kg-1 (p < 0.0001) in the ethanol model and doses of 100 mg kg-1 (p < 0.5) and 200 mg kg-1 (p < 0.01) in the indomethacin model reduced the gastric lesions. Also, the extract reduced the MPO, MDA, TNF-α and IL-1ß levels and increased the GSH and IL-10 levels. The pre-treatment with the extract led to the upregulation of SOD and the downregulation of COX-2 by immunohistochemical analysis. It also showed a cytoprotective effect in the histopathological analysis and stimulated the restoration of the mucus content as observed in the periodic acid-Schiff analysis without modifying the pH, volume or total acidity of the gastric juice. Taken together, N. cochenillifera extract can be applied as a novel gastroprotective ingredient for food or pharmaceutical products.

Untargeted serum and liver metabolomics analyses reveal the gastroprotective effect of polysaccharide from Evodiae fructus on ethanol-induced gastric ulcer in mice.

This study aimed at investigating the gastroprotective effect of Evodiae fructus polysaccharide (EFP) against ethanol-induced gastric ulcer in mice. Biochemical indexes along with untargeted serum and liver metabolomics were determined. Results showed that pre-treatment of EFP alleviated ethanol-induced gastric ulcer in mice. EFP lessened oxidative stress and inflammation levels of stomachs, showing as increments of SOD and GSH-Px activities, GSH content and IL-10 level, and reductions of MDA and IL-6 levels. Meanwhile, EFP activated the Keap1/Nrf2/HO-1 signaling pathway through increasing Nrf2 and HO-1 protein expressions, and decreasing Keap1 protein expression. Serum and liver metabolomics analyses indicated that 10 metabolic potential biomarkers were identified among normal control, ulcer control and 200 mg/kg·bw of EFP groups, which were related to 5 enriched metabolic pathways including vitamin B6 metabolism, nicotinate and nicotinamide metabolism, pentose phosphate pathway, bile secretion and ascorbate and aldarate metabolism. Further pearson's correlation analysis indicated that there were some positive and negative correlations between the biomarkers and the biochemical indexes. It could be concluded that the gastroprotection of EFP might be related to anti-oxidative stress, anti-inflammation, activation of Keap1/Nrf2/HO-1 signaling pathway and alteration of metabolic pathways. This study supports the potential application of EFP in preventing ethanol-induced gastric ulcer.

First Evidence of Gastroprotection by Schinus molle: Roles of Nitric Oxide, Prostaglandins, and Sulfhydryls Groups in Its Mechanism of Action.

Schinus molle is a plant traditionally used in Mexico to treat gastric disorders. However, no scientific evidence has been reported on its gastroprotective effect. The aim of the current contribution was to conduct a bioassay-guided study on S. molle to evaluate its gastroprotective activity in a model of Wistar rats given ethanol orally to induce gastric lesions. The hexane and dichloromethane extracts from the tested plant showed over 99% gastroprotection at a dose of 100 mg/kg. From the hexane extract, two of the three fractions (F1 and F2) afforded over 99% gastroprotection. The F1 fraction was subjected to column chromatography, which revealed a white solid. Based on the ESI-MS analysis, the two main compounds in this solid were identified. The predominant compound was probably a triterpene. This mixture of compounds furnished about 67% gastroprotection at a dose of 100 mg/kg. Pretreatment with L-NAME, indomethacin, and NEM was carried out to explore the possible involvement of nitric oxide, prostaglandins, and/or sulfhydryl groups, respectively, in the gastroprotective activity of the white solid. We found evidence for the participation of all three factors. No antisecretory activity was detected (tested by pylorus ligation). In conclusion, evidence is herein provided for the first time of the gastroprotective effect of S. molle.

Evidence for the Involvement of Cytokines Modulation and Prokinetic Properties in Gastric Ulcer Healing Effects of Helicteres sacarolha A. St.-Hil. A. Juss.

Preparations of Helicteres sacarolha (Malvaceae) leaves and roots are used in the form of decoction, infusion or maceration, to treat gastrointestinal disturbances, among others. Studies supporting some of its ethnomedicinal uses are still incipient. The present study aimed to investigate it potential effect on chronic ulcer, ulcerative colitis and possible prokinetic activities as part of its mechanism of action. The powdered leaves of Helicteres sacarolha (HEHs) was prepared by maceration in 70 % hydroethanolic solution. Its qualitative phytochemical constituents were investigated by direct flow injection analysis coupled to atmospheric pressure chemical ionization ion trap tandem mass spectrometry (FIA-APCI-IT-MSn ). The gastric ulcer healing effect was evaluated in acetic acid induced chronic ulcer in mice and the lesions were evaluated, including analysis of blood plasma cytokine levels. The prokinetic properties (gastric emptying and intestinal transit) were carried out in mice. Potential anti-ulcerative colitis activity was evaluated in rats using 2,4,6-trinitrobenzenesulfonic acid (5 % TNBS) -induced colitis. All animal experiments were carried out at the doses of 20, 50 and 250 mg/kg (p.o.). Eight compounds were putatively identified, specifically lariciresinol, and its derivatives, kaempferol derivatives and Tricin-O-Glc. The extract promoted increased gastric ulcer healing at all doses tested. Modulation of the cytokines involved inhibition of some key pro-inflammatory cytokines with maximum effect on IL-1ß (70 %, 50 mg/kg, p<0.05), TNF-α (79 %, 20 mg/kg, p<0.01), and in the anti-inflammatory cytokines, namely IL-10 (57 %, 50 mg/kg, p<0.05) and IL-17 (79 %, only at 50 mg/kg, p<0.05). Histological findings demonstrated a mitigated inflammatory activity, and tissues undergoing regeneration. HEHs treatment caused delayed gastric emptying, and increased intestinal transit, but had no effect in the experimentally induced ulcerative colitis. We report for the first time putatively the presence of Lariciresinol and tricin derivatives from the hydroethanolic leaves extract of H. sacarolha. Its possible mechanism of actions of gastric ulcer healing involves cytokines modulation, mitigation of inflammatory response and tissue regeneration and provoked opposing effect in the gastrointestinal system. The present study demonstrates the therapeutic potential of H. sacarolha leaves used in Brazilian ethnomedicine in the treatment of chronic gastric ulcer.

Dimethyl Cardamonin from Fruits of Campomanesia reitziana D. Legrand Promotes Gastroprotection and Gastric Healing Effects in Rodents.

Campomanesia reitziana D. Legrand (Myrtaceae) displays antiulcer properties when given to rodents. The major active chemical components of C. reitziana are chalcones, including 4',6'-dihydroxy-2'-methoxy-3',5'-dimethylchalcone or dimethyl cardamonin (DMC); therefore, we hypothesized that this compound could have antiulcer effects and the present study aimed to evaluate its gastroprotective and gastric healing properties. DMC was isolated from the fruits of C. reitziana, and its gastroprotective effect was evaluated by ethanol and indomethacin-induced gastric ulcer models in mice (0.1 mg/kg, i.p. and 1 and 3 mg/kg, p.o.). Oxidative stress and inflammatory parameters were analyzed in the gastric tissue. Moreover, its gastric healing effect was evaluated in rats. In addition, the compound's mode of action was evaluated in vivo and in vitro by measuring H+ -K+ -ATPase activity. Finally, the cytotoxic potential of DMC was tested in fibroblasts and human gastric adenocarcinoma cells. The DMC reduced the ethanol-induced gastric ulcer in mice by 77 %, increased the adhered mucus, and reduced lipoperoxides levels. The block of nonprotein sulfhydryls (NP-SH) compounds by pretreatment with N-ethylmaleimide (NEM), the inhibition of nitric oxide synthase with Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), or the antagonism of α2 receptor using yohimbine reversed the gastroprotective effects of DMC. Furthermore, DMC reduced the acidity of gastric content in pylorus-ligated rats but did not change H+ , K+ -ATPase (isolated from rabbit) activity in vitro. DMC reduced the lesion area in acetic acid-induced ulcers and decreased myeloperoxidase activity. DMC did not change the viability of fibroblast cells (L929) but reduced the viability of human gastric adenocarcinoma cells (AGS). The results confirmed that DMC could significantly enhance the gastric healing process and prevent ulcers due to improving protective factors on the gastric mucosa and reducing gastric acid secretion.

Integrated serum pharmacochemistry and investigation of the anti-gastric ulcer effect of Zuojin pill in rats induced by ethanol.

CONTEXT: Zuojin Pill (ZJP) has been used to treat gastrointestinal problems in China for hundreds of years. OBJECTIVE: To discover more potential active ingredients and evaluate the gastroprotective mechanisms of ZJP. MATERIALS AND METHODS: An approach involving UPLC-Q-Orbitrap HRMS and serum pharmacochemistry was established to screen the multiple chemical constituents of ZJP. Male Sprague-Dawley (SD) rats were divided into six groups: normal control, ulcer control, omeprazole (30 mg/kg), and three ZJP groups (1.0, 2.0 and 4.0 g/kg). After oral treatment with ZJP or omeprazole for 7 days, all groups except the normal control group were orally administered 5 mL/kg ethanol to induce gastric ulceration. Histopathological assessment of gastric tissue was performed by haematoxylin and eosin staining. Antioxidant parameters and inflammatory mediators were determined using ELISA Kit and immunohistochemical analysis. RESULTS: Ninety components were identified in ZJP. Among them, 23 prototypes were found in rat serum after oral administration of ZJP. The ulcer inhibition was over 90.0% for all the ZJP groups. Compared with the ulcer control rats, ZJP (4.0 g/kg) enhanced the antioxidant capacity of gastric tissue: superoxide dismutase (1.33-fold), catalase (2.61-fold), glutathione (2.14-fold), and reduced the malondialdehyde level (0.48-fold). Simultaneously, the ZJP meaningfully lowered the content of tumour necrosis factor-α (0.76-fold), interleukin-6 (0.66-fold), myeloperoxidase (0.21-fold), and nuclear factor kappa B (p65) (0.62-fold). DISCUSSION AND CONCLUSIONS: This study showed ZJP could mitigate ethanol-induced rat gastric ulcers, which might benefit from the synergistic actions of multiple ingredients. The findings could support the quality control and clinical trials of ZJP.

Novel Isoxazole Derivative Attenuates Ethanol-Induced Gastric Mucosal Injury through Inhibition of H+/K+-ATPase Pump, Oxidative Stress and Inflammatory Pathways.

Isoxazole derivatives are significant enough due to their wide range of pharmacological and therapeutic activities. The purpose of the current study is to use computational, in vitro, in vivo, and extensive molecular approaches to examine the possible anti-ulcer activity of 4-benzylidene-3 methyl-1,2-isoxazol-5(4H)-one (MBO). Biovia Discovery Studio visualizer (DSV) was utilized for virtual screening. A tissue antioxidant investigation, H+/K+-ATPase test, and anti-H. pylori activities were carried out. ELISA, immunohistochemistry, and PCR methods were employed for the proteome analysis. An ethanol-induced stomach ulcer model was used to examine the anti-ulcer potential in rats. The binding affinities for MBO ranged from -5.4 to -8.2 Kcal/mol. In vitro findings revealed inhibitory activity against H. pylori and the H+/K+-ATPase pump. It also enhanced levels of glutathione, catalase, and glutathione-S-transferase and reduced lipid peroxidation levels in gastric tissues of rats. In vivo results showed the gastro-protective effect of MBO (30 mg/kg) in ulcerative rat stomachs. The proteomic study revealed decreased expression of inflammatory markers (cyclooxygenase-2, p-NFkB, and TNF-α). In RT-PCR analysis, the expression levels of H+/K+-ATPase were reduced. Furthermore, ADMET (absorption, distribution, metabolism, excretion and toxicity) studies revealed that MBO has high GIT solubility and has a safer profile for cardiac toxicity. This study suggests that MBO displayed anti-ulcer potential, which may have been mediated through the inhibition of the H+/K+-ATPase pump, as well as antioxidant and anti-inflammatory pathways. It has the potential to be a lead molecule in the treatment of peptic ulcers with fewer adverse effects.

Gastroprotective effect of hydroalcoholic extract from Agaricus blazei Murill against ethanol-induced gastric ulcer in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The use of mushrooms in medicine is quite old and the first report about the use of genus Agaricus in treatment of ulcers occurred in Byzantine period. This mushroom is widely consumed as food, tea, food supplements, as well as nutraceutical and cosmeceutical applications, being cultivated and appreciated in several countries such as Brazil, Korea, Japan and China. AIM OF THE STUDY: This study aimed to characterize the chemical profile and the potential gastroprotective effect of hydroalcoholic extract from Agaricus blazei Murill (HEAb). MATERIALS AND METHODS: The extract was chemically characterized by elemental analysis, UPLC-QTOF-MSE, Nuclear Magnetic Resonance (NMR) and high-performance liquid chromatography (HPLC) techniques to elucidate the metabolites present in the extract. The quantification of phenolic compounds and the in vitro antioxidant activities were performed and the gastroprotective effect of this extract was evaluated against ethanol-induced gastric ulcer model. HEAb was administered by gavage at 5, 25 and 50 mg kg-1 and N-acetylcysteine at 300 mg kg-1 (positive control). Furthermore, the pathways of nitric oxide (NO), Cyclic Guanylate Monophosphate (cGMP), prostaglandins (PGs) and the involvement of ATP-sensitive K+ Channels were modulated. RESULTS: Mannitol, malic acid, pyroglutamic acid, L-agaritine and L-valine were putatively identified by UPLC-QTOF-MSE in HEAb. In addition, it was possible to identify mannitol by the intense signals in the NMR spectra, being still quantified as the main compound in the extract by HPLC. The contents of total phenols and flavonoids corroborated with the good antioxidant activity of HEAb. This study observed that HEAb at 25 and 50 mg kg-1 had gastroprotection effect demonstrated by the reduction of histopathological parameters and the reduction of mastocytosis in the stomach of mice. CONCLUSIONS: In this study was possible to conclude that HEAb has gastroprotective effect related to the involvement of NO and PG pathways in the ethanol-induced gastric ulcer model in mice.

Design of a dual pH and temperature responsive hydrogel based on esterified cellulose nanocrystals for potential drug release.

In this study, new stimuli - responsive hybrid hydrogels were achieved via succinylated cellulose nanocrystals (Su-CNC). The innovation was concerned with the inclusion of Su-CNC, at different degree of substitution (DS), into hydrogel network to render it pH and thermo-responsive characters through free radical polymerization reaction with poly(N-isopropylacrylamide) (PNIPAm). The prepared hydrogel was also examined for the in vitro release of Famotidine at different pH values. As clearly evident from the results, all the hydrogels prepared with different DS of Su-CNC, which were nominated as Su-CNC / PNIPAm (1-3), showed a high response to temperature change since their swelling behavior and hydrophilicity were decreased at 35 °C and upwards. This led to the more hydrophobicity character and thus the hydrogel shrinkage occurred. On the other hand, at pH 6, the hydrogels exhibited a significant Equilibrium Swelling Ratio (ESR) attaining 18.1, 17.3 and 16.8 (g/g) for Su-CNC / PNIPAm (1-3), respectively. However, Su-CNC / PNIPAm 2 hydrogel showed a significant response to the pH change from 8 to 2 which was advised to be selected as a potential pH responsive hydrogel for the in vitro Famotidine release.

Anti-inflammatory, ulcerogenic and platelet activation evaluation of novel 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids.

This study reports the synthesis of novel neolignans-celecoxib hybrids and the evaluation of their biological activity. Analogs8-13(L13-L18) exhibited anti-inflammatory activity, inhibited glycoprotein expression (P-selectin) related to platelet activation, and were considered non- ulcerogenic in the animal model, even with the administration of 10 times higher than the dose used in reference therapy. In silico drug-likeness showed that the analogs are compliant with Lipinski's rule of five. A molecular docking study showed that the hybrids8-13(L13-L18) fitted similarly with celecoxib in the COX-2 active site. According to this data, it is possible to infer that extra hydrophobic interactions and the hydrogen interactions with the triazole core may improve the selectivity towards the COX-2 active site. Furthermore, the molecular docking study with P-selectin showed the binding affinity of the analogs in the active site, performing important interactions with amino acid residues such as Tyr 48. Whereas the P-selectin is a promising target to the design of new anti-inflammatory drugs with antithrombotic properties, a distinct butterfly-like structure of 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids synthesized in this work may be a safer alternative to the traditional COX-2 inhibitors.

Anti-Cancer and Medicinal Potentials of Moringa Isothiocyanate.

Moringa oleifera (M. oleifera), which belongs to the Moringaceae family, is a common herb, rich in plant compounds. It has a variety of bioactive compounds that can act as antioxidants, antibiotics, anti-inflammatory and anti-cancer agents, etc., which can be obtained in different body parts of M. oleifera. Isothiocyanates (ITCs) from M. oleifera are one class of these active substances that can inhibit cancer proliferation and promote cancer cell apoptosis through multiple signaling pathways, thus curbing cancer migration and metastasis, at the same time they have little adverse effect on normal cells. There are multiple variants of ITCs in M. oleifera, but the predominant phytochemical is 4-(α-L-rhamnosyloxy)benzyl isothiocyanate, also known as moringa isothiocyanate (MIC-1). Studies have shown that MIC-1 has the possibility to be used clinically for the treatment of diabetes, neurologic diseases, obesity, ulcerative colitis, and several cancer types. In this review, we focus on the molecular mechanisms underlying the anti-cancer and anti-chronic disease effects of MIC-1, current trends, and future direction of MIC-1 based treatment strategies. This review combines the relevant literature of the past 10 years, in order to provide more comprehensive information of MIC-1 and to fully exploit its potentiality in the clinical settings.

Chemical Constituents and Anti-Gastric Ulcer Activity of Essential Oils of Alpinia officinarum (Zingiberaceae), Cyperus rotundus (Cyperaceae), and Their Herbal Pair.

The essential oil (EO) of the herbal pair (HP), Alpinia officinarum-Cyperus rotundus (HP G-X) has been conventionally used in traditional Chinese medicine (TCM) for 'warming the stomach' and relieving pain. However, its pharmacologically active compounds, as well as the mechanism of its anti-gastric ulcer properties remain unclear. In this study, the EOs obtained from HP G-X and its corresponding single herbs were analyzed using GC/MS. A total of 74, 56, and 85 compounds were detected in A. officinarum (GLJ), C. rotundus (XF), and HP G-X, accounting for 93.2 %, 89.5 %, and 92.0 % of the total content, respectively. GLJ mainly contains 1,8-cineol (22.0 %) and α-terpineol (11.8 %), whereas cyperenone (22.4 %) and cyperene (12.3 %) were the major constituents in XF. These four compounds were also detected in the HP G-X with relatively high composition as 11.8 %, 5.5 %, 11.8 %, and 10.6 %, respectively. Although no new compounds were detected in HP G-X, the relative concentration of some compounds increased, while others decreased or even disappeared. HP G-X showed the lowest toxicity (TC50 >800 µg/mL) against human gastric mucosal epithelial cells (GES-1) and had the best protective effect against ethanol-induced GES-1 cell damage compared to the individual herbs. In vitro studies demonstrated that HP G-X and the corresponding single herbs significantly reduced IL-6, TNF-α, and COX-2. In addition, in vivo investigations indicated that HP G-X can protect the gastric mucosa of mice from ethanol-induced damage by inhibiting the inflammatory reaction and providing analgesia. It can also inhibit the expression of NF-κBp65, COX-2, and TRPV1 protein, reduce the concentrations of IL-6 and TNF-α, and relieve heat-induced pain. This study further substantiated the traditional application of HP G-X against gastric ulcers through both in vivo and in vitro investigations.