Antioxidant potentialities and gastroprotective effect of Reichardia picroides extracts on Ethanol/HCl induced gastric ulcer rats.

The goal of this study was to determine for the first time the polyphenol content, antioxidant, and gastroprotective properties of the roots and leaves of Reichardia picroides. TPC considerably varied as a function of organs and solvent nature and ranged from 50 to 284.80 mg GAE/g DW. Leaves exhibited the highest amount of phenolics by using acetone 70%, the same tendency was observed for antioxidant activity. Besides, in vivo gastro-protective effects following HCl/EtOH-induced ulcer models displayed that roots extract at a high dose (500 mg) seemed to be the best performing extract with a decrease of ulceration index (UI) and an increase in the percentage of protection (PP), SOD, CAT, and GPX activities. All these data have been proved with principal component analysis (PCA). Overall, the results indicated that R. picroides could be considered a valuable source of natural compounds, which are beneficial for human health.

Antiulcerogenic and healing activity of hecogenin acetate in rodents.

Peptic ulcers are lesions in the gastric and duodenal mucosa generated by an imbalance between protective factors (gastroduodenal mucus secretion, bicarbonate production, adequate blood flow) and harmful factors (excess pepsin or hydrochloric acid). Some drugs used in peptic ulcer therapy are associated with adverse effects. The aim of this study was to evaluate the antiulcerogenic and healing activity of hecogenin acetate (HA) in acute and chronic models of gastric lesions in rodents. The antiulcerogenic activity of HA was evaluated in models of gastric lesions induced by absolute ethanol and in acidified ethanol with HA (5, 10, and 20 mg/kg). For the model of gastric lesions induced by ischemia and reperfusion, rats were pre-treated with HA (5, 10, 20 mg/kg). After that, they were submitted to 30 min of ischemia, followed by 1 h of reperfusion. To evaluate the healing activity was induced gastric ulcer using acetic acid (80%) in rats. After 24 h, they were treated for 7 consecutive days with HA (10 and 20 mg/kg). They were evaluated the possible signs of toxicity, measurement of the lesions, collagen deposition, and histological analysis. HA significantly reduced the area of the lesion in models of gastric lesions induced by absolute and acidified ethanol, ischemia-induced gastric lesions and reperfusion, and regarding healing. In the collagen deposition, the presence and increase of collagen demonstrate the healing effect. The AH has antiulcerogenic and healing potential demonstrated by the decrease in gastric injury and presence of collagen fibers, respectively.

Anti-ulcerogenic effect of methanolic extract of Elaeagnus conferta Roxb. seeds in Wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Elaeagnus conferta Roxb. (Elaeagnaceae) is a subtropical shrub mainly native to India, Vietnam, Malaysia and South China, whose various parts are used for treatment of diabetes, gastric ulcers, pain, oxidative stress and pulmonary disorders. Though the other parts of the plant have been reported for their ethnic use i.e. fruits as astringent locally and for cancer systemically, leaves for body pain and flowers for pain in chest and the seeds are mentioned as edible, there is no report per se on the medicinal use of seeds. Based on the fact that seeds of closely resembling species i.e. Elaeagnus rhamnoides has demonstrated significant anti-gastroulcerative property, the probability of the seeds of E. conferta possessing similar activity seemed quite significant. AIM OF THE STUDY: Phytochemical investigation and assessment of pharmacological mechanism(s) involved in anti-ulcer effect of methanolic extract of the seeds of E. conferta. MATERIALS AND METHODS: Bioactive phytoconstituents were isolated by column chromatography. These were identified by spectroscopic techniques including infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) and mass spectrometry. Methanolic extract (MEC) of the seeds was prepared by cold maceration and its anti-ulcerogenic potential was evaluated using indomethacin (50 mg/kg) and water immersion stress models in male rats. The animals were pre-treated with different doses of MEC (400 and 800 mg/kg) and the therapeutic effect was compared with standard drug i.e. ranitidine (RANT; 50 mg/kg). The ameliorative effects of MEC were investigated on gastric juice pH, total acidity, free acidity and ulcer index. The assays of malionaldehyde (MDA), catalase (CAT), superoxide dismutase (SOD), glutathione (GSH) and pro-inflammatory cytokines i.e. interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were carried out to find out the possible mechanism(s) of protection. Further, histopathological changes were also studied. RESULTS: Chromatography studies and further confirmation by spectroscopic techniques revealed the presence of four different compounds in MEC i.e oleic acid (1), stearic acid (2), ascorbic acid (3) and quercetin (4). MEC exhibited anti-ulcerogenic effect in dose dependent manner which may be attributed to suppression of pro-inflammatory cytokines (IL-6, TNF-α) and MDA (112.7%), and up-regulation of protective factors such as CAT (90.48%), SOD (92.77%) and GSH (90.01%). Ulcer inhibition, reduction in total and free acidity and increase in gastric juice pH were observed in MEC treated rats as compared to disease control animals. Histopathological findings confirmed decreased cell infiltration, less epithelial cell damage and regeneration of gastric mucosa in dose dependent manner. CONCLUSIONS: The anti-ulcer effect of MEC may be attributed to its ability to scavenge free radicals and anti-inflammatory property via suppression of TNF-α and IL-6, thus offers a complete and holistic approach for management of peptic ulcer.

Tablet of Spondias mombin L. Developed from Nebulized Extract Prevents Gastric Ulcers in Mice via Cytoprotective and Antisecretory Effects.

Spondias mombin L. (Anacardiaceae) has a worldwide distribution and is present in all regions of Brazil. Its leaves, flowers and bark are used as teas in folk medicine to treat diseases of the digestive system. This study aimed to evaluate the acute non-clinical toxicity, gastroprotective activity, and the related mechanisms of action of nebulized extract and tablets based on dried Spondias mombin (SmNE). SmNE screening showed the presence of flavonoids (0.65%), polyphenols (25.50%), where the major compound is gallic acid. In the acute oral toxicity assay, a dose of 2000 mg/kg of SmNE administered orally in Swiss mice did not induce any behavioral changes. SmNE (250 or 500 mg/kg p.o) significantly reduced the ulcerative lesion area when compared to the control group in ethanol and non-steroidal anti-inflammatory drug (NSAIDs) models. Results showed that treatment with SmNE (250 mg/kg) reduced acid secretion and gastric content, accompanied with an increase in pH. Previous administration of indomethacin and glibenclamide reversed the protection provided by SmNE, confirming the participation of prostaglandins (PGs) and ATP-sensitive potassium channels (KATP) in its gastroprotective effect. The SmNE tablets met the pharmacopeial quality requirements with gastroprotective activity and similar protection in comparison to the isolated extract administrated. In conclusion, SmNe has a gastroprotective activity related to cytoprotective mechanisms, such as the participation of endogenous prostaglandins and KATP channels, having an anti-secretory effect with systemic action. The formulation obtained presented gastroprotective effects similar to the administration of the extract, the tablets showed favorable compression characteristics by the direct route and met the pharmacopeial quality requirements.

The essential oil from Baccharis trimera (Less.) DC improves gastric ulcer healing in rats through modulation of VEGF and MMP-2 activity.

ETHNOPHARMACOLOGICAL RELEVANCE: Baccharis trimera (Less.) DC known as "carqueja" in Brazil has been acknowledged as a medicinal plant in folk medicine for the treatment of stomach aches and gastrointestinal disorders. AIM OF THE STUDY: The present study aimed to evaluate the gastroprotective and healing effects of essential oil from B. trimera (EOBT) against gastric ulcer lesions caused by absolute ethanol and acetic acid, respectively, and to identify the mechanism of action of this essential oil in male Wistar rats. MATERIALS AND METHODS: The plant material used to obtain EOBT was collected in the southern region of Brazil and was analyzed by chromatography-mass spectrometry (GCMS) demonstrate its characteristic chemical composition, with carquejyl acetate as its main component. Different doses of EOBT (50, 100, and 200 mg/kg) were administered orally in male Wistar rats as an acute treatment against absolute ethanol-induced gastric lesions. The gastric healing effect of EOBT (100 mg/kg) was evaluated once a day after 7, 10, and 14 days of treatment. After treatment, the stomachs of rats from all groups were collected to measure the lesion area (mm2), the activity of myeloperoxidase (MPO), and the relative expression of caspases -3, -8, -9, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). The zymography method was used to elucidate the activity of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) in the healing action of EOBT. We also analyzed toxicological parameters (body weight evolution and biochemical parameters) that could result after treatment with this essential oil for 14 days. RESULTS: Pretreatment with EOBT (100 and 200 mg/kg) significantly decreased the severity of gastric damage induced by absolute ethanol and decreased MPO activity in gastric tissue. After 10 and 14 days of treatment with EOBT (100 mg/kg) once a day, the lesion area was significantly reduced by 61% and 65.5%, respectively, compared to the negative control group. The gastric healing effect of EOBT was followed by a decrease in the expression of COX-1 compared to that in the negative control group. Notably, treatment with EOBT for 14 days increased the expression of VEGF compared to that using an anti-ulcer drug (lansoprazole). Additionally, analyses of MMP-2 and MMP-9 activities in the gastric mucosa confirmed the accelerated gastric healing effect of EOBT, with a significant decrease in the activity of pro-MMP-2. No sign of toxicity was observed after treatment with EOBT for 14 consecutive days. CONCLUSION: These findings indicated that EOBT was effective in preventing and accelerating ulcer healing by decreasing MPO activity, increasing VEGF expression, and decreasing MMP-2 activity. These actions collectively contribute to the rapid recovery of gastric mucosa following treatment with EOBT, without any observed toxicity.

Umbelliferone (7-hydroxycoumarin): A non-toxic antidiarrheal and antiulcerogenic coumarin.

Gastrointestinal diseases are very common problems; available treatments are very limited and come with a range of side effects. Coumarins are an extensive class of phenolic compounds that can be found in plants, fungi and bacteria. The 7-hydroxycoumarin, also known as umbelliferone (UMB), is a compound that comes from coumarin and has been showing biological activities in other studies. As of this scenario, the present study was designed to evaluate the acute oral toxicity, mutagenic, antidiarrheal, anti-bacterial, and antiulcerogenic effects, and antioxidant capacity of UMB. An investigation was conducted through the hippocratic screening method and through histopathological analysis in animals to evaluate the effects of acute oral administration of a dose of 50, 100 and 200 mg/kg of UMB. A micronucleus test on peripheral blood of Swiss mice, which were orally treated with three doses (50, 100 and 200 mg/kg), was conducted to evaluate mutagenic activities. The antiulcerogenic activity was accomplished through the ethanol-induced damage method. Antidiarrheal activities were tested for inducing diarrhea with castor oil and evaluating intestinal transit duration; additionally, the antimicrobial effect against some enteropathogenic bacteria was analyzed. Finally, the antioxidant capability was determined by the capacity of the UMB sample to kidnap the stable radical 2,2-diphenyl-1-picrylhydrazyl. Of the evaluated doses, signs of toxicity after acute administration of the compound were not observed. UMB presented antiulcerogenic activity (100 and 200 mg/kg), which was explained because of its antioxidant capacity. A gastro protective effect was similar to the positive control, and the UMB was able to significantly reduce intestinal transit, and also diarrheal symptoms. Furthermore, UMB had an anti-bacterial effect with minimum inhibitory concentration fluctuating between 62.5 and 1000 µg/mL. Based on these findings, we can suggest that UMB has important biological activities in vivo and in vitro and is not toxic under the evaluated circumstances, which demonstrates its large potential for pharmacological use.

Preclinical development of gastro-protective botanical candidate from Woodfordia fruticosa (Linn.) Kurz: Chemical standardization, efficacy, pharmacokinetics and safety pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Woodfordia fruticosa is traditionally used in the Ayurvedic system of medicine for the treatment of diarrhoea, poisoning, menstrual disorders, ulcers and fertility. In the present study, we report a standardized extract preparation through modern scientific approach for anti-ulcer activity. MATERIALS AND METHODS: The hydro-alcoholic extract of flowers of W. fruticosa was standardized using four chemical markers. The standardized extract was coded as ICB014. HPLC method was developed for identification and quantification of Gallic Acid, Oenothein-C, Quercetin and Kaempferol. Based on the prior published H+, K+-ATPase activity and Anti-bacterial activity against Helicobacter pylori of ICB014, was evaluated for its in-vivo efficacy in gastric ulcers models in rats followed by regulatory safety studies. RESULTS: The extract demonstrated efficacy at 31.25-62.5 mg/kg in gastric ulcer models. The extract was safe by oral route up to 2000 mg/kg in a single dose and NOAEL of 800 mg/kg in 28 days repeat study. Bioequivalent capsule formulation was prepared. CONCLUSIONS: The extract showed anti-ulcer potential and is ready for clinical evaluation.

Synthesis, biological evaluation and docking study of N-(2-(3,4,5-trimethoxybenzyl)benzoxazole-5-yl) benzamide derivatives as selective COX-2 inhibitor and anti-inflammatory agents.

A series of N-(2-(3,4,5-trimethoxybenzyl)-benzoxazole-5-yl)benzamide derivatives (3a-3n) was synthesized and evaluated for its in vitro inhibitory activity against COX-1 and COX-2. The compounds with considerable in vitro activity (IC50 < 1 µM), were evaluated in vivo for their anti-inflammatory and ulcerogenic potential. Out of the fourteen newly synthesized compounds; 3b, 3d, 3e, 3h, 3l and 3m were found to be most potent COX-2 inhibitors in in vitro enzymatic assay with IC50 in the range of 0.14-0.69 µM. In vivo anti-inflammatory activity of these six compounds (3b, 3d, 3e, 3h, 3l and 3m) was assessed by carrageenan induced rat paw edema method. The compound 3b (79.54%), 3l (75.00%), 3m (72.72%) and 3d (68.18%) exhibited significant anti-inflammatory activity than standard drug ibuprofen (65.90%). Ulcerogenic activity with histopathological studies was performed, and the screened compounds demonstrated significant gastric tolerance than ibuprofen. Molecular Docking study was also performed with resolved crystal structure of COX-2 to understand the interacting mechanisms of newly synthesized inhibitors with the active site of COX-2 enzyme and the results were found to be in line with the biological evaluation studies of the compounds.

Gastro-protective, therapeutic and anti-inflammatory activities of Pistacia lentiscus L. fatty oil against ethanol-induced gastric ulcers in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Pistacia lentiscus L. (Anacardiaceae) (PL) is a flowering plant that grows in the Mediterranean area. It is traditionally used in the treatment of various skin, respiratory and gastrointestinal disorders AIM OF THE STUDY: In the present study, we investigated the anti-ulcerogenic activity of Pistacia lentiscus fatty oil (PLFO) on ethanol-induced gastric ulcers in Wistar rats MATERIAL AND METHODS: PLFO was orally administered to two experimental groups of rats before or after ethanol induction of gastric ulcer. The lesions of the gastric mucosa were evaluated by macroscopic and histopathological examination. In addition, the amount of nitric oxide (NO) and pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the supernatant from cultures of gastric mucosa explants were assessed. Finally, the mucus production and iNOS (inducible NO synthase) expression were determined by histochemical and immunohistochemical analysis, respectively RESULT: Our results indicated that the PLFO pretreatment or PLFO treatment significantly reduced ulcerated and hemorrhagic areas. Additionally, pretreatment or treatment with PLFO after ethanol-induced ulceration significantly reduced the plasma concentration of NO. Furthermore, a significant decrease of NO, IL-6 and TNF-α levels was observed in explant culture supernatants. iNOS expression was also reduced in the gastric mucosa. In contrast, mucus production by goblet cells was enhanced. Interestingly, histological analysis of the gastric mucosa has indicated that PLFO- pretreated and treated groups displayed normal histology CONCLUSION: Our results demonstrate that PLFO display significant prophylactic and therapeutic effects against gastric ulcers. Importantly, the mechanism underlying PLFO activities might implicate inhibition of inflammatory responses during gastric ulcer.

Anti-inflammatory activity and gastroprotective effect of Hertia cheirifolia L. roots extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Hertia cheirifolia L. is used traditionally to treat rheumatic pains and known as a medicinal plant having several pharmaceutical and biological activities. The present study evaluated in vivo the anti-inflammatory and gastroprotective effects of the methanolic extract from H. cheirifolia L. MATERIALS AND METHODS: Reverse phase high-performance liquid chromatography (RP-HPLC) was performed to identify various chemical components of the plant extract. Anti-inflammatory and gastroprotective activities were assessed on carrageenan-induced paw edema and HCl/ethanol-induced gastric lesions in rats, respectively. RESULTS: (RP-HPLC) analysis indicated that coumarin is the abundant component in the extract (53.80%). Intraperitoneal administration of the methanolic extract at different doses showed interesting activities in rats in a dose-dependent manner. At 100 mg/kg, this extract showed the highest acute anti-inflammatory activity and an important inhibition of gastric lesions with inhibition percentage of 79.41% and 88.53%, respectively. CONCLUSION: Altogether, the results of this study reveal the anti-inflammatory and gastroprotective effects of H. cheirifolia extract and promote the traditional use of this plant in the treatment of different pain and inflammatory diseases.

Pharmacological activities of the organic extracts and fatty acid composition of the petroleum ether extract from Haplophyllum tuberculatum leaves.

ETHNOPHARMACOLOGICAL RELEVANCE: Haplophyllum tuberculatum is used in traditional medicine to treat many disorders including inflammation and pain. The aim of this study is to investigate the organic extracts from H. tuberculatum leaves against inflammation, gastric ulcer and pain. MATERIALS AND METHODS: Acute toxicity was studied in vivo to determine the toxic doses of the organic extracts. Anti-inflammatory activity was also evaluated in vivo using carrageenan-induced paw edema in Wistar rats. Gastroprotective activity was tested using the HCl/ethanol-induced gastric ulcer test in rats. Peripheral and central analgesic activities were assessed using the acetic acid-induced writhing test and the hot-plate method, respectively. The chemical composition of the fatty acids in the petroleum ether (PE) extract was determined with GC-MS. RESULTS: At 25, 50 and 100mg/kg PE extract was the most active against inflammation. Percentages inhibition 5h after carrageenan-injection were 51.12; 86.71% and 96.92%, respectively. The same extract at 100mg/kg showed good analgesic activities using the acetic acid-induced writhing test and the hot-plate method. The chloroform, ethyl acetate (EtOAc) and butanolic (n-BuOH) extracts exhibited strong anti-inflammatory, gastroprotective and analgesic activities at 100mg/kg. The GC-FID analysis revealed that the PE extract was rich in γ-linolenic acid (45.50%) followed by palmitic acid (18.48%), linoleic acid (10.73%), erucic acid (4.72), stearic acid (3.96%) and oleic acid (2.57%). CONCLUSION: The results of the present study support the traditional use of the leaves of H. tuberculatum and may possibly serve as prospective material for further development of safe new phytochemical anti-inflammatory, gastroprotective and/or analgesic agents.

Antiulcer activity of methanol-chloroform extract of Channa striatus fillet.

Channa striatus (Haruan) is Malaysian freshwater fish that is traditionally used to treat ailments related to wound and also ulcers. The aimed of the present study was to determine the mechanisms of anti-ulcer activity of chloroform: methanol extract of C. striatus fillet (CMCS) in rats. The antiulcer profile of CMCS, given orally in the doses of 50, 250 and 500mg/kg, was assessed using the ethanol- and indomethacin-induced gastric ulcer models. The mechanisms of antiulcer of CMCS were determined as follows; i) the antisecretory activity of CMCS was measured using the pyloric ligation rat model, and; ii) the role of nitric oxide (NO) and sulfhydryl compounds in the modulation of CMCS antiulcer activity were determined by pre-treating the rats with L-NAME or NEM, respectively, followed by the pre-treatment of rats with CMCS before subjecting the animals to the ethanol-induced gastric ulcer model. From the results obtained, CMCS exerted significant (P<0.05) antiulcer activity in both models of gastric ulcer wherein the macroscopic and microscopic analysis of the stomach supported the antiulcer claim. With regard to its antisecretory effect, CMCS did not change the volume and pH, but reduce the total acidity only at the lower doses of the gastric juice. Moreover, CMCS demonstrated antiulcer activity was reversed by NEM, but not affected by L-NAME. In conclusion, CMCS shows antiulcer activity that is modulated via its cytoprotective, but not antisecretory effect, and in the presence of sulfhysryl compounds, but not NO.

Chemical characterization, toxicology and mechanism of gastric antiulcer action of essential oil from Gallesia integrifolia (Spreng.) Harms in the in vitro and in vivo experimental models.

Gallesia integrifolia is a Brazilian Amazon tree whose bark decoction is popularly used to treat peptic ulcer. The essential oil from the inner stem bark of G. integrifolia (EOGi) was chemically characterized by GC/MS. The in vitro cytotoxicity and genotoxicity were evaluated in CHO-K1 cells, while the in vivo oral acute toxicity was performed in mice. The gastroprotective effect of EOGi was assessed in acidified ethanol and piroxicam and ulcer healing on acetic acid -induced ulcer models in rodents. Anti-secretory, mucus, K+-ATP channels, prostaglandins (PGs), nitric oxide (NO), TNF-α, IL-1ß, IL-10, catalase (CAT) and myeloperoxidase (MPO) activities and in vitro Helicobacter pylori action by EOGi were evaluated. EOGi exhibited cytotoxic effects only at 72h and no acute toxicity. EOGi showed gastroprotective and ulcer healing effects. EOGi gastroprotection was attenuated by indomethacin pre-treatment. Gastric volume and total acidity were reduced, while gastric pH was elevated. EOGi increased mucus and NO productions and CAT activity, and inhibited MPO activity, TNF-α and IL-1ß concentrations and augmented IL-10. EOGi was not active against H. pylori. These results indicated that EOGi is safe and exerts preventive and curative gastric ulcer effects by multitarget actions. Twenty compounds were identified and (-)-alpha-santalene was the main compound.

Gastroprotective activity of the resin from Virola oleifera.

CONTEXT: The resin from the trunk wood of Virola oleifera (Schott) A. C. Smith (Myristicaceae) is used in folk medicine to hasten wound repair and to treat pain and inflammatory conditions, and our previous report indicated the anti-oxidative properties in other oxidative stress model. OBJECTIVE: To investigate the protective effects of resin from V. oleifera in two experimental models of gastric ulcer oxidative-stress dependent. MATERIALS AND METHODS: Plant material was collected and the resin was subjected to partitioning with organic solvents. The buthanol fraction was subjected to chromatographic and spectrometric methods for isolation and structural elucidation. The resin was quantified for polyphenols and flavonoids by colorimetric methods. Furthermore, the antioxidant activity of resin was determined by three different methods. The ulcers were induced acutely in Swiss male mice with ethanol/HCl and indomethacin using single-doses of 10 and 100 mg/kg. The gastroprotection of the experimental groups was comparable to reference control lansoprazole (3 mg/kg). RESULTS: The high content of polyphenols (∼82%) and the presence of epicatechin and eriodictyol were determined. The LD50 was estimated at 2500 mg/kg. At minimum (10 mg/kg) and maximum (100 mg/kg) dosage of resin, both in ethanol/HCl as indomethacin ulcer induction models demonstrate reduction of lesions (minimum: ∼97% and ∼66%; maximum: ∼95% and ∼59%). DISCUSSION: The gastroprotection might be related to tannins, phenolic acids and flavonoids present in the resin by antioxidant properties. CONCLUSIONS: The results indicate that this resin has gastroprotective activity probably associated with the presence of phenolic antioxidant substances.

Hydroethanolic extract of Baccharis trimera promotes gastroprotection and healing of acute and chronic gastric ulcers induced by ethanol and acetic acid.

Ethanol is a psychoactive substance highly consumed around the world whose health problems include gastric lesions. Baccharis trimera is used in folk medicine for the treatment of gastrointestinal disorders. However, few studies have evaluated its biological and toxic effects. To validate the popular use of B. trimera and elucidate its possible antiulcerogenic and cytotoxic mechanisms, a hydroethanolic extract of B. trimera (HEBT) was evaluated in models of gastric lesions. Rats and mice were used to evaluate the protective and antiulcerogenic effects of HEBT on gastric lesions induced by ethanol, acetic acid, and chronic ethanol consumption. The effects of HEBT were also evaluated in a pylorus ligature model and on gastrointestinal motility. The LD50 of HEBT in mice was additionally estimated. HEBT was analyzed by nuclear magnetic resonance, and a high-performance liquid chromatography fingerprint analysis was performed. Oral HEBT administration significantly reduced the lesion area and the oxidative stress induced by acute and chronic ethanol consumption. However, HEBT did not protect against gastric wall mucus depletion and did not alter gastric secretory volume, pH, or total acidity in the pylorus ligature model. Histologically, HEBT accelerated the healing of chronic gastric ulcers in rats, reflected by contractions of the ulcer base. Flavonoids and caffeoylquinic acids were detected in HEBT, which likely contributed to the therapeutic efficacy of HEBT, preventing or reversing ethanol- and acetic acid-induced ulcers, respectively. HEBT antiulcerogenic activity may be partially attributable to the inhibition of free radical generation and subsequent prevention of lipid peroxidation. Our results indicate that HEBT has both gastroprotective and curative activity in animal models, with no toxicity.

Acute Toxicity and Gastroprotection Studies of a New Schiff Base Derived Manganese (II) Complex against HCl/Ethanol-Induced Gastric Ulcerations in Rats.

Manganese is a crucial element for health. In this study, the gastroprotective efficacy of Mn (II) complex (MDLA) against acidified ethanol (HCl/Ethanol)-induced gastric ulceration in rats was evaluated. The animals were distributed into 5 groups. Groups 1 and 2 received carboxymethylcellulose (CMC), group 3 was pretreated with omeprazole, and groups 4 and 5 were given 10 and 20 mg/kg of MDLA, respectively. After one hour, CMC and HCl/Ethanol were given to groups 2-5 whilst the animals in group 1 were ingested with CMC. After sacrifice, gastric lesions were evaluated by wall mucus, gross appearance, histology, antioxidant enzymes and immunohistochemistry. Group 2 displayed severe gastric damage with a significant reduction in wall mucus. Conversely, gastric lesions were reduced in groups 3-5 by 85.72%, 56.51% and 65.93%, respectively. The rats in groups 3-5 showed up-regulation of heat shock protein 70 (Hsp70) with down-regulation of Bcl-2-associated protein x (Bax). Pretreatment with omeprazole or MDLA led to an increase in the uptake of Periodic Acid Schiff (PAS) stain in the glandular part of the gastric tissue, raised levels of prostaglandin E2 (PGE2) and superoxide dismutase (SOD), and a reduction in malondialdehyde (MDA) concentrations. These results suggested the gastroprotective action of Mn (II) complex.

Aqueous extract of Senecio candicans DC induce liver and kidney damage in a sub-chronic oral toxicity study in Wistar rats.

Senecio candicans DC. (Asteraceae) is used as a remedy for gastric ulcer and stomach pain in the Nilgiris, district, Tamil Nadu. The present investigation was carried out to evaluate the sub-chronic toxicity of an aqueous extract of Senecio candicans (AESC) plant in Wistar albino rats. The study was conducted in consideration of the OECD 408 study design (Repeated Dose 90-Day Oral Toxicity Study in Rodents) and the extract was administered via gavage at doses of 250, 500 or 750 mg/kg body weight per day for 90-days. Hematological, biochemical parameters were determined on days 0, 30, 60 and 90 of administration. Animals were euthanized after 90 d treatment and its liver and kidney sections were taken for histological study. The results of sub-chronic study showed significant increase (P < 0.05) in serum uric acid, creatinine, aspartate transaminase (AST) and alanine transaminase (ALP) levels. Histological examination of liver showed mild mononuclear infiltration in the portal trait, enlarged nucleus around the central vein and mild loss of hepatocyte architecture in rats treated with 750 mg/kg of AESC. Histological examination of kidney showed focal interstitial fibrosis, crowding of glomeruli and mild hydropic change with hypercellular glomeruli in rats treated with 750 mg/kg of AESC. However, no remarkable histoarchitectural change in hepatocytes and glomeruli were observed in rats treated with lower concentrations (250 and 500 mg/kg b.w.) of AESC compared to control group animals. The no-observed adverse effect level (NOAEL) of AESC in the present study was 500 mg/kg b.w. Signs of toxic effects are evident from the current study. Although AESC contains low concentrations of PA, findings from this study suggest that regular consumers of herbal remedies derived from this plant may develop kidney and liver toxicity. Further studies on the isolation and characterization of PAs are necessary to determine the safe dose level of the extract for therapeutic use in traditional medicine.

Does the gastroprotective action of a medicinal plant ensure healing effects? An integrative study of the biological effects of Serjania marginata Casar. (Sapindaceae) in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Serjania marginata (Sapindaceae), a medicinal plant commonly found in the Brazilian Cerrado, Paraguay, Bolivia and Argentina, is also known as "cipó-uva" or "cipó-timbó". Ethnopharmacological studies indicate that the leaves from this medicinal plant are used in folk medicine to treat gastric pain. The overall objective of this study was to evaluate the gastroprotective and healing effect of the hydroalcoholic extract obtained from S. marginata (HESM) leaves using rodent experimental models. As part of the integrative study of this medicinal plant, we also evaluated the acute toxicity, antimicrobial, antidiarrheal, (anti)mutagenic, and hemodynamic effects. MATERIAL AND METHODS: We performed a pharmacological study to test the acute toxicity and antimutagenic effect (Ames assay) of the HESM. The HESM was tested against different necrosis-promoting agents and experimental manipulations, such as absolute ethanol, cysteamine, pyloric ligature, and ischemia-reperfusion (I/R) injury. The gastroprotective effect of the HESM was assessed by analyzing the gastric juice (volume, pH, total acidity) and the mucus in the gastric mucosa from rats. We assessed the levels of NO, sulfhydryl compounds, PGE2, vanilloid receptor, glutathione (GSH), and malondialdehyde (MDA), as well as the myeloperoxidase (MPO) activity. The gastric healing effects of the HESM were evaluated during 7 or 14 days of treatment. The intestinal motility, antidiarrheal action, and antibacterial effects (microdilution methods) of the HESM were also evaluated. RESULTS: The phytochemical analysis of the HESM revealed the presence of saponins, flavonoid glycosides, and tannins. The extract exhibited no sign of acute toxicity or mutagenic effect in vitro. In contrast, this extract exhibited a protective effect against the mutagenic action of direct- and indirect-acting mutagens. Only the oral administration of HESM (250mg/kg) significantly decreased the severity of gastric damage induced by ethanol (60.13%) and I/R (58.31%). The HESM exerts its gastroprotective effects by decreasing the MPO and MDA activities in the gastric tissue and by increasing the amount of adherent mucus covering the gastric mucosa. In vitro, the extract also displayed evident antimicrobial effects against Helicobacter pylori. However, the preventive effect of the HESM was not accompanied by an ulcer-healing effect. The treatment with HESM (14 days) significantly increased gastric lesions in 99% of the tested animals compared with the control group. This result represents a highly relevant piece of evidence that should resonate as an alert against the chronic use of this medicinal plant as an antiulcer in folk medicine. CONCLUSIONS: Despite the anti-H. pylori and gastroprotective actions of S. marginata in experimental models, the gastric injuries aggravation induced after chronic treatment with the HESM argues against the use of this plant species in folk medicine.

Cimetidine-induced Leydig cell apoptosis and reduced EG-VEGF (PK-1) immunoexpression in rats: Evidence for the testicular vasculature atrophy.

The antiulcer drug cimetidine has shown to cause changes in the testicular microvasculature of adult rats. Since Leydig cells (LCs) produce the pro-angiogenic factor, EG-VEGF (endocrine gland-derived vascular endothelial growth factor), also known as prokineticin 1 (PK-1), this study examined the effect that cimetidine might have on LCs in testes with damaged vasculature. Rats received intraperitoneal injections of 100mg/kg of cimetidine (cimetidine group) or saline vehicle (control group) for 50 days. Serum testosterone levels were measured by chemiluminescence immunoassay and testicular sections were subjected to TUNEL and immunohistochemical reactions for caspase-3, 17ß-HSD6, CD163 (ED2 macrophage), PK-1 and androgen receptor (AR). LCs in the cimetidine group showed TUNEL and caspase-3 positive labeling and apoptotic ultrastructural features. Moreover, the presence of 17ß-HSD6-positive inclusions inside macrophages and the reduced number of LCs, AR immunoreactivity and serum testosterone levels correlated with a decrease in either the number of PK-1-immunostained LCs or PK-1 immunoreactivity. Although it is not clear which cell type is the primary target of cimetidine in the testicular interstitial compartment, these findings support a direct link between cimetidine-induced testicular vascular atrophy and LCs damage.

Antiulcerogenic activity of Carica papaya seed in rats.

The purpose of the present study was to evaluate the gastroprotective and healing effects of the methanolic extract of the seed of the papaya Carica papaya L. (MECP) in rats. Models of acute gastric ulcer induction by ethanol and indomethacin and of chronic ulcer by acetic acid were used. The gastric juice and mucus parameters were evaluated using the pylorus ligation model, and the involvement of sulfhydryl compounds (GSH) and nitric oxide in the gastroprotective effect was analyzed using the ethanol model. The toxicity was assessed through toxicity tests. No signs of toxicity were observed when the rats received a single dose of 2000 mg/kg of extract. The MECP in doses of 125, 250, and 500 mg/kg significantly reduced the gastric lesion with 56, 76, and 82 % inhibition, respectively, and a dose of 30 mg/kg lansoprazole showed 79 % inhibition in the ethanol model. MECP (125, 250, 500 mg/kg) and cimetidine (200 mg/kg) reduced the gastric lesion in the indomethacin model, with 62, 67, 81, and 85 % inhibition, respectively. The MECP (500 mg/kg) and cimetidine (200 mg/kg) treatments showed a reduction in ulcerative symptoms induced by acetic acid by 84 and 73 %, respectively. The antiulcerogenic activity seems to involve GSH because the inhibition dropped from 72 to 13 % in the presence of a GSH inhibitor. Moreover, the MECP showed systemic action, increasing the mucus production and decreasing gastric acidity. Treatments with MECP induce gastroprotection without signs of toxicity. This effect seems to involve sulfhydryl compounds, increased mucus, and reduced gastric acidity.