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.

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.

Geraniol accelerates the gastric healing, minimizes ulcers recurrence, and reduces anxiolytic-like behavior in ulcerated rodents by oral or inhaled route.

BACKGROUND: Geraniol (GE) is dietary acyclic monoterpene alcohol found in essential oils from aromatic plants with therapeutic value against gastric ulcers already described. HYPOTHESIS/PURPOSE: To assess whether oral GE accelerates gastric healing or prevents ulcer recurrence, and to evaluate the hypothesis that GE promotes antiulcer effects by the inhaled route and that promotes changes in the behavior of ulcerated rodents. METHODS: Gastric healing effects, underlining mechanisms, and behavioral changes were measured in80% acetic acid-induced gastric ulcer model in rats receiving GE by oral (30 mg/kg) or inhaled route (1 mg/L of air/min); whereas the effects of GE to avoid ulcer recurrence was evaluated in mice submitted to 10% acetic acid plus IL-1ß ulcer. RESULTS: GE administered by both routes accelerates gastric healing, increasing mucin and GSH levels, CAT, and GST activities, and reducing MPO activity. Moreover, oral, and inhaled GE minimized ulcer recurrence reducing gastric TNF and IL-6 levels and preserving mucin levels. Interestingly, the inhalation or oral intake of GE promotes anxiolytic-like effects in ulcerated rats. CONCLUSION: Data altogether suggest that the GE accelerates gastric healing through the strengthening of protective factors of the gastric mucosa, promoting a quality healing that reduces the recurrence of the lesion. Besides, the anxiolytic-like effect of GE may also contribute to its gastric healing action since anxiety is recognized as one of the etiologic agents of ulcers.

Gastroprotective and gastric healing effects of the aqueous extract of Casearia sylvestris in rodents: Ultrasound, histological and biochemical analyzes.

ETHNOPHARMACOLOGICAL IMPORTANCE: Casearia sylvestris Sw. (Salicaceae) is a native plant from the Americas, where it is also known as "guaçatonga" or "erva-de-bugre." Although its leaves have been commonly used to treat inflammation and gastrointestinal disorders in South America, the antiulcer effects of an aqueous extract from this medicinal plant, similar to popular use, have not to be investigated yet. AIM OF THE STUDY: This study evaluated the hypothesis that the aqueous extract a of C. sylvestris (AEC) prevents the gastric ulcers and accelerates the healing of ulcers already installed, by assessing ultrasound imaging, histological and biochemical analyses. MATERIALS AND METHODS: Rats (females) were treated with AEC (3, 30 or 300 mg/kg) prior to the ethanol or piroxicam-induced gastric ulcers. The healing effect of AEC (300 mg/kg) was examined in 80% acetic acid-induced ulcer in rats, whereas the quality of healing was evaluated in recurrent 10% acetic acid-induced ulcer in mice with recurrence induced by interleukin 1ß. To assess the responses of the lesions, in addition to the classical methods used to analyze gastroprotection (ex vivo), we also measured the gastric wall thickness (in vivo) using ultrasonography. After euthanasia, the extent of ulcer was determined and the levels of reduced glutathione (GSH), lipid hydroperoxides (LOOH), nitrate, and the activities of myeloperoxidase (MPO), N-acetyl-ß-D-glycosaminidase (NAG), superoxide dismutase (SOD), and glutathione S-transferase (GST) were measured. The antisecretory activity of AEC was also examined based on pylorus ligated rats. Furthermore, gastric tissue samples were analyzed histologically, and phytochemical analyses of the C. sylvestris extract were parallelly performed. RESULTS: The AEC (30 or 300 mg/kg) prevented ulcers in the ethanol- and piroxicam-induced acute. Moreover, the AEC at a dose of 300 mg/kg also accelerated the gastric healing of acetic acid-induced ulcer in rats by 48% and the ultrasonography records shown a decrease in the wall thickness and the extent of edema of ulcerous lesions promoted by the extract. The gastric healing effect of AEC was also accompanied by reduced MPO and NAG activities at acetic acid-induced ulcer in rats; as well as was by the reduction in the nitrate and LOOH levels, the increase in mucin and SOD activity, and by a partial recovery of GSH levels. The AEC (300 mg/kg) minimized the ulcer recurrence in mice exposed to IL-1ß, but the extract administration did not change pH or peptic activity of gastric juice in pylorus ligated rats. CONCLUSION: The results of this study provide convincing evidence for the therapeutic efficacy of C. sylvestris with respect to gastroprotection and indicate that ultrasound examination would be a potentially promising approach for evaluating gastroprotective effects in vivo. Collectively, our findings indicate that the gastric the gastroprotective and healing effects of aqueous extract C. sylvestris involve a reduction in acid secretion, promotion of the antioxidant system, reductions in the migration of neutrophils and mast cells, with a consequent lower inflammatory response, and the preservation of mucin.

Lupeol Stearate Accelerates Healing and Prevents Recurrence of Gastric Ulcer in Rodents.

Objective: The focus of this study was to evaluate the gastric healing effect of lupeol stearate (LS) and its ability to minimize ulcer recurrence in rodents. Methods: To evaluate the gastric healing properties of LS, rats were subjected to 80% acetic acid-induced ulcer model and treated with vehicle, LS (1 mg/kg, p.o.), or omeprazole (20 mg/kg, p.o.), twice daily by seven days. The gastric ulcers were evaluated macroscopically, histologically, and biochemically. To evaluate the effects of LS in gastric ulcer recurrence, mice were ulcerated with 10% acetic acid and treated with vehicle, LS (1 mg/kg, p.o.), or ranitidine (100 mg/kg, p.o.), twice a day for ten days. Then, ulcer recurrence in these animals was induced by IL-1ß at five days after the treatment period. Results: The oral treatment with LS accelerated gastric healing by 63% in rats compared to the vehicle group, evidenced by histological improvement and increased gastric mucin levels. Moreover, the gastric healing effects of LS in rats were accompanied by an elevation in glutathione S-transferase activity and a reduction in myeloperoxidase activity. Furthermore, the LS treatment reduced the recurred lesions in mice. Conclusions: The oral treatment of LS accelerates gastric healing in rats by favoring mucus production and reducing neutrophil migration, and it also can reduce ulcer recurrence. These data highlighted this compound as promising for developing new pharmacological strategies for the management of gastric ulcer.

Neuroprotective effects of strength training in a neuroinflammatory animal model.

BACKGROUND: The preventive role of muscular strength on diminishing neuroinflammation is yet unknown. In this study, the role of the prophylactic muscular strength exercise was investigated in order to verify whether it would diminish cognitive alterations and modify the antioxidant intracellular scenery in an animal neuroinflammatory model in of the CA1 region of the hippocampus. METHODS: The animals received muscular strength training (SE) three times a week for eight weeks. Subsequently, the stereotaxic surgery was performed with an intra-hippocampal infusion of either saline solution (SAL) or lipopolysaccharide (LPS). Next, we performed the behavioral tests: object recognition and social recognition. Then, the animals were euthanized, and their hippocampus and prefrontal cortex were collected. In another moment, we performed the dosage of the antioxidant activity and histological analysis. RESULTS: The results showed that the muscular strength exercises could show a beneficial prophylactic effect in the cognitive deficiencies caused by acute neuroinflammation. Regarding oxidative stress, there was an increase in catalase enzyme activity (CAT) in the group (SE + LPS) compared to the control groups (p < 0.05). As for the cognitive alterations, there were found in the (SE + LPS) group, diminishing the mnemonic hazard of the discriminative and social memories compared to the control groups (p < 0.05). CONCLUSION: We concluded, therefore, that the exercise performed prophylactically presents a protective effect capable of minimizing such mnemonic deficits and increasing catalase enzyme activity in rats that suffered a local neuroinflammatory process in the hippocampus.

Baccharis dracunculifolia DC Hydroalcoholic Extract Improves Intestinal and Hippocampal Inflammation and Decreases Behavioral Changes of Colitis Mice.

The hydroalcoholic extract of B. dracunculifolia (HEBD) and its major compound p-coumaric acid were evaluated against the severity of intestinal inflammation and behavioral changes like depressive and anxious behavior in colitis mice. Colitis was induced in Swiss mice by oral dextran sulfate sodium (DSS) administration for five days. The mice received vehicle (10 ml/kg), HEBD (3, 30, or 300 mg/kg), or p-coumaric acid (15 mg/kg) orally, once a day for twelve days. Behavioral tests were performed on the 11th and 12th days after the beginning of the treatments. Moreover, the colon, cortex, and hippocampus were collected to analyze oxidative and inflammatory parameters. The treatment with HEBD (300 mg/Kg), but not p-coumaric acid, showed decreased disease activity index (DAI) values compared to the vehicle group and partially preserved the villi architecture and mucin levels. Furthermore, the HEBD increased the antioxidant defenses in the colon and hippocampus and reduced the myeloperoxidase activity and IL-6 levels in the colon from colitis mice. Colitis mice treated with HEBD did not show depressive-like behavior in the tail suspension test. HEBD reduced colon inflammation, while it maintains antioxidant defenses and mucin levels in this tissue. It may reduce neuropsychiatric comorbidities associated with colitis through its antioxidant effects.

Taxifolin and gastro-adhesive microparticles containing taxifolin promotes gastric healing in vivo, inhibits Helicobacter pylori in vitro and proton pump reversibly in silico.

Taxifolin (3,5,7,3,4-pentahydroxy flavanone or dihydroquercetin, Tax) was identified as a gastroprotective compound and a gastroadhesive formulation was recently developed to prolong its residence time and release in the stomach. So, the gastric healing effectiveness of Tax and gastro-mucoadhesive microparticles containing Tax (MPTax) against the acetic acid induced-gastric ulcer in rats was investigated in this study. Moreover, the interactions between Tax and H+/K+-ATPase were investigated in silico, and its anti- H. pylori activity was determined in vitro. The oral treatment with MPTax (81.37 mg/kg, containing 12.29% of Tax) twice a day for seven days reduced the ulcer area by 63%, compared to vehicle-treated group (Veh: 91.9 ± 10.3 mm2). Tax (10 mg/kg, p.o) reduced the ulcer by 40% but with a p = 0.07 versus Veh group. Histological analysis confirmed these effects. Tax and MPTax increased the gastric mucin amount, reduced the myeloperoxidase activity, and increased the glutathione reduced content at ulcer site. However, only MPTax decreased the lipoperoxide accumulation at ulcer site. Besides, Tax and MPTax normalize the catalase and glutathione S-transferase activity. Tax showed reversible interaction with H+/K+-ATPase in silico and its anti-H. pylori effects was confirmed (MIC = 625 µg/mL). These results suggest that the antiulcer property of Tax involves the strengthening of the gastric protective factors in parallel to its inhibitory interaction with H+/K+-ATPase and H. pylori. Considering that ulcer healing action displayed by Tax was favored by gastroadhesive microparticles, this approach seems to be promising for its oral delivery to treat acid-peptic diseases.

Dual role of eugenol on chronic gastric ulcer in rats: Low-dose healing efficacy and the worsening gastric lesion in high doses.

This study evaluated the gastric healing activity of eugenol, the main bioactive compound from clove (Syzygium aromaticun) essential oil. Five groups of female Wistar rats were submitted to acetic acid-induced ulcer model and treated with Vehicle (1 mL/kg, p.o.), eugenol (1, 10 or 100 mg/kg, p.o) or omeprazole (20 mg/kg, p.o), twice a day, by seven or fourteen days. Macroscopic, microscopic and biochemical analyses were performed in the ulcerated site. Eugenol (1 mg/kg, p.o) administered by 7 or 14 days accelerated the gastric healing process by 33% and 52%, respectively. The healing actions of eugenol were accompanied by the rescue on the histological architecture and the normalization of the superoxide dismutase and catalase activity. Moreover, eugenol (1 mg/kg, p.o) reduced the gastric mucosal myeloperoxidase activity and increased the mucin secretion. In contrast, eugenol at a dose of 100 mg/kg administered by 7 days enhanced 49% the ulcerated area, but at 10 mg/kg did not change the ulcer area after 7 or 14 days of treatment. Thus, despite the undesirable results due to the worsening of the gastric lesion with the use of eugenol in high doses, the antiulcer potential of this compound is evident and manageable in an adequate dose.

Irinotecan-induced intestinal mucositis in mice: a histopathological study.

PURPOSE: Intestinal mucositis is an important adverse effect of antineoplastic therapy, which remains without adequate treatment. The present study aimed to carry out a complete evaluation of the histopathological changes during irinotecan-induced intestinal mucositis, using the protocol most found in the pharmacological reports nowadays to better understand irinotecan toxicity and support future studies on drug discovery. METHODS: Intestinal mucositis was induced by treating swiss mice for 4 days with irinotecan (75 mg/kg, i.p.). After 72 h post irinotecan, the mice were sacrificed and the small intestine and colon were excised to performed histological analysis by stained tissue with hematoxylin/eosin (H&E). RESULTS: Histoarchitecture loss, villus/crypt ratio reduction, atrophy of the muscular layer, hypertrophy in the submucosal and mucous layers, ruptures in the epithelium, as well as extent cellular infiltrate and presence of micro abscesses and the fusion of the crypts were observed in the histological analysis. Moreover, duodenum and colon had increased intraepithelial lymphocytes and mitotic figures. However, submucosal ganglia were decreased in the duodenum and increased in the colon. CONCLUSIONS: The data obtained in the present study provides new evidence that irinotecan-induced intestinal mucositis highly affects small intestine and colon, further contributing to establish criteria in light of the histopathological changes induced by irinotecan during intestinal mucositis and facilitating inter-study comparisons.

The pathophysiology of acute gastric ulcer development in normotensive and hypertensive rats: A comparative study.

Although gastric ulcers and hypertension are diseases that affect a large part of the population, the association of these comorbidities is still poorly studied. Therefore, the present study investigated the response of normotensive (NTR) and spontaneously hypertensive (SHR) rats to gastric ulcers induced by indomethacin or ethanol. For that, adult male and female NTR and SHR received indomethacin (100 mg/kg, p.o) or ethanol P.A (5 ml/kg, p.o) to induce gastric ulcer, after the pre-treatment with prostaglandin E2 (PGE2) and carbenoxolone (CBX), respectively. The results revealed that, when compared to NTR, the SHR, both male and female, showed lower lesion area indexes when exposed to indomethacin. On the other hand, ethanol caused an area of lesion approximately 60% larger in the male and female SHR in comparison with the NTR. Significantly, the pre-treatment with PGE2 or CBX prevented the gastric ulcer damage promoted by indomethacin or ethanol, respectively. The histological analyses of the gastric mucosa from ethanol-induced ulcer revealed severe disruption of gastric architecture and bleeding points, that have been exacerbated in the SHR group. The gastric tissue from the SHR group also showed high levels of nitrite, a marker of nitric oxide production, which was accompanied by an increase in lipid hydroperoxide levels, an important biomarker of oxidative damage, in comparison with NTR. Taking together, the results of the present study showed important differences in the development of gastric ulcer between NTR and SHR. Further studies are needed for an in-depth analysis of the pathophysiological mechanisms involved in these responses.

Maytenus robusta Reissek, a medicinal plant popularly used to treat digestive diseases, promotes ameliorative effects in colon and liver of mice exposed to dextran sulfate sodium.

ETHNOPHARMACOLOGICAL RELEVANCE: Maytenus robusta Reissek (Celesteraceae), popularly named as cafezinho do mato or coração de bugre, is employed to treat inflammatory digestive diseases in the south of Brazil. However, despite popular usage, the effects of this species on an experimental model of ulcerative colitis are unknown. AIM OF THE STUDY: To evaluate the effects of M. robusta extract (HEMR) on colon and liver from mice with colitis induced by dextran sulfate sodium (DSS). MATERIALS AND METHODS: Firstly, the cytotoxicity of HEMR and its effects on ROS and nitrite production in IEC-6 cells were evaluated. The experimental colitis was established by adding 3% DSS on drinking water of mice and the effects of HEMR (1-100 mg/kg, p.o, once a day by 7 days) in colonic and hepatic tissues were analyzed. RESULTS: The HEMR (1-100 µg/mL) did not alter the cell viability but reduced nitrite production of IEC-6 stimulated by LPS. Moreover, HEMR (100 mg/Kg) attenuates macro and microscopic alterations in the colon from mice exposed to DSS, as evidenced by a reduction of the colon shortening, attenuation of the epithelial erosion, submucosal edema and preservation of the Goblet cells integrity, as well as the restoration of mucin depletion. The treatment with HEMR increased GSH amount, reduced LOOH levels and normalizes CAT activity in the colon. The group treated with HEMR showed increased GST activity, reduced MPO activity and decreased inflammatory cytokines secretion (TNF and IL-6) in the colonic tissue. In the liver, HEMR increased GST activity, decreased the GPx activity and reduced IL-6 levels. Furthermore, the HEMR treatment reduced AST and ALT serum levels in mice exposed to DSS. Finally, the HEMR was able to reduce intestinal transit. CONCLUSIONS: HEMR treatment minimizes inflammation of the colon and maintaining the antioxidant homeostasis. In addition, HEMR may be a potential tool to prevent hepatic injury secondary to ulcerative colitis.

Açaí berries (Euterpe oleracea Mart.) dried extract improves ethanol-induced ulcer in rats.

OBJECTIVES: Açaí (Euterpe oleracea) is widely consumed in Brazil and known for its numerous health-beneficial properties. This study investigated the gastroprotective potential of the dried açaí berries extract (DAE). METHODS: Dried açaí berries extract effect was evaluated against ethanol-induced gastric ulcer in rats. Its ability to regulate antioxidant defenses and reduce inflammatory parameters was evaluated in the ulcerated tissues. The scavenger capability of DAE was assessed by DPPH assay, and phytochemical composition was accessed by UHPLC. KEY FINDINGS: The extract showed radical scavenger activity in vitro (IC50  = 210 µg/ml) and gastroprotective effect in vivo, reducing the ulcerated area by 83%, 67% and 48% at doses of 30 and 100 mg/kg (p.o) and 3 mg/kg (i.p), respectively, compared with vehicle group. Besides, DAE (100 mg/kg, p.o) increased the GSH content and GST activity in ulcerated mucosa. Animals treated with DAE showed normalized levels of SOD activity, elevated CAT activity and decreased MPO activity, as well as reduced TNF-α levels, compared with vehicle group. Peonidin-3-glucoside, peonidin-3-rutinoside, cyanidin-3,5-hexoside-pentoside, cyaniding-3-glucoside, pelargonidin-3-glucoside and pelargonidin-3-rutinoside were identified in DAE. CONCLUSIONS: Our findings suggest that DAE reduces the inflammation and maintains the oxidative balance of gastric mucosa, therefore being a promising natural resource or useful nutraceutical to protect gastric mucosa.

Gastroprotective properties of Lupeol-derived ester: Pre-clinical evidences of Lupeol-stearate as a potent antiulcer agent.

Lupeol (1) was isolated from hexane branch extract of Maytenus salicifolia and the Lupeol stearate (2), Lupeol palmitate (3), Lupeol myristate (4), Lupeol laurate (5) and Lupeol caprylate (6) were obtained reacting 1 with an adequate carboxylic acid. Swiss mice were treated with vehicle, carbenoxolone or Lupeol esters before administration of ethanol/HCl or indomethacin. Additionally, the involvement of nitric oxide (NO), sulfhydryl compounds (NP-SH), α-2 adrenergic receptors (α2-AR) and prostaglandins (PGE) in antiulcer effects was investigated using appropriate inhibitors or antagonist. Oxidative and inflammatory parameters were measured after euthanasia and anti-secretory effects was evaluated in pylorus-ligated rats. Ethanol/HCl ulcerated the gastric mucosa by 64.45 ± 6.58 mm2, which the oral treatment with 1, 4 and 6 (10 mg/kg), and 3 and 5 (30 mg/kg) reduced the lesion area. Interestingly, 2 reduced the gastric ulcer by oral route in a potent and dose-dependent manner (ED50 = 0.40 mg/kg), which was accompanied by the increase in reduced glutathione levels and by the reduction of lipids peroxidation and myeloperoxidase and superoxide dismutase activities. Moreover, 2 (0.1 mg/kg) also prevented the ulcerogenesis by intraperitoneal route. The participation of NO, NP-SH, α2-AR and PGE in 2-mediated gastroprotection was confirmed. In indomethacin-induced ulcer, 2 (1 mg/kg, p.o) also reduced the ulcer area and increased the PGE2 levels. However, 2 did not alter the gastric acid secretion. Therefore, these findings indicate that the obtention of 2 potentiated the antiulcer activity of 1 and that this compound can elicit gastroprotective action due a diversified mode of action.

Luteolin prevents irinotecan-induced intestinal mucositis in mice through antioxidant and anti-inflammatory properties.

BACKGROUND AND PURPOSE: Intestinal mucositis refers to mucosal damage caused by cancer treatment, and irinotecan is one of the agents most associated with this condition. Focusing on the development of alternatives to prevent this important adverse effect, we evaluated the activity of the flavonoid luteolin, which has never been tested for this purpose despite its biological potential. EXPERIMENTAL APPROACH: The effects of luteolin were examined on irinotecan-induced intestinal mucositis in mice. Clinical signs were evaluated. Moreover, histological, oxidative, and inflammatory parameters were analysed, as well as the possible interference of luteolin in the anti-tumour activity of irinotecan. KEY RESULTS: Luteolin (30 mg·kg-1 ; p.o. or i.p.) prevented irinotecan-induced intestinal damage by reducing weight loss and diarrhoea score and attenuating the shortening of the duodenum and colon. Histological analysis confirmed that luteolin (p.o.) prevented villous shortening, vacuolization, and apoptosis of cells and preserved mucin production in the duodenum and colon. Moreover, luteolin treatment mitigated irinotecan-induced oxidative stress, by reducing the levels of ROS and LOOH and augmenting endogenous antioxidants, and inflammation by decreasing MPO enzymic activity, TNF, IL-1ß, and IL-6 levels and increasing IL-4 and IL-10. Disruption of the tight junctions ZO-1 and occludin was also prevented by luteolin treatment. Importantly, luteolin did not interfere with the anti-tumour activity of irinotecan. CONCLUSION AND IMPLICATIONS: Luteolin prevents intestinal mucositis induced by irinotecan and therefore could be a potential adjunct in anti-tumour therapy to control this adverse effect, increasing treatment adherence and consequently the chances of cancer remission.

Gastroprotective activity of hydroalcoholic extract of the leaves of Urera baccifera in rodents.

ETHNOPHARMACOLOGICAL IMPORTANCE: The species Urera baccifera (L.) Gaudich. ex Wedd. (Urticaceae) is native to the Americas and is distributed widely throughout Brazil, where it is known as urtiga-brava, urtiga-vermelha, or urtigão. The leaves are often used as anti-inflammatory and antirheumatic agents and for the treatment of gastric disorders. However, the pharmacological mode of action underlying the gastroprotection induced by this species has not been investigated. AIM OF THE STUDY: To contribute to the knowledge of the gastroprotective mode of action of the hydroalcoholic extract of U. baccifera (HEU) leaves. MATERIALS AND METHODS: Antiulcerogenic effect of HEU against ethanol-induced acute gastric ulcer was evaluated in rats and mice at doses of 3-300 mg/kg. NO-synthase inhibitor (L-NAME), SH blocker (NEM), cyclooxygenase inhibitor (indomethacin) and alpha 2-adrenergic receptor antagonist yohimbine were used to evaluate the participation of cytoprotective factors in HEU gastroprotection. Moreover, the levels of reduced gluthatione (GSH) and cytokines (TNF, IL-6, IL4 and IL-10), as well as the enzymatic activity of gluthatione S-transferase (GST), myeloperoxidase (MPO), superoxide dismutase (SOD) and catalase (CAT) were measure. Moreover, the samples were analyzed histologically and the antisecretory capability of HEU were quantified using pylorus ligated rats. RESULTS: The phytochemical analysis of HEU (UPLC/ESI-IT-MS) identified the flavonoids diosmetin and apigenin glucuronide. Furthermore, HEU decreased the occurrence of ethanol-induced ulcers at 30 and 300 mg/kg by 57% and 66%, respectively, compared with the vehicle. The gastroprotective effects were accompanied by increased GSH levels and GST and SOD activity as well as by reduced MPO activity in vivo and in vitro, revealing antioxidant effects and inhibition of neutrophil infiltration. The beneficial effects of 30 and 300 mg/kg HEU were also observed upon histological analyses. Regarding the mode of action, the gastroprotective effect of HEU was abolished by the pre-administration of L-NAME, NEM, indomethacin or yohimbine. Moreover, HEU was able to decrease the IL-6, IL-4 and IL-10 in ulcerated tissue, as well as the pepsin activity of the gastric juice in pylorus-ligated rats. CONCLUSION: Together, the results confirmed that the gastroprotection elicited by HEU was due reduction in oxidative damage, neutrophil migration, and peptic activity. This work validates the popular use of U. baccifera to treat gastric disorders and supports important future research for the identification of gastroprotective molecules from this species.

Role of the antioxidant properties in the gastroprotective and gastric healing activity promoted by Brazilian green propolis and the healing efficacy of Artepillin C.

Green propolis is a resinous substance used in folk medicine given its anti-inflammatory, antibacterial, and anti-ulcer effects. Our research group has already confirmed the gastroprotective activity of hydroalcoholic extract from green propolis (HEGP), as well as of its main isolated compounds. In continuity, this study evaluated the antioxidant mode of action involved in the preventive effect induced by HEGP, and its therapeutic gastric healing potential on installed ulcers. In addition, the healing effect of its main compound Artepillin C was also investigated. Acute and chronic ulcers were induced in rats by given ethanol or acetic acid, respectively. In acute model, the rats were orally pre-treated with vehicle (water plus 1% Tween, 1 mL/kg), HEGP (30-300 mg/kg), or carbenoxolone (200 mg/kg) 1 h prior the ulcer induction. In the chronic ulcer protocol, the rats received vehicle (water plus 1% Tween, 1 mL/kg), HEGP (300 mg/kg), or omeprazole (20 mg/kg) twice a day by 7 days, whereas groups of mice received vehicle (water plus 1% Tween, 1 mL/kg), Artepillin C (18 mg/kg), or ranitidine (20 mg/kg) twice a day by 4 days. Ulcerated tissue was collected for histological, histochemical, immunostaining, oxidative, and inflammatory analyses. The in vitro scavenger activity of HEGP was also verified using the DPPH assay. The oral pre-treatment with HEGP (100 and 300 mg/kg) prevented the gastric epithelial damage promoted by ethanol. Besides, HEGP (100 and 300 mg/kg) reduced SOD activity about 11% and 26%, respectively, and increased the activity of GST around 20% and CAT in 80%. HEGP (300 mg/kg) also reduced the production of reactive oxygen species, as well as lipoperoxidation levels in the ethanol-ulcerated tissue. In the acetic acid-induced chronic ulcer, the daily treatment with HEGP (300 mg/kg) accelerates the healing process by 71%. In this model, HEGP normalized SOD and CAT activity and increased GST activity by 109% when compared to non-ulcerated rats. In both models, the extract administration increased the mucin PAS staining and reduced the myeloperoxidase activity at the ulcer site. Moreover, the treatment with HEGP enhanced the PCNA immunostaining, but did not alter the concentration of collagen in the acetic acid-ulcerated tissue. The extract had a direct DPPH radical-scavenging ability (LogIC50: 0.56). Besides, as expected, HPLC analysis showed Artepillin C as a major compound and its administration at 18 mg/kg also accelerated the gastric healing ulcer process in mice. Our findings confirm that HEGP displays both gastroprotective and gastric healing properties, contributing to the validation of its popular use as preventive and therapeutic approaches. These actions occur through the increase in mucin production and the reestablishment of the oxidative balance due to a reduction in gastric inflammation.

Hesperidin, a citrus flavanone glycoside, accelerates the gastric healing process of acetic acid-induced ulcer in rats.

The flavonoid hesperidin is abundantly found in citrus fruits and is used to treat vascular diseases. Previous studies described its gastroprotective actions against stress or ethanol-induced ulcer in rodents; however, results from indomethacin-induced ulcer were controversy. Therefore, given its clinical use and contradictory findings in acute models, this study aims to evaluate the effect of hesperidin (1-10 mg/kg, p.o) on chronic gastric ulcer induced by acetic acid in rats, a model that resembles the ulcer in humans. Moreover, the effects of hesperidin on mucin levels and on inflammatory and oxidative parameters at ulcer site were also measured. The treatment with hesperidin at 3 and 10 mg/kg, once a day, by seven days, accelerated by 34 and 62%, respectively, the ulcer healing process when compared to vehicle-treated group (99.1 ±â€¯6.4 mm2). Histological and histochemistry analyses confirmed the healing effect with significant favoring of mucin production. Hesperidin also promoted the preservation of reduced glutathione levels in the gastric mucosa tissue, as well as the normalization of superoxide dismutase and catalase activities at similar levels to those found in the non-ulcerated group. In addition, flavonoid administration increased the enzymatic activity of glutathione-S-transferase by 35%. Tissue lipoperoxides and myeloperoxidase activity were reduced after hesperidin treatment. In conclusion, the flavonoid hesperidin revealed a gastric healing activity in the ulcerated mucosa, an effect that showed to be associated with the reduction of oxidative damage at ulcer site, due to the reduction of the neutrophil migration and the strengthening of the mucus barrier next to the mucosa.

Hydroalcoholic extract from Baccharis dracunculifolia recovers the gastric ulcerated tissue, and p-coumaric acid is a pivotal bioactive compound to this action.

Baccharis dracunculifolia is a medicinal plant native to southeastern Brazil and is the main botanical source used by bees (Apis mellifera) in the manufacture of green propolis and display similar gastroprotective action and chemical profile. This article reports the healing gastric ulcer activity of the hydroethanolic extract of B. dracunculifolia (HEBD) in an acetic acid-induced ulcer model. In addition to the extract, the isolated compounds ferulic acid, p-coumaric acid, caffeic acid, baccharin, and aromadendrin-4'-O-methyl ether were also assayed. HEBD at a dose of 300 mg/kg reduced the ulcerated area by 49.4% after treatment for 7 days, twice a day. Histological analyses revealed that the margins and base of the ulcer obtained significant regeneration, and periodic acid Schiff base staining showed a 78.2% increase in the mucin levels. The action on the enzymatic antioxidant system demonstrated an increased activity of superoxide dismutase and glutathione-S-transferase, in addition to raising glutathione reduced levels and myeloperoxidase activity. HEBD did not show cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylterazole bromine test. In vitro, HEBD inhibited the H+ /K+ -ATPase enzyme and showed antioxidant activity in the 2,2 diphenyl-1-picryllydrazyl test. Regarding the isolated compounds, oral administration of p-coumaric acid (15 mg/kg) reduced the ulcerated area by 66.2%. The results suggest that HEBD recovers the gastric ulcerated tissue, raising mucus and antioxidant enzyme levels, and reducing the H+ /K+ -ATPase activity. In addition, the findings confirm that p-coumaric acid is a pivotal bioactive compound on the gastric healing effects elicited by HEBD. © 2019 BioFactors, 45(3):479-489, 2019.

Hydroalcoholic extract of Tagetes erecta L. flowers, rich in the carotenoid lutein, attenuates inflammatory cytokine secretion and improves the oxidative stress in an animal model of ulcerative colitis.

Given the role of oxidative stress in ulcerative colitis (UC) etiology, and the amount of lutein (a carotenoid with antioxidant properties) in the dry hydroalcoholic extract of Tagetes erecta flowers (DHETE), this study investigated the intestinal anti-inflammatory properties of DHETE in an animal model of UC. The amount of lutein in the extract was determined by 1H-nuclear magnetic resonance spectroscopy, and total phenols, radical scavenger capability, cytotoxicity, and effects on reactive oxygen species and nitric oxide production were evaluated in vitro. Experimental UC was established by adding 5% dextran sulfate sodium (DSS) to drinking water, with the effects of DHETE (30-300 mg/kg, once a day for 7 days) on the morphological (colon length and weight), clinical (disease activity index and body weight loss), microscopic (histological score and mucin levels), and biochemical parameters analyzed. The lutein concentration found in DHETE was 8.2%, and DHETE scavenged 2,2-diphenyl-1-picrylhydrazyl radicals at 1000 µg/mL The exposure of intestinal epithelial cells to DHETE did not change its viability but reduced reactive oxygen species and nitric oxide production after lipopolysaccharide stimulation. In vivo, DHETE (300 mg/kg) attenuated weight loss, disease activity index, colon shortening, and histopathological changes promoted by DSS intake. Moreover, DHETE increased mucin colonic staining. The treatment with DHETE decreased myeloperoxidase activity as well as tumor necrosis factor and interleukin-6 levels. The extract also increased reduced glutathione levels and catalase activity and normalized superoxide dismutase and glutathione-S-transferase activities. In conclusion, DHETE reduced colitis severity by attenuating inflammatory cytokine secretion and improved the endogenous antioxidant defense in DSS-induced UC in mice.