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The co-administration of 3α-hydroxymasticadienoic acid (3α-OH MDA) and diligustilide (DLG) generates a synergist gastroprotective effect on indomethacin-induced gastric damage. However, the related protective activities of the compounds alone (or in combination) remain unclear. In the present study, we evaluated the anti-inflammatory and antioxidative activities, as well as the potential modulation of important gasotransmitters of each compound individually and in combination using the indomethacin-induced gastric damage model. Male Wistar rats were treated orally with the 3α-OH MDA, DLG, or their combination (at a fixed ratio of 1:1, 1:3, and 3:1) 30 min before the generation of gastric mucosal lesions with indomethacin (30 mg/kg, p.o.). Three hours later, the gastric injury (mm2) was determined. Results from these experiments indicate, in addition to maintaining basal levels of PGE2, the gastroprotective effect of the pre-treatment with 3α-OH MDA (70%), DLG (81%), and their combination (72%) which was accompanied by significant decreases in leukocyte recruitment, as well as decreases in TNF-α and LTB4 gastric levels (p

The roots of Ligusticum porteri J.M. Coult. & Rose, Apiaceae, are used in Mexican traditional medicine for the treatment of gastrointestinal disorders. The dimeric phthalide (Z´)-diligustilide found in their organic extracts is associated with the gastroprotective properties. In this study, the gastroprotective effect of nanoemulsion of the volatile oil from the roots of L. porteri (at doses of 1, 3, 10, and 30 mg/kg) in the indomethacin-induced gastric damage model was tested, and nitric oxide (NO) and hydrogen sulfide (H2S) gastric levels were determinate. The volatile oil obtained by steam distillation (0.63% yield) contained 37 constituents, as assessed by GC-MS analysis, where the significant compounds were 4-phenyl-3-buten-2-ol (20.54%) and (Z)-3-butylidenephthalide (20.54%) that correspond to phthalide monomers. These results demonstrate that nanoemulsion of the volatile oil from L. porteri (at 10 and 30 mg/kg) shows a significant gastroprotective effect (72 and 92% respectively) against indomethacin-induced gastric damage, which is not different from the gastroprotective effect of omeprazole (69%) (p

Introduction The development of electrochemical sensors for the detection of small molecules has already had a significant effect on the study of biology because of their selectivity and ability to measure low concentrations of small molecules that regulate various functions in living organisms. Hydrogen sulfide (H2S) is a gasotransmitter produced at low levels in several tissues including the stomach. Here, we propose a new method for detecting low concentrations of this transmitter in the rat stomach, in-vivo and in real time, with applications in pharmacology and physiology. Methods Wistar rats fasted for 12 h. Then, the control group was given an intragastrical dose of saline. l -Cysteine (50 mg/kg) or dl -propargylglycine (50 mg/kg) were administered to the test groups to modify the H2S levels. Ranitidine (50 mg/kg), omeprazole (40 mg/kg) or carbenoxolone (30 mg/kg) were used as reference anti-ulcer drugs. Thirty minutes later, the electrode was inserted in the middle of the stomach cavity of the anesthetized animals. The basal levels of H2S were recorded every 5 min for 30 min. Next, gastric lesions were induced with pure ethanol, and the recording continued for 30 additional minutes. Results The exogenous administration of an H2S precursor ( l -cysteine) increased the level of this gasotransmitter whereas dl -propargylglycine, a selective inhibitor of the enzyme cystathionine γ lyase, reduced the total concentration of H2S. The administration of carbenoxolone, a gastroprotective, increased the total amount of H2S. However, the administration of the anti-secretors omeprazole and ranitidine did not modify the total concentration of H2S. Discussion This work provides the basis for a real-time analysis of the changes in-vivo of the gasotransmitter H2S in the normal and injured stomach and the exploration of the effect of drugs on the regulation of H2S.

(Z,Z’)-Diligustilide (DLG) or levistolide A is a dimeric phthalide isolated from Ligusticum porteri (Osha), the roots of which are used in the traditional treatment of many diseases including gastric aches. However, its action has not been completely elucidated. We analyzed the contributions of hydrogen sulfide and S-nitrosothiols to the action of DLG. Animals were pretreated with freshly formed in vitro nitrosothiol using Na2S and sodium nitroprusside to elucidate participation in the action of DLG. We also evaluated the production of H2S in vivo and in real time on the stomach via a specific electrode introduced into the stomachs of anaesthetized animals pretreated with DLG. Treatment with 10 mg/kg DLG increases gastric H2S production in vivo from 7.8 ± 0.81 ppm to 13.1 ± 3.01 ppm and prevents the decrease in gastric injury caused by absolute ethanol. In addition, it maintains endogenous concentrations of GSH and NO·. Exogenous S-nitrosothiols protect the gastric mucosa from damage, suggesting that the action of DLG might be associated with S-nitrosothiol and H2S formation.

The study of pharmacological interactions between herbal remedies and conventional drugs is important because consuming traditional herbal remedies as supplements or alternative medicine is fairly common and their concomitant administration with prescribed drugs could either have a favorable or unfavorable effect. Therefore, this work aims to determine the pharmacological interactions of a turmeric acetone extract (TAE) and its main metabolite (curcumin) with common anti-ulcer drugs (ranitidine and bismuth subsalicylate), using an ethanol-induced ulcer model in Wistar rats. The analysis of the interactions was carried out via the Combination Index-Isobologram Equation method. The combination index (CI) calculated at 0.5 of the affected fraction (fa) indicated that the TAE or curcumin in combination with ranitidine had a subadditive interaction. The results suggest that this antagonistic mechanism is associated to the mucoadhesion of curcumin and the TAE, determined by rheological measurements. Contrastingly, both the TAE and curcumin combined with bismuth subsalicylate had an additive relationship, which means that there is no pharmacological interaction. This agrees with the normalized isobolograms obtained for each combination. The results of this study suggest that mucoadhesion of curcumin and the TAE could interfere in the effectiveness of ranitidine, and even other drugs.

The gastroprotective effect of a turmeric acetone extract (TAE) (Curcuma longa L. [Zingiberaceae]) was evaluated and compared against its major curcuminoids; curcumin (CUR), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC). Additionally, to demonstrate the importance of the metabolites’ ratio in the extract on the synergistic effect, different mixtures were evaluated. An ethanol-induced gastric injury model was used to evaluate the gastroprotection activity in Wistar rats. The pharmacologic interaction analysis was performed using the Combination Index (CI)-Isobologram Equation method. The CI calculated at 0.5 of affected fraction (fa) for the TAE indicated a synergistic interaction between its components. However, when the proportion of curcuminoids changed from 3.7:1:10 in TAE to a 1:1:1 ratio, the CI implied an antagonistic effect. The binary combinations of curcuminoids (1:1) also showed an antagonistic interaction. The results of this work suggest that the proportion of curcuminoids in the TAE is crucial for the gastroprotective effect against ethanol-induced damage.

The aims of the study were to evaluate the pharmacodynamic interaction between 3α-hydroxymasticadienonic acid and diligustilide (DLG), isolated from the plants Amphiptherygium adstringens and Ligusticum porteri, respectively, using the indomethacin-induced gastric injury model, as well as their individual gastroprotective efficacy in this model. Male Wistar rats were orally administered with 3α-hydroxymasticadienonic acid, DLG or the mixture of 3α-hydroxymasticadienonic acid-DLG (at a fixed-ratio combination of 1:1, 1:3, and 3:1). Thirty minutes later, the gastric damage was induced by a single oral dose of indomethacin (30 mg/kg). Three hours later, the gastric injury (mm2 ) was determined. 3α-hydroxymasticadienonic acid and DLG as individual compounds showed a gastroprotective effect against indomethacin-induced gastric damage (p < .05). The effective dose (ED50 ) values for each compound were 6.96 ± 1.25 mg/kg for 3α-hydroxymasticadienonic acid and 2.63 ± 0.37 mg/kg for DLG. The isobolographic analysis performed showed that the combination exhibited super-additive interaction as the experimental ED50 values (Zexp) were lower than theoretical additive dose values (Zadd; p < .05). Our results identify the super-additive (synergist) interaction between 3α-hydroxymasticadienonic acid and DLG and the gastric safety of both compounds in the indomethacin-induced gastric injury model, suggesting their potential in the future as a strategy to decrease the gastric damage associated to the chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs).

Ethnopharmacological relevance The rhizome of Ligusticum porteri Coulter& Rose (LP) has been traditionally used by the ethnic group Raramuri in the North of Mexico for treatment of diabetes, tuberculosis, stomachaches, diarrhea and ritual healing ceremonies. It is use as antiulcer remedy has been extended to all Mexico. Aim of the study To evaluate the gastroprotective activity of LP organic extracts and the major natural product diligustilide (DLG),using as experimental model the inhibition of the ethanol-induced lesions in rats. Materials and methods Gastric ulcers were induced by intragastric instillation of absolute ethanol (1 mL). We tested the gastroprotective activity of the organic extracts of LP and the pure compound DLG. The ulcer index (UI) was determined to measure the activity. In order to elucidate the action mechanism of DLG the animals were treated with l -NAME, N-ethylmalemide, Forskolin, 2′,5′-dideoxyadenosine, Indomethacin, Glibenclameide, Diazoxide, NaHS and DL-Propargylglycine. The pylorus-ligated rat model was used to measure gastric secretion. Results The oral administration of organic extracts of Ligusticum porteri showed gastroprotective effect at 30 mg/Kg on ethanol induced gastric lesions; hexane and dichloromethane extracts were the most active. DLG was the major compound in the hexane extract. This compound at 10 mg/kg prevented significantly the gastric injuries induced by ethanol. The alkylation of endogenous non-protein-SH groups with N-ethylmaleimide abolished the gastroprotective effect of DLG and blocking the formation of endogenous prostaglandins by the pretreatment with indomethacin attenuated the gastroprotective effect of DLG. Conclusion The gastroprotective activity demonstrated in this study tends to support the ethnomedical use of Ligusticum porteri roots. DLG, isolated as major compound of this medicinal plant has a clear gastroprotective effect on the ethanol-induced gastric lesions. The results suggest that the antiulcer activity of DLG depends on the participation of the endogenous non-protein –SH groups and prostaglandins.

Introduction: Perillyl alcohol (POH) is a hydroxylated monocyclic monoterpene found in lemon and lavender essential oils, among others. It’s widely recognized by antitumoral activity. Despite the great potential of nanoformulations for pharmaceutics, to the date the obtainment a perillyl alcohol-nanoemulsion (NPOH) and its toxicity investigation were not previously reported. On this context, the present study aim to evaluate the toxicity of NPOH on zebrafish (Danio rerio). Lethal concentration (LC50), effects on behaviour and acute administrations effects (48h) on histopathological parameters of the gills, liver and kidneys were performed. Results: Exposure to different concentrations of NPOH (25, 35, 50 e 125 µg/L - expressed as POH content) allowed determination of LC50= 33.4 µg/L. Moreover, NPOH at 50 and 125 µg/L induced 100% of mortality, in addition the alterations of behavior. NPOH at 25 and 35 µg/L induced higher damage to gills tissue when compared to remaining concentrations and control group (surfactant at 125 µg/L) (p < 0.001, p < 0.01 and p < 0.05, Anova, Tukey-Kramer test). NPOH at 25, 35 e 50 µg/L induced significative damage to liver tissue, when compared to control (p < 0.01 and p < 0.05). No significant histopathological alterations were observed in kidneys. Thus, our results suggest that NPOH present toxicity pattern in accordance to nanoformulations and xenobiotics.