Anti-Inflammatory Activity of N'-(3-(1H-indol-3-yl)benzylidene)-2-cyanoacetohydrazide Derivative via sGC-NO/Cytokine Pathway.

The N-acylhydrazone function has been reported as a pharmacophore group of molecules with diverse pharmacological activities, including anti-inflammatory effects. Therefore, this study was designed to evaluate the anti-inflammatory potential of the compound N'-(3-(1H-indol-3-yl)benzylidene)-2-cyanoacetohydrazide (JR19) in vivo. The study started with the carrageenan-induced peritonitis model, followed by an investigation of leukocyte migration using the subcutaneous air pouch test and an assessment of the antinociceptive profile using formalin-induced pain. A preliminary molecular docking study focusing on the crystallographic structures of NFκB, iNOS, and sGC was performed to determine the likely mechanism of action. The computational study revealed satisfactory interaction energies with the selected targets, and the same peritonitis model was used to validate the involvement of the nitric oxide pathway and cytokine expression in the peritoneal exudate of mice pretreated with L-NAME or methylene blue. In the peritonitis assay, JR19 (10 and 20 mg/kg) reduced leukocyte migration by 59% and 52%, respectively, compared to the vehicle group, with the 10 mg/kg dose used in subsequent assays. In the subcutaneous air pouch assay, the reduction in cell migration was 66%, and the response to intraplantar formalin was reduced by 39%, particularly during the inflammatory phase, suggesting that the compound lacks central analgesic activity. In addition, a reversal of the anti-inflammatory effect was observed in mice pretreated with L-NAME or methylene blue, indicating the involvement of iNOS and sGC in the anti-inflammatory response of JR19. The compound effectively and significantly decreased the levels of IL-6, TNF-α, IL-17, and IFN-γ, and this effect was reversed in animals pretreated with L-NAME, supporting a NO-dependent anti-inflammatory effect. In contrast, pretreatment with methylene blue only reversed the reduction in TNF-α levels. Therefore, these results demonstrate the pharmacological potential of the novel N-acylhydrazone derivative, which acts through the nitric oxide pathway and cytokine signaling, making it a strong candidate as an anti-inflammatory and immunomodulatory agent.

(-)-Carveol Prevents Gastric Ulcers via Cytoprotective, Antioxidant, Antisecretory and Immunoregulatory Mechanisms in Animal Models.

Background: (-)-Carveol (p-Mentha-6,8-dien-2-ol) is a monocyclic monoterpenic alcohol, present in essential oils of plant species such as Cymbopogon giganteus, Illicium pachyphyllum and in spices such as Carum carvi (cumin). Pharmacological studies report its antitumor, antimicrobial, neuroprotective, vasorelaxant, antioxidant and anti-inflammatory activity. Hypothesis/Purpose: The objective of this study was to evaluate the acute non-clinical oral toxicity, gastroprotective activity of monoterpene (-)-Carveol in animal models and the related mechanisms of action. Methods: Acute toxicity was assessed according to OECD guide 423 in mice. Ethanol, stress, NSAIDs and pylorus ligation-induced gastric ulcer models were used to investigate antiulcer properties. The related mechanisms of action were using the ethanol-gastric lesions protocol. Results: (-)-Carveol has low toxicity, with a lethal dose 50% (LD50) equal to or greater than 2,500 mg/kg according to OECD guide nº 423. In all gastric ulcer induction methods evaluated, (-)-Carveol (25, 50, 100 and 200 mg/kg, p.o.) significantly reduced the ulcerative lesion in comparison with the respective control groups. To investigate the mechanisms involved in the gastroprotective activity, the antisecretory or neutralizing of gastric secretion, cytoprotective, antioxidant and immunoregulatory effects were evaluated. In the experimental protocol of pylorus ligation-induced gastric ulcer, (-)-Carveol (100 mg/kg) reduced (p < 0.001) the volume of gastric secretion in both routes (oral and intraduodenal). The previous administration of blockers NEM (sulfhydryl groups blocker), L-NAME (nitric oxide synthesis inhibitor), glibenclamide (KATP channel blocker) and indomethacin (cyclo-oxygenase inhibitor), significantly reduced the gastroprotection exercised by (-)-Carveol, suggesting the participation of these pathways in its gastroprotective activity. In addition, treatment with (-)-Carveol (100 mg/kg) increased (p < 0.001) mucus adhered to the gastric wall. Treatment also increased (p < 0.001) levels of reduced glutathione (GSH), superoxide dismutase (SOD) and interleukin-10 (IL-10). It also reduced (p < 0.001) malondialdehyde (MDA), myeloperoxidase (MPO), interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) levels. Conclusion: Thus, it is possible to infer that (-)-Carveol presents gastroprotective activity related to antisecretory, cytoprotective, antioxidant and immunomodulatory mechanisms.

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.

Antifungal activity and antidiarrheal activity via antimotility mechanisms of (-)-fenchone in experimental models.

BACKGROUND: (-)-Fenchone is a bicyclic monoterpene present in essential oils of plant species, such as Foeniculum vulgare and Peumus boldus, used to treatment of gastrointestinal diseases. Pharmacological studies report its anti-inflammatory, antioxidant, and antinociceptive activity. AIM: To investigate antidiarrheal activity related to gastrointestinal motility, intestinal secretion and antimicrobial activity. METHODS: A castor oil-induced diarrhea model was used to evaluate antidiarrheal activity. Intestinal transit and gastric emptying protocols were used to assess a possible antimotility effect. Muscarinic receptors, presynaptic α2-adrenergic and tissue adrenergic receptors, KATP channels, nitric oxide were investigated to uncover antimotility mechanisms of action and castor oil-induced enteropooling to elucidate antisecretory mechanisms. The antimicrobial activity was evaluated in the minimum inhibitory concentration model, the fractional inhibitory concentration index using the (-)-fenchone association method with standard antifungal agents. RESULTS: (-)-Fenchone (75, 150 and 300 mg/kg) showed antidiarrheal activity, with a significant decrease in the evacuation index. This activity is possibly related to a percentage of reduced intestinal transit (75, 150 and 300 mg/kg). The antimotility effect of (-)-fenchone decreased in the presence of pilocarpine, yohimbine, propranolol, L-NG-nitroarginine methyl ester or glibenclamide. In the enteropooling model, no reduction in intestinal fluid weight was observed. (-)- Fenchone did not show antibacterial activity; on the other hand, inhibits the growth of strains of fungi with a minimum fungicide concentration of 32 µg/mL. However, when it was associated with amphotericin B, no synergism was observed. CONCLUSION: The antidiarrheal effect of (-)-fenchone in this study involves antimotility effect and not involve antisecretory mechanisms. (-)-Fenchone presents antifungal activity; however, it did not show antibacterial activity.

Intestinal Anti-Inflammatory Activity of Terpenes in Experimental Models (2010-2020): A Review.

Inflammatory bowel diseases (IBDs) refer to a group of disorders characterized by inflammation in the mucosa of the gastrointestinal tract, which mainly comprises Crohn's disease (CD) and ulcerative colitis (UC). IBDs are characterized by inflammation of the intestinal mucosa, are highly debilitating, and are without a definitive cure. Their pathogenesis has not yet been fully elucidated; however, it is assumed that genetic, immunological, and environmental factors are involved. People affected by IBDs have relapses, and therapeutic regimens are not always able to keep symptoms in remission over the long term. Natural products emerge as an alternative for the development of new drugs; bioactive compounds are promising in the treatment of several disorders, among them those that affect the gastrointestinal tract, due to their wide structural diversity and biological activities. This review compiles 12 terpenes with intestinal anti-inflammatory activity evaluated in animal models and in vitro studies. The therapeutic approach to IBDs using terpenes acts basically to prevent oxidative stress, combat dysbiosis, restore intestinal permeability, and improve the inflammation process in different signaling pathways.

A Review of the Role of Flavonoids in Peptic Ulcer (2010-2020).

Peptic ulcers are characterized by erosions on the mucosa of the gastrointestinal tract that may reach the muscle layer. Their etiology is multifactorial and occurs when the balance between offensive and protective factors of the mucosa is disturbed. Peptic ulcers represent a global health problem, affecting millions of people worldwide and showing high rates of recurrence. Helicobacter pylori infection and the use of non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most important predisposing factors for the development of peptic ulcers. Therefore, new approaches to complementary treatments are needed to prevent the development of ulcers and their recurrence. Natural products such as medicinal plants and their isolated compounds have been widely used in experimental models of peptic ulcers. Flavonoids are among the molecules of greatest interest in biological assays due to their anti-inflammatory and antioxidant properties. The present study is a literature review of flavonoids that have been reported to show peptic ulcer activity in experimental models. Studies published from January 2010 to January 2020 were selected from reference databases. This review refers to a collection of flavonoids with antiulcer activity in vivo and in vitro models.

Estragole prevents gastric ulcers via cytoprotective, antioxidant and immunoregulatory mechanisms in animal models.

BACKGROUND: Estragole is an aromatic organic compound belonging to the class of phenylpropanoids derived from cinnamic aldehydes and present in essential oils of plant species, such asRavensara anisata (madeira), Ocimum basilicum (manjericão/alfavaca) and Croton zehntneri (canelinha). Pharmacological studies report its anti-inflammatory, antioxidant and vasorelaxant activity. HYPOTHESIS/PURPOSE: This study aimed to evaluate the acute non-clinical toxicity, gastroprotective activity and the related mechanisms of action. METHODS: Acute toxicity was assessed according to OECD guide 423 in mice. Ethanol, stress, piroxicam and pylorus ligation-induced gastric ulcer models were used to investigate antiulcer properties. The related mechanisms of action were using the ethanol-gastric lesions protocol. RESULTS: In the acute oral toxicity assay, doses of 300 or 2000 mg/kg of estragole administered orally in Swiss mice did not induce any behavioral changes. However, the dose of 2000 mg/kg showed a decrease in water and feed intake. Lethal dose 50 % (LD50) was set to be equal to or greater than 2500 mg/kg, according to OECD. In all evaluated protocols, estragole (31.25, 62.5, 125 and 250 mg/kg) significantly reduced the area of ​​ulcerative lesion when compared to control groups. To investigate the mechanisms involved in the gastroprotective activity, the antisecretory or neutralizing of gastric secretion, cytoprotectant, antioxidant and immunoregulatory effects were evaluated. Results showed that treatment with estragole (250 mg/kg) reduced (p < 0.05) the volume of the gastric juice. Besides, sulfhydryl groups, nitric oxide, mucus and prostaglandins seems to be involved in the gastroprotective property. Treatment also increased (p < 0.001) levels of reduced glutathione (GSH), interleukin-10 (IL-10) and positive cells marked for glutathione peroxidase (GPx) and cyclooxygenase 2 (COX-2). It also reduced (p < 0.001) malondialdehyde (MDA), myeloperoxidase (MPO), interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α) and inducible nitric oxide synthase (iNOS) (p < 0.05) levels. CONCLUSION: Thus, it is possible to infer that estragole presents gastroprotective activity related to antisecretory, cytoprotective, antioxidant and immunomodulatory mechanisms.