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Qualea grandiflora is one of the species widely used in folk medicine to treat gastric ulcers in Cerrado of the central region of Brazil. The hydroalcoholic extract of bark (HE) of Qualea grandiflora was investigated for their ability to prevent and heal lesions in the gastric mucosa. The oral administration of HE exhibited antiulcer activity decreasing the ulcerative index induced by HCl/ethanol solution, indomethacin/bethanechol and stress. In the Shay model, results showed that HE (p.o.) only reduced the severity of gastric lesions without effects on pH, gastric acidity or volume. When given by intraduodenal route, HE changed the pH, but did not modify the other parameters of the gastric juice. These data were in accordance with those obtained when HE was administered orally for 14 days after gastric ulcers were induced by acetic acid in rats. HE presented healing process in subacute gastric ulcer induced by acetic acid in rats. Moreover, histological examinations showed the simple columnar epithelium, lamina propria with simple branched tubular glandules with dilated lumen and large amounts of mucus secretion. Phytochemical investigation of HE led to the detection of terpenes, steroids, saponins, phenolic compounds and tannins in this extract, which may be involved in the observed activity. [ABSTRACT FROM AUTHOR]

ETHNOPHARMACOLOGICAL RELEVANCE: Qualea parviflora Mart. is a medicinal species commonly found in the Brazilian Cerrado biome. AIM OF THE STUDY: Based on ethnopharmacological data, methanolic extract from Qualea parviflora (QP) bark was evaluated for its antiulcer, analgesic, anti-hemorrhagic, mutagenic and anti-Helicobacter pylori activities. MATERIAL AND METHODS: The gastroprotective action of the extract was evaluated in rodent experimental models (HCl/ethanol, ethanol or NSAID). We also evaluated mutagenic effect (Ames assay), anti-Helicobacter pylori, anti-hemorrhagic action, analgesic and inflammatory effects (hot-plate test and carrageenin-induced hind paw edema) of methanolic extract from Qualea parviflora. RESULTS: QP (500 mg/kg, p.o.) was able to protect gastric mucosa against HCl/ethanol solution (77%), absolute ethanol (97%), and also against injurious effect of NSAID (36%). When QP was challenged with sulfhydryl depletor compound, the gastroprotective action of extract was abolished. QP treatment was able to maintain the GSH level and show a concentration-dependent inhibition effect on the lipid peroxidation. QP present anti-Helicobacter pylori effect (MIC=75 microg/mL), anti-hemorrhagic and antidiarrheal action but not present analgesic or anti-inflammatory effect. CONCLUSION: methanolic extract from Qualea parviflora had gastroprotective effect related to the increase of gastric mucosa defensive factors such PGE(2) levels and maintain the basal gastric glutathione levels. The methanolic extract also showed anti-Helicobacter pylori activity, anti-hemorrhagic effect and antioxidant action, but absence of analgesic, mutagenic and toxic effects, a profile that adds safety to its use. [ABSTRACT FROM AUTHOR]

ETHNOPHARMACOLOGICAL RELEVANCE: Cordia verbenacea is a medicinal plant popularly used in Brazil as anti-inflammatory, antiulcer and anti-rheumatic agent without detailed pharmacological and toxicological studies. AIM OF THE STUDY: The study was aimed to investigate the effects of Cordia verbenacea in antiulcer, analgesic and antioxidant assays, as well as to evaluate its toxic effects and phytochemical profile. MATERIAL AND METHODS: Antiulcer activity of plant extract was evaluated using ethanol/HCl, ethanol and piroxican-induced gastric lesions methods. The pH, volume and total acid of gastric juice were determined by pylorus-ligated assay. Analgesic activity was evaluated by writhing, tail-flick and hot-plate tests. Antioxidant activity was determined by in vitro lipoperoxidation assay. Acute toxicity and number of deaths were evaluated by Hippocratic screening. RESULTS: The ethanol leaf extract shows a potent antiulcer activity in the ethanol/HCl and absolute ethanol-induced gastric lesions. The IC(50) value of plant extract on the lipid peroxidation was 76.11mug/ml. Preliminary phytochemical tests were positive for flavonoids, steroids, saponins, fixed acids, alkaloids and phenols. In the analgesic models the extract did not present any activity. CONCLUSIONS: Cordial verbenaceae showed a potent antiulcer activity at the dose of 125mg/kg and this effect may be associated with an improvement in stomach antioxidant mechanisms. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer is a highly aggressive disease that is frequently diagnosed in advanced stages. Melatonin, with its numerous antitumor properties, holds great promise in cancer treatment. Herein, we investigated the effects of melatonin on apoptosis, cell migration, and kinase levels in human ovarian carcinoma SKOV-3 cells and determined whether these effects are mediated by the activation of the MT1 receptor., Methods: SKOV-3 cells were exposed to different concentrations of melatonin based on the presence of MT1 receptor, and we also performed specific silencing of the melatonin receptor gene MTNR1A., Results: Our findings revealed that melatonin reduced cell viability as shown by the MTT assay, and flow cytometry analysis showed increased rates of apoptosis and necrosis in all melatonin-treated cells. Melatonin significantly decreased the migratory and invasive capacities of the cells. Propidium iodide labeling indicated that melatonin induced cell cycle arrest by reducing DNA content in the S and G2/M phases in SKOV-3 cells. Additionally, the levels of AKT, ERK1/2, JNK, CREB, p70S6K, STAT3/5, and p38 MAP kinase involved in cell survival, proliferation, motility, and stress responses were depressed by melatonin and further reduced after MT1 knockdown. These molecules were found to be associated with lower overall survival in ovarian cancer patients., Conclusions: Melatonin had obvious oncostatic actions on ovarian cancer cells, and MT1 receptor knockdown intensified its antitumor effect. The inhibition of the MT1 receptor resulted in a substantial reduction in the migratory and invasive capacities of the cells, suggesting its potential as a therapeutic target for the treatment of ovarian cancer., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Orofacial pain has significant psychological and physiological effects. Citral (3,7-dimethyl-2,6-octadienal) is the main component of Cymbopogon citratus (DC) Stapf, an herb with analgesic properties. Although citral has been considered a potent analgesic, its putative effects on orofacial pain are still unknown., Objective: The objective of this study is to test the hypothesis that citral modulates orofacial pain using two experimental models: formalin-induced hyperalgesia in the vibrissae area and during persistent temporomandibular hypernociception using Complete Freund's Adjuvant - CFA test., Methods: For the formalin test, citral (100 and 300 mg/kg, oral gavage) or its vehicle (Tween 80, 1 %) were given 1 h before the formalin injection subcutaneously (sc) into the vibrissae area. For the CFA model, we analyzed the prophylactic (100 mg/kg of citral by oral gavage, 1 h before CFA injection) and the chronic therapeutic (citral treatment 1-hour post-CFA injection and daily post-CFA injection) effect of citral or its vehicle in animals treated with CFA for 8 days., Results: Citral caused a decrease in formalin-induced local inflammation and the time spent performing nociceptive behavior in a dose-dependent fashion. Similarly, prophylactic and therapeutic citral treatment decreased the CFA-induced persistent mechanical hypernociception in the temporomandibular area., Conclusion: Our data strengthen the notion that citral plays a powerful antinociceptive role by decreasing orofacial hypernociception in formalin and CFA models., Competing Interests: Declaration of Competing Interest The authors have not disclosed any conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Obesity causes low-grade inflammation that results in the development of comorbidities. In people with obesity, exacerbation of gastric lesion severity and delayed healing may aggravate gastric mucosal lesions. Accordingly, we aimed to evaluate the citral effects on gastric lesion healing in eutrophic and obese animals. C57Bl/6 male mice were divided into two groups: animals fed a standard diet (SD) or high-fat diet (HFD) for 12 weeks. Gastric ulcers were induced using acetic acid (80%) in both groups. Citral (25, 100, or 300 mg/kg) was administered orally for 3 or 10 days. A vehicle-treated negative control (1% Tween 80, 10 mL/kg) and lansoprazole-treated (30 mg/kg) were also established. Lesions were macroscopically examined by quantifying regenerated tissue and ulcer areas. Matrix metalloproteinases (MMP-2 and -9) were analyzed by zymography. The ulcer base area between the two examined periods was significantly reduced in HFD 100 and 300 mg/kg citral-treated animals. In the 100 mg/kg citral-treated group, healing progression was accompanied by reduced MMP-9 activity. Accordingly, HFD could alter MMP-9 activity, delaying the initial healing phase. Although macroscopic changes were undetectable, 10-day treatment with 100 mg/kg citral exhibited improved scar tissue progression in obese animals, with reduced MMP-9 activity and modulation of MMP-2 activation.

Ischaemia and reperfusion (I/R)-induced gastrointestinal disorders are caused by free radicals, resulting in organ damage and functional disarrangement. This study aimed to investigate the healing effects of hydroalcoholic extracts from the leaves of Eugenia punicifolia (Kunth) DC. (HEEP) in male and female Wistar rats with I/R-induced peptic injuries, and the role of antioxidants in improving this response. After I/R-induced gastric and duodenal injuries, male and female [intact (INT) and ovariectomized (OVZ)] rats were orally treated with HEEP for 6 days. Biochemical analysis was used to determine the catalase (CAT), superoxide dismutase (SOD), and myeloperoxidase (MPO) activities, as well as malondialdehyde and reduced glutathione levels, to measure the gastric and duodenal healing process. Six days of HEEP treatment significantly decreased the I/R-induced gastric [male (73.68%), INT (52.83%), and OVZ (43.13%)] and duodenal damage [male (57.03%), INT (56.04%), and OVZ (54.83%)] in all groups. In OVZ rats, the healing effect of HEEP occurred because of the increased activity of SOD (2x) and CAT (1.16x) in the gastric mucosa. In the duodenal mucosa of INT rats, the extract reduced MPO (20.83%) activity. The 6-day HEEP treatment improved the healing of I/R-induced peptic ulcer injury, with the system acting differently in males and females. The antioxidant system is an important component of the HEEP activity during post-I/R mucosal recovery. This result revealed the importance of antioxidant compounds in minimizing the severity of I/R-related events., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Nerol ( cis -3,7-dimethyl-2,6-octadien-1-ol) is a monoterpene widely used in cosmetic products, household detergents and cleaners, as well as a flavoring in several food products. Despite the high level of human exposure to nerol, an absence of studies regarding potential genetic toxicity in human cells exists. The aim of this investigation was to examine the cytotoxic and genotoxic potential of this monoterpene on human peripheral blood mononuclear cells as well as hepatic metabolizing HepG2/C3A human cell line. Cytotoxicity was assessed using trypan blue staining and MTT assay while genotoxicity was determined utilizing the comet and micronucleus test. Cytotoxicity tests showed cell viability greater than 70% for concentrations between 2.5 and 500 µg/ml. Both cell types exhibited significant DNA damage and chromosomal mutations after medium and high concentration incubation with nerol indicating that the safety of use of this monoterpene in various formulations to which humans are exposed needs to be monitored and requires more comprehensive investigations.

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 (mm 2 ), 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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The concept of Developmental Origins of Health and Disease (DOHaD) states that exposure to malnutrition early in life increase the incidence of non-communicable chronic diseases throughout the lifespan. In this study, a reduction in serum testosterone and an increase in estrogen levels were shown in older rats born to protein malnourished dams (6% protein in the diet) during gestation and lactation. Intraprostatic levels of reduced glutathione were decreased, while tissue expression of glutathione S-transferase pi and sulfiredoxin-1 were increased in these animals. Strong immunostaining for alfametilacil CoA racemase (AMACR), vascular endothelial growth factor-A (VEGF-A), and aquaporin-1 (AQP1) was also observed. In silico analysis confirmed commonly deregulated proteins in the ventral prostate of old rats and patients with prostate cancer. In conclusion, the increase in oxidative stress associated with an imbalance of sex hormones may contribute to prostate carcinogenesis in offspring, highlighting early-life malnutrition as a key risk factor for this malignance., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). The persistent inflammation is being mainly attributed to local oxidative stress and inflammasome activation implicated in the ensuing demyelination and axonal damage. Since new control measures remain necessary, we evaluated the preventive and therapeutic potential of a beta-selenium-lactic acid derivative (LAD-βSe), which is a source of organic selenium under development, to control experimental autoimmune encephalomyelitis (EAE) that is an animal model for MS. Two EAE murine models: C57BL/6 and SJL/J immunized with myelin oligodendrocyte glycoprotein and proteolipid protein, respectively, and a model of neurodegeneration induced by LPS in male C57BL/6 mice were used. The preventive potential of LAD-βSe was initially tested in C57BL/6 mice, the chronic MS model, by three different protocols that were started 14 days before or 1 or 7 days after EAE induction and were extended until the acute disease phase. These three procedures were denominated preventive therapy -14 days, 1 day, and 7 days, respectively. LAD-βSe administration significantly controlled clinical EAE development without triggering overt hepatic and renal dysfunction. In addition of a tolerogenic profile in dendritic cells from the mesenteric lymph nodes, LAD-βSe also downregulated cell amount, activation status of macrophages and microglia, NLRP3 (NOD-like receptors) inflammasome activation and other pro-inflammatory parameters in the CNS. The high Se levels found in the CNS suggested that the product crossed the blood-brain barrier having a possible local effect. The hypothesis that LAD-βSe was acting locally was then confirmed by using the LPS-induced neurodegeneration model that also displayed Se accumulation and downmodulation of pro-inflammatory parameters in the CNS. Remarkably, therapy with LAD-βSe soon after the first remitting episode in SJL/J mice, also significantly downmodulated local inflammation and clinical disease severity. This study indicates that LAD-βSe, and possibly other derivatives containing Se, are able to reach the CNS and have the potential to be used as preventive and therapeutic measures in distinct clinical forms of MS., (Copyright © 2020 Toledo, Fraga-Silva, Borim, de Oliveira, Oliveira, Périco, Hiruma-Lima, de Souza, de Oliveira, Padilha, Pinatto-Botelho, dos Santos, Sartori and Zorzella-Pezavento.)

Citral is a mixture of monoterpenes present in the essential oil of several plants, such as Cymbopogon citratus and Zingiber officinale , possessing anti-inflammatory, anti-ulcerogenic, and antipyretic actions. We investigated the action of citral on body temperature (Tb) and inflammatory signaling in eutrophic and obese mice during Systemic Inflammation (SI) induced by Lipopolysaccharide (LPS). Thus, we assessed the effect of citral (25, 100, and 300 mg/kg) and ibuprofen in LPS-induced SI in Swiss male mice fed a standard diet (SD) or high-fat diet (HFD) for 12 weeks. Following SI induction, we measured Tb and collected the serum, hypothalamus, and gastric mucosa for biochemical measurements. Acute treatment with citral decreased the Tb of both SD and HFD-fed animals. Citral (300 mg/kg) treatment caused a significantly lower Tb variation in HFD-fed animals than in those fed the SD. Citral reduced peripheral levels of tumor necrosis factor (TNF)-α in SD and HFD mice and decreased serum leptin concentration in HFD mice 90 min after the LPS challenge. Furthermore, citral also reduced interleukin (IL)-6 levels in the hypothalamus of obese mice. In summary, citral effectively reduced Tb during SI by reducing inflammatory mediators with a distinct action profile in HFD mice when compared with SD.

Citral, 3,7-dimethyl-2,6-octadien-1-al, one of the main components of the essential oils obtained from several plants, is used as a food additive and as a fragrance for detergents, cosmetics and other toiletries. The literature shows disparity regarding citral genotoxicity. Thus, the main objective of our work was to evaluate the genotoxic effects of citral in human cell cultures, HepG2 and leukocytes. Cytotoxicity assays (trypan blue and MTT) showed citral toxic effects in HepG2 cells (with metabolizing liver enzymes), which contrasted with the absence of toxicity in leukocytes. After citral exposure, both cell types did not demonstrate clastogenic/aneugenic effects in the micronucleus test. However, for the comet assay, citral exposure lead to significant genotoxic effects in both HepG2 (even to citral low concentrations) and leukocytes. The use of citral must be viewed with caution due to its ability to induce DNA damages, especially after being metabolized by cells with active liver enzymes.

Ethnopharmacological Relevance: Terminalia catappa L. (Combretaceae), known as "amendoeira da praia" in Brazil, has been recognized as a medicinal plant in folk medicine for the treatment of gastrointestinal disorders and other inflammatory conditions. The present study aimed to investigate the preventive and healing effects of the infusion of leaves of T. catappa (ILTC) against gastric lesions caused by ischemia and reperfusion (I/R) injury and characterize its mechanism of action in the gastric mucosa of rats., Materials and Methods: Different doses (30, 100, and 300 mg/kg) of ILTC were orally administered as acute and subacute treatments against I/R-induced gastric lesion in rats. After treatment, the stomach of rats was collected to measure the lesion area, redox parameters malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) and inflammatory parameters myeloperoxidase activity (MPO), interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α). The activities of matrix metalloproteinases 2 and 9 (MMPs 2 and 9) were assessed by zymography method to clarify the mechanisms of the healing acceleration promoted by ILTC., Results: Pretreatment with ILTC (100 mg/kg) was effective in preventing the aggravation of lesions in the acute model by reducing MPO activity by 38% relative to control group, despite the lack of clarity of this action at the macroscopical level at the lesion area (p < 0.05). After three days of treatment with ILTC (30 and 100 mg/kg), this infusion significantly reduced the lesion area by 95% and 89%, respectively, compared the control (p < 0.05). The gastric healing effect of all doses of ILTC was followed by a reduction in MPO activity (decrease by 70-78%). Compared to the negative control, an improvement in gastric healing owing to treatment with ILTC was observed and this was followed by an increase in MMP-2 (20-47%) (p < 0.05)., Conclusion: Three days of treatment with ILTC could accelerate the healing process in I/R-induced lesions in rats. By decreasing MPO levels, ILTC enabled the action of MMP-2, which led to tissue recovery in the gastric mucosa., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

: Machaerium hirtum (Vell.) Stellfeld (Fabaceae) known in Brazil as "jacaranda de espinho" or "espinheira santa nativa" is a medicinal plant commonly used in folk medicine to treat ulcers, cough and diarrhea. This study aimed to investigate the anti-inflammatory and antinociceptive effects of hydroalcoholic extracts from M. hirtum twig (HEMh) using in vivo experimental models of nociception through the involvement of transient receptor potential channels, acid-sensing ion channel (ASIC), nitrergic, opioidergic, glutamatergic, and supraspinal pathways. Our results revealed an antinociceptive effect of HEMh mediated by the opioidergic, L-arginine-nitric oxide and glutamate systems, as well as by interactions with TRPA1/ASIC channels. The anti-inflammatory effect of HEMh evaluated with a xylene-induced ear edema and by the involvement of arachidonic acid and prostaglandin E2 (PGE 2 ) showed involvement of the COX pathway, based on observed decreases in PGE 2 levels. A phytochemical investigation of the HEMh led to the isolation of α-amyrin, β-amyrin, allantoin, apigenin-7-methoxy-6- C -β-D-glucopyranoside, and apigenin-6- C -β-D-glucopyranosyl-8- C -β-D-xylopyranoside. In conclusion, the acute oral administration of HEMh inhibits the nociceptive behavioral response in animals through the nitrergic, opioid, glutamatergic pathways, and by inhibition of the TRPA1 and ASIC channels, without causing locomotor dysfunction. In addition, its anti-inflammatory effect is associated with the COX pathway and decreased PGE 2 levels., Competing Interests: The authors declare that they have no conflicts of interest.

The analysis by HPLC-PDA of the hydroalcoholic extract of the leaves of M. eriocarpum together with the injection of the fractions containing the already identified metabolites allowed the detection of at least 5 flavonoids, of which two are derived from apigenin and three from luteolin. After isolating larger amounts of isovitexin (I), assays were performed to evaluate the allelopathic activity together with the crude extract. The results show that the initial inhibition indexes were very similar to those observed in the treatments with F17 (Fraction enriched in isovitexin) and F18 (isovitexin), mainly in the concentrations of 500 and 1000 mg L -1 . The index of the number of lateral roots, an increase of the inhibitory effect is observed with the increase of the concentration of M. eriocarpum extract.

Peptic ulcer disease (PUD) is a multifactorial and complex disease caused by an imbalance of protective and aggressive factors (endogenous and exogenous). Despite advances in recent years, it is still responsible for substantial mortality and triggering clinical problems. Over the last decades, the understanding of PUD has changed a lot with the discovery of Helicobacter pylori infection. However, this disease continues to be a challenge due to side-effects, incidence of relapse from use of various anti-ulcer medicines, and the rapid appearance of antimicrobial resistance with current H. pylori therapies. Consequently, there is the need to identify more effective and safe anti-ulcer agents. The search for new therapies with natural products is a viable alternative and has been encouraged. The literature reports the importance of monoterpenes based on the extensive pharmacological action of this class, including wound healing and anti-ulcerogenic agents. In the present study, 20 monoterpenes with anti-ulcerogenic properties were evaluated by assessing recent in vitro and in vivo studies. Here, we review the anti-ulcer effects of monoterpenes against ulcerogenic factors such as ethanol, nonsteroidal anti-inflammatory drugs (NSAIDs), and Helicobacter pylori, highlighting challenges in the field., Competing Interests: The authors declare no conflict of interest.

Chrysin exhibits anti-inflammatory and antioxidant activities. Here, the gastroprotective effect of chrysin was investigated in mouse models of gastric ulcer induced by absolute ethanol, acetic acid, and ischemia-reperfusion injury. The gastric-healing effect was evaluated at 7 and 14 days after treatment; the mechanism of action was verified using the expression of metalloproteinase 2 ( MMP-2 ) and 9 ( MMP-9 ), caspase-3, cyclooxygenase 1 ( COX-1 ) and 2 ( COX-2 ), epidermal growth factor ( EGF ), and interleukin-10. Chrysin (10 mg/kg) inhibited macroscopic lesions and increased catalase activity in the mouse model established using absolute ethanol. It ameliorated the gastric ulcer caused by acetic acid by improving the expression of inflammatory genes such as COX-2 , inhibiting negative remodeling promoted by MMP-9, increasing cell proliferation effect via EGF , and reducing cellular apoptosis by modulating caspase-3. A faster healing effect was evident in the first 7 days of treatment compared to 14 days of treatment, indicating the pharmacological potential of chrysin. Overall, these results demonstrate the potent effect of chrysin in the gastrointestinal tract and elucidate the genes involved in the healing of gastric ulcers. Moreover, an increase in the levels of gastric mucosa defensive factors is involved in the activity of chrysin in the gastric mucosa., Competing Interests: The authors declare that they have no conflicts of interest.Abbreviations:

Ethnopharmacological Relevance: Eugenia punicifolia (Kunth) DC. (Myrtaceae), an Amazonian medicinal plant known as "pedra-ume-caá," is popularly used as a natural remedy for inflammation, wounds, infections, diabetes, fever, and flu. Its anti-inflammatory, antinociceptive, and gastroprotective effects have already been characterized. We evaluated the gastric healing effect of the hydroalcoholic extract of the leaves of E. punicifolia (HEEP) in male and female Wistar rats against nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol., Materials and Methods: The healing effect of HEEP on the gastric mucosa of adult male and female Wistar rats was measured after the chronic application of aggressive factors such as NSAIDs or 80% ethanol. Male, and intact and ovariectomized (OVZ) female rats were treated with HEEP for two days (NSAIDs) or one, two, four, and six days (80% ethanol). The stomachs were analyzed macroscopically for ulcerative lesions (mm 2 ), and the healing process was measured using biochemical analysis with anti-inflammatory and antioxidant parameters., Results: Macroscopic evaluation of the gastric mucosa showed that gastric lesions induced by NSAIDs were significantly healed (66%) and pro-inflammatory interleukin 5 cytokine level was decreased after two-day oral treatment with HEEP compared with those in the negative control group (p < 0.05). However, the gastric lesions induced by NSAIDs did not heal in HEEP-treated female rats (p > 0.05). In addition, four-day treatment with HEEP significantly healed the gastric lesions induced by ethanol in male and female rats (63% and 78%, respectively) compared to those of the negative control group (p < 0.05). However, the OVZ group required six days of HEEP treatment to heal gastric ulcers (67% compared to the control group). HEEP exerts the healing effect against ethanol by significantly reducing neutrophil infiltration into the gastric mucosa by decreasing myeloperoxidase activity in male and OVZ rats after four and six days of treatment, respectively (p < 0.05). Four-day treatment with HEEP also increased the level of a non-enzymatic antioxidant, reduced glutathione in intact females compared to that of the negative control group (p < 0.05)., Conclusion: These findings indicated that HEEP was effective in promoting the healing of gastric ulcers induced by NSAIDs or ethanol. The gastric healing effects of this extract could be affected by female sex hormone interference; in future, comprehensive studies should be performed by considering sex differences., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Byrsonima intermedia is a species of bush popularly used to treat gastrointestinal disorders, such as gastric ulcers, gastritis, and diarrhea. Previous studies have revealed that the methanolic crude extract of B. intermedia leaves has gastroprotective and healing properties. In this new study, we specifically investigated two purified partitions, ethyl acetate (EtOAc) and water (AcoAq), obtained from the crude extract to characterize the antiulcer effects of these two partitions and the mechanisms of action of this medicinal plant. The healing effects of these partitions on the gastric and duodenal mucosa were assessed after ischemia-reperfusion (I/R) or acetic acid-induced injury. The involvement of tumor necrosis factor-alpha (TNF-alpha), interleukin 1β (IL-1β), interleukin 10 (IL-10), and myeloperoxidase (MPO) activity and glutathione (GSH) levels were determined. The antibacterial activity against Helicobacter pylori was evaluated using microdilution methods. The phytochemical analysis of AcoAq revealed a predominance of oligomeric proanthocyanidins and galloyl quinic esters, whereas EtOAc was found to contain concentrated flavonoids. Both partitions led to a significant reduction in gastric lesions, but AcoAq was more effective than EtOAc with regard to anti-Helicobacter pylori activity in addition to protecting the gastric mucosa against ethanol, non-steroidal anti-inflammatory drugs (NSAIDs) and duodenal mucosal damage induced by cysteamine. Additionally, both partitions were associated with a significant increase in gastric and duodenal healing and increased gastric mucosal GSH content after damage induced by acetic acid. On the other hand, after 6 days of treatment, EtOAc was more effective than AcoAq in ameliorating gastric damage upon initiation of the gastric I/R, which was accompanied by a significant reduction in the activity of gastric mucosal MPO, IL 1-β and TNF-alpha, as well as an elevation in IL-10 and GSH content. These results demonstrate that the oligomeric proanthocyanidins and galloyl quinic esters present in AcoAq were more effective in the prevention of gastric and duodenal ulcers due to the antioxidant effects of these compounds, whereas the flavonoids present in EtOAc were more effective due to their anti-inflammatory activity on the gastric and duodenal tissue. All these results confirm that the rich phytochemical diversity of B. intermedia contributes to the pharmacological actions of this medicinal plant on the gastrointestinal tract in addition to its activity against H. pylori., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Beta-myrcene [or myrcene (1,6-Octadiene, 7-methyl-3-methylene-)] and the essential oils containing this monoterpene have been widely used in cosmetics, detergents, and soaps, and as flavoring additives for food and beverages. Due to the potentially high level of human exposure to beta-myrcene, and absence of studies involving its genotoxicity in human cells, the aim of this study was to investigate the cytotoxic and genotoxic potential of this terpenoid in non-metabolizing cells (leukocytes) and liver metabolizing cells (HepG2/C3A cells). Prior to the genotoxic assessment by the comet and micronucleus (MN) assays, a range of beta-myrcene concentrations was tested in a preliminary MTT assay. Regarding the MTT assay, the results showed cytotoxic effects for leukocytes at 250 µg/ml and higher concentrations, while for HepG2/C3A cells, absence of cytotoxicity was noted relative to all tested concentrations (after 24 hr exposure). Thus, the concentrations of 2.5, 10, 25, 50, and 100 µg/ml for leukocytes, and 2.5, 100, and 1000 µg/ml for HepG2/C3A cells were selected for subsequent assays. Genotoxicity evaluation demonstrated significant DNA damage in the comet assay and significant chromosomal abnormalities including nucleoplasmic bridges and nuclear buds in HepG2/C3A cells at beta-myrcene concentrations of 100 and 1000 µg/ml. Under our experimental conditions, caution is recommended in the use of beta-myrcene, since this compound produced genotoxic effects especially after metabolic activation using human HepG2/C3A cells, which may be associated with carcinogenic and teratogenic effects previously reported in the literature.

Aim: To evaluate the sex-specific effects of a hydroalcoholic extract from Eugenia punicifolia (HEEP) leaves on gastric ulcer healing., Methods: In this rat study involving males, intact (cycling) females, and ovariectomized females, gastric ulcers were induced using acetic acid. A vehicle, lansoprazole, or HEEP was administered for 14 d after ulcer induction. Body weight was monitored throughout the treatment period. At the end of treatment, the rats were euthanized and the following in vivo and in vitro investigations were performed: macroscopic examination of the lesion area and organ weights, biochemical analysis, zymography, and evaluation of protein expression levels. Additionally, the concentration-dependent effect of HEEP was evaluated in terms of subacute toxicity and cytotoxicity., Results: Compared to the vehicle, HEEP demonstrated a great healing capacity by substantially reducing the ulcerative lesion area in males (52.44%), intact females (85.22%), and ovariectomized females (65.47%), confirming that HEEP accelerates the healing of acetic acid-induced gastric lesions and suggesting that this effect is modulated by female sex hormones. The antiulcer effect of HEEP was mediated by prostaglandin E 2 only in male rats. Overall, the beneficial effect of HEEP was the highest in intact females. Notably, HEEP promoted the expression of vascular endothelial growth factor (intact vs ovariectomized females) and decreased the expression of Caspase-8 and Bcl-2 (intact female vs male or ovariectomized female). Additionally, HEEP enhanced fibroblast proliferation and migration into a wounded area in vitro , confirming its healing effect. Finally, no sign of subacute toxicity or cytotoxicity of HEEP was observed., Conclusion: In gastric ulcers, HEEP-induced healing (modulated by female sex hormones; in males, mediated by prostaglandin) involves extracellular matrix remodeling, with gastric mucosa cell proliferation and migration., Competing Interests: Conflict-of-interest statement: The authors declare that they have no commercial, personal, political, intellectual, or religious interests related to the work presented herein.

Some plants popularly employed for the treatment of peptic ulcers have proved to be attractive sources of new drugs. Despite extensive research, the pharmacological and toxicological potentials of these plants are not fully understood. In this context, the aim of this work was to analyze the multielemental composition of the methanolic extracts of three of those plants, Alchornea glandulosa (AG), Davilla elliptica (DE) and Davilla nitida (DN), with the intention of contributing to the understanding of the mechanisms of action of these extracts. For this purpose, we used the analytical technique of total reflection X-ray fluorescence (TXRF) by synchrotron radiation at the Brazilian Synchrotron Light Source (LNLS/CNPEM). It was possible to determine the concentrations of the elements: P, S, Cl, K, Ca, Ti, Cr, Mn, Fe, Ni, Cu, Zn, Rb and Br in all of the samples. Selenium (Se) was detected only in the DN extract. An inverse relationship between the concentrations of elements with proven effectiveness and the gastroprotective activity of extracts considering induction protocols with ethanol and non-steroidal anti-inflammatory drugs (NSAIDs) was obtained. This data suggests that the function of the extract is not only associated with providing the elements for restoring the gastric mucosa but that it also promotes the displacement of these elements from other parts of the mucosa to the damaged area. Correlations between the concentrations of the elements were also obtained. In the DE extract, which is the most effective extract for both induction protocols, the obtained correlations were above 70% among almost all of the elements, and no anticorrelations were found. For the other two extracts, in the less effective extract (AG) anticorrelations above 70% were predominantly found. Meanwhile, in the DN extract, a few high anticorrelations were found, which may explain its intermediate stage of effectiveness., Competing Interests: The authors declare there are no competing interests.

Arrabidaea brachypoda (DC) Bureau is a medicinal plant found in Brazil. Known as "cipó-una", it is popularly used as a natural therapeutic agent against pain and inflammation. This study evaluated the chemical composition and antinociceptive activity of the dichloromethane fraction from the roots of A. brachypoda (DEAB) and its mechanism of action. The chemical composition was characterized by high-performance liquid chromatography, and this fraction is composed only of dimeric flavonoids. The antinociceptive effect was evaluated in formalin and hot plate tests after oral administration (10-100 mg/kg) in male Swiss mice. We also investigated the involvement of TRPV1 (transient receptor potential vanilloid 1), TRPA1 (transient receptor potential ankyrin 1), TRPM8 (transient receptor potential melastatin 8), and ASIC (acid-sensing ion channel), as well as the opioidergic, glutamatergic, and supraspinal pathways. Moreover, the nociceptive response was reduced (30 mg/kg) in the early and late phase of the formalin test. DEAB activity appears to involve the opioid system, TRPM8, and ASIC receptors, clearly showing that the DEAB alleviates acute pain in mice and suggesting the involvement of the TRPM8 and ASIC receptors and the opioid system in acute pain relief., Competing Interests: The authors declare no conflict of interest.

Citral is a mixture of the two monoterpenoid isomers (neral and geranial) widely used as a health-promoting food additive safe for human and animal (approved by the US Food and Drug Administration). In vitro studies have reported on the capability of citral to reduce inflammation. Here, we report antipyretic effects of citral in vivo using the most well-accepted model of sickness syndrome, i.e., systemic administration of lipopolysaccharide ( LPS ) to rats. Citral given by gavage caused no change in control euthermic rats (treated with saline) but blunted most of the assessed parameters related to the sickness syndrome [fever (hallmark of infection), plasma cytokines (IL-1β, IL-6, and TNF-α) release, and prostaglandin E 2 (PGE 2 ) synthesis (both peripherally and hypothalamic)]. Moreover, LPS caused a sharp increase in plasma corticosterone levels that was unaltered by citral. These data are consistent with the notion that citral has a corticosterone-independent potent antipyretic effect, acting on the peripheral febrigenic signaling (plasma levels of IL-1β, IL-6, TNF-α, and PGE 2 ), eventually down-modulating hypothalamic PGE 2 production.

Geraniol is an acyclic monoterpene alcohol present in the essential oil of many aromatic plants and is one of the most frequently used molecules by the flavor and fragrance industries. The literature also reports its therapeutic potential, highlighting itself especially as a likely molecule for the development of drugs against cancer. In view of these considerations, this study was designed to evaluate the cytotoxic and genotoxic potential of geraniol, in an in vitro protocol, using two types of human cells: one without the ability to metabolize (peripheral blood mononuclear cells - PBMC), and the other with this capability (human hepatoma cell line - HepG2) through the comet assay and the micronucleus test. Four concentrations (10, 25, 50, and 100 µg/mL) were selected for the genotoxic assessment for PBMC and three (1.25, 2.5, and 5 µg/mL) for HepG2 cells based on cytotoxicity tests (MTT assay). Results showed that geraniol did not present genotoxic or clastogenic/aneugenic effects on both cell types under the conditions studied. However, caution is advised in the use of this substance by humans, since a significant reduction in viability of HepG2 and a marked decrease in cell viability on normal PBMC were verified.

Aim: To evaluate the anti-inflammatory intestinal effect of the ethanolic extract (EtOHE) and hexane phase (HexP) obtained from the leaves of Combretum duarteanum ( Cd )., Methods: Inflammatory bowel disease was induced using trinitrobenzenesulfonic acid in acute and relapsed ulcerative colitis in rat models. Damage scores, and biochemical, histological and immunohistochemical parameters were evaluated., Results: Both Cd -EtOHE and Cd -HexP caused significant reductions in macroscopic lesion scores and ulcerative lesion areas. The vegetable samples inhibited myeloperoxidase increase, as well as pro-inflammatory cytokines TNF-α and IL-1β. Anti-inflammatory cytokine IL-10 also increased in animals treated with the tested plant samples. The anti-inflammatory intestinal effect is related to decreased expression of cyclooxygenase-2, proliferating cell nuclear antigen, and an increase in superoxide dismutase., Conclusion: The data indicate anti-inflammatory intestinal activity. The effects may also involve participation of the antioxidant system and principal cytokines relating to inflammatory bowel disease., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest exists.

The objective of this study was to evaluate the pharmacological mechanisms involved in anti-inflammatory and antidiarrheal actions of hydroalcoholic extract obtained from the leaves of Cissus sicyoides (HECS). The anti-inflammatory effect was evaluated by oral administration of HECS against acute model of edema induced by xylene, and the mechanisms of action were analysed by involvement of arachidonic acid (AA) and prostaglandin E₂ (PGE₂). The antidiarrheal effect of HECS was observed and we analyzed the motility and accumulation of intestinal fluid. We also analyzed the antidiarrheal mechanisms of action of HECS by evaluating the role of the opioid receptor, α₂ adrenergic receptor, muscarinic receptor, nitric oxide (NO) and PGE₂. The oral administration of HECS inhibited the edema induced by xylene and AA and was also able to significantly decrease the levels of PGE₂. The extract also exhibited significant anti-diarrheal activity by reducing motility and intestinal fluid accumulation. This extract significantly reduced intestinal transit stimulated by muscarinic agonist and intestinal secretion induced by PGE₂. Our data demonstrate that the mechanism of action involved in the anti-inflammatory effect of HECS is related to PGE₂. The antidiarrheal effect of this extract may be mediated by inhibition of contraction by acting on the intestinal smooth muscle and/or intestinal transit.

Solanum paniculatum L. (Solanaceae) is a plant species widespread throughout tropical America, especially in the Brazilian Savanna region. It is used in Brazil for culinary purposes and in folk medicine to treat liver and gastric dysfunctions, as well as hangovers. Fractionation of the ethanolic extracts (70%) from aerial parts (leaves and twigs) of S. paniculatum led to the isolation of the two new saponins (22R, 23S, 25R)-3β, 6α, 23-trihydroxy-5α-spirostane 6-O-β-D-xylopyranosyl-(1"" → 3"')-O-[β-D-quinovopyranosyl(1″' → 2')]-O-[α-L-rhamnopyranosyl(1" → 3')]-O-β-D-quinovopyranoside (1) and diosgenin 3-O-β-D-glucopyranosyl(1" → 6')-O-β-D-glucopyranoside (2) together with four know compounds: caffeic acid (3), diosgenin β-D-glucopyranoside (4), rutin (5), and quercetin 3-O-α-L-rhamnopyranosyl (1"' → 6 ″)-O-β-D-galactopyranoside (6). The structures of these compounds were elucidated by extensive use of 1D and 2D NMR experiments along with HRESIMS analyses. Different doses (31.25-500 mg/kg) of ethanolic extract of leaves from S. paniculatum were evaluated against gastric ulcer induced by ethanol in rats. The lower dose of extract able to promote antiulcer effect was 125 mg/kg. The treatment with S. paniculatum by oral route was able to decrease gastric lesion area and also reduced levels of myeloperoxidase (MPO) in the gastric mucosa. Our results reveal for the first time, steroidal saponins from S. paniculatum and the antiulcer effect of this species at this lower dose., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Syngonanthus arthrotrichus and Syngonanthus bisulcatus, currently known for Comanthera aciphylla (Bong.) L.R.Parra & Giul. and Comanthera bisulcata (Koern.) L.R. Parra & Giul, popularly known in Brazil as "sempre-vivas," are plants from the family Eriocaulaceae. They are found in the states of Minas Gerais and Bahia. The species are known to be rich in flavonoids to which their gastroprotective activity has been attributed. In this research, experimental protocols were performed to elucidate the associated mechanisms of action., Methods: The activity was evaluated using induced gastric ulcer models (acetic acid and ethanol-induced gastric lesions in NEM or L-NAME pre-treated mice, and by ischemia/reperfusion). Antioxidant enzymes, serum somatostatin, and gastrin were also evaluated., Results: In chronic gastric ulcers, a single daily oral dose of Sa-FRF or Sb-FRF (100 mg/kg body wt.) for 14 consecutive days accelerated ulcer healing to an extent similar to that seen with an equal dose of cimetidine. The pre-treatment of mice with NEM (N-ethylmaleimide) or L-NAME (N-nitro-L-arginine) abolished the protective activity of Sa-FRF, Sa-FDF, Sb-FDF and Sb-FRF or Sa-FRF and Sb-FRF, respectively, which indicates that antioxidant compounds and nitric oxide synthase activity are involved in the gastroprotective. Sa-FRF and Sb-FRF (100 mg/kg p.o) protected the gastric mucosa against ulceration that was induced by ischemia/reperfusion (72 and 76 %, respectively). It also decreased lipid peroxidation and restored total thiols in the gastric wall of mice that had been treated with ethanol. When administered to rats submitted to ethanol-induced gastric lesions, Sa-FRF and Sb-FRF (100 mg/kg, p.o.) increased the somatostatin serum levels, while the gastrin serum levels were proportionally decreased., Conclusions: The results indicate significant healing effects and gastroprotective activity for the Sa-FRF and Sb-FRF, which probably involves the participation of SH groups, nitric oxide (NO), the antioxidant system, somatostatin, and gastrin. All are integral parts of the gastrointestinal mucosa's cytoprotective mechanisms against aggressive factors.

The aim of this study was to evaluate the effect of Himatanthus sucuuba on the maternal reproductive outcome and fetal anomaly incidence in rats. Pregnant rats were randomly divided into three experimental groups as follows: Control = treated with water (vehicle), treated 250 = treated with H. sucuuba at dose 250 mg/kg, and treated 500 = treated with H. sucuuba at dose 500 mg/kg. The rats were orally treated, by gavage, with H. sucuuba or vehicle (water) during preimplantation and organogenic period (from gestational day 0-14). At day 21 of pregnancy, all rats were killed to obtain maternal-fetal data. The treatment with H. sucuuba at dose of 250 mg/kg caused reduction in placental efficiency and an increase preimplantation loss rate and placenta weight compared with the control. The treated 500 group presented a significant decrease in maternal weight gain, maternal weight gain minus gravid uterus weight, fetal weight, and placental efficiency compared with the control. In this group, there was a decrease in body weight at day 20 of pregnancy and metacarpus ossification and an increase in the preimplantation loss rate and skeletal anomalies compared with other groups. Himatanthus sucuuba extract caused intrauterine growth restriction, preimplantation loss, and developmental delay in the high doses tested., (© 2015 Wiley Periodicals, Inc.)

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., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Inflammation and haemorrhage are the main characteristics of tissue injury in botropic envenomation. Although some studies have shown that anti-venom prevents systemic reactions, it is not efficient in preventing tissue injury at the site of the bite. Therefore, this work was undertaken to investigate the anti-inflammatory effects of the methanolic extract and fractions from D. elliptica and to evaluate the role of matrix metalloproteinases (MMPs) in this process. Effects of the extract and fractions from D. elliptica were evaluated using a carrageenan-induced paw oedema model in rats, and leukocyte rolling was visualized by intravital. The quantification of MMPs activities (MMP-2 and MMP-9) extracted from the dermis of mice treated with extract and fractions alone or incubated with venom was determined by zymographic analyses. Our results show that intraperitoneal (i.p.) injection of fractions significantly reduced paw oedema after the carrageenan challenge. Treatment with the tannins fraction also resulted in considerable inhibition of the rolling of leukocytes and this fraction was able to decrease the activation of MMP-9. These results confirmed the anti-inflammatory activity of the methanolic extract and tannins fraction of D. elliptica and showed that the dermonecrosis properties of B. jararaca venom might be mediated through the inhibition of MMP-9 activity.

Citrus aurantium L., commonly known as bitter orange, is widely used in folk medicine, but there is little data in the literature about the effects on pregnancy. The aim of the present study was to evaluate the influence of essential oil obtained from fruits of Citrus aurantium on the maternal reproductive outcome and fetal anomaly incidence in rats. Pregnant Wistar rats were randomized into four groups (n minimum = 12 animals/group): G1 = control, G2 to G4 = treated with essential oil from C. aurantium at dose 125, 250 and 500 mg/kg, respectively. Rats were orally treated, by gavage, with plant essential oil or vehicle during pre-implantation and organogenic period (gestational day 0-14). On gestational day 20 the rats were anaesthetized and the gravid uterus was weighed with its contents and the fetuses were analyzed. Results showed that the treated group with 500 mg/kg presented decreased placental weights and placental index, although the treatment with bitter orange essential oil did not show any alteration in maternal reproductive performance, toxicological effect, changes in ossification sites, and malformation index. In conclusion, the treatment of Citrus aurantium essential oil was not teratogenic and did not alter the maternal reproductive outcome.

Ethnopharmacological Relevance: An ethnopharmacological survey indicated that leaves from Eugenia punicifolia (Kunth) DC. (Myrtaceae) are popularly used as a natural therapeutic agent to treat pain and inflammation., Aim of the Study: The overall objective of the present study was to evaluate the antinociceptive, anti-inflammatory and gastroprotective activities of a hydroalcoholic extract of leaves from Eugenia punicifolia (HEEP) in rodents., Material and Methods: The antinociceptive effects of HEEP were evaluated in mice after oral administration in chemical (formalin and glutamate) and thermal (hot-plate) tests. We evaluated the involvement of the glutamatergic, opioidergic and nitrergic pathways in the antinociception of HEEP and the effect of HEEP on the inhibition of p38α MAPK. The anti-inflammatory effect of HEEP was evaluated in mice and rats using xylene-induced ear edema and carrageenan-induced paw edema, respectively. Furthermore, the gastroprotective effect of HEEP was evaluated in rats with acute gastric lesions induced by ethanol or indomethacin. Finally, we performed a phytochemical analysis of HEEP., Results: The oral administration of HEEP (125, 250 and 500mg/kg, p.o.) significantly inhibited the neurogenic and inflammatory phases of formalin-induced licking, and HEEP (250mg/kg, p.o.) also significantly inhibited the nociception caused by glutamate. The antinociceptive effects of HEEP were significantly reversed by l-arginine (500mg/kg, i.p.) but not by naloxone (1mg/kg, i.p.) in the formalin test. HEEP did not affect animal motor performance in the rotarod model. In addition, HEEP also increased the paw withdraw latency in the hot-plate test. HEEP significantly inhibited ear edema induced by xylene (64%) and paw edema induced by carrageenan (50%) compared to the control group. Furthermore, HEEP (3-30mg/mL) also inhibited the phosphorylation of p38α MAPK by approximately 90%. In addition, HEEP (125, 250 and 500mg/kg, p.o.) protected the rats against ethanol (88.4-99.8%) and indomethacin (53-72.3%) and increased the mucus levels of the gastric mucosa without producing an antisecretory effect. The phytochemical profile of HEEP obtained using HPLC-PDA showed secondary metabolites already reported for the genus, mostly flavonoids, gallotannins and proanthocyanidins., Conclusions: These data show for the first time that HEEP has significant antinociceptive and anti-inflammatory effects, which appear to be related to the inhibition of the glutamatergic system, the synthesis of nitric oxide and the inhibition of the phosphorylation of p38α MAPK. HEEP also has interesting gastroprotective effects related to the maintenance of protective factors, such as mucus production. These results support the use of Eugenia punicifolia in popular medicine and demonstrate that this plant has therapeutic potential for the development of phytomedicines with antinociceptive, anti-inflammatory and gastroprotective properties., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Citral (3,7-dimethyl-2,6-octadienal) is an open-chain monoterpenoid present in the essential oils of several medicinal plants. The aim of this work was to evaluate the effects of orally administered citral in experimental models of acute and chronic nociception, inflammation, and gastric ulcers caused by non-steroidal anti-inflammatory drugs (NSAIDs). Oral treatment with citral significantly inhibited the neurogenic and inflammatory pain responses induced by intra-plantar injection of formalin. Citral also had prophylactic and therapeutic anti-nociceptive effects against mechanical hyperalgesia in plantar incision surgery, chronic regional pain syndrome, and partial ligation of sciatic nerve models, without producing any significant motor dysfunction. In addition, citral markedly attenuated the pain response induced by intra-plantar injection of glutamate and phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator), as well as by intrathecal (i.t.) injection of ionotropic and metabotropic glutamate receptor agonists (N-methyl-D-aspartic acid [NMDA] and 1-amino-1,3-dicarboxycyclopentane [trans-ACPD], respectively), substance P, and cytokine tumour necrosis factor-α. However, citral potentiated behaviours indicative of pain caused by i.t., but not intra-plantar, injection of a transient receptor potential vanilloid receptor type 1 (TRPV1) agonist. Finally, the anti-nociceptive action of citral was found to involve significant activation of the 5-HT2A serotonin receptor. The effect of citral was accompanied by a gastro-protective effect against NSAID-induced ulcers. Together, these results show the potential of citral as a new drug for the treatment of pain., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The monoterpene β-myrcene has been widely used in cosmetics, food and beverages, and it is normally found in essential oil from citrus fruit. The aim of this study was to investigate the anti-ulcer effects of β-myrcene on experimental models of ulcers that are induced by ethanol, NSAIDs (non-steroidal anti-inflammatory drugs), stress, Helicobacter pylori, ischaemia-reperfusion injury (I/R) and cysteamine in order to compare with the essential oil of Citrus aurantium and its major compound limonene. The results indicate that the oral administration of β-myrcene at a dose of 7.50mg/kg has important anti-ulcer activity with significantly decreased gastric and duodenal lesions as well as increased gastric mucus production. The results showed treatment with β-myrcene caused a significant increase in mucosal malondialdehyde level (MDA), an important index of oxidative tissue damage. The β-myrcene was also endowed with marked enhancement of antioxidant enzyme activity from GR system as evidenced by the decreased activity of superoxide dismutase (SOD) and increased levels of glutathione peroxidase (GPx), glutathione reductase (GR), and total glutathione in gastric tissue. Our results also shown that treatment with β-myrcene is not involved with thioredoxin reductase (TrxR) activity. Our results reveal, for the first time, the importance of β-myrcene as an inhibitor of gastric and duodenal ulcers and demonstrate that an increase in the levels of gastric mucosa defence factors is involved in the anti-ulcer activity of β-myrcene., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Geraniol is an acyclic monoterpene alcohol commonly used as a flavoring agent. The present study was undertaken to investigate antiulcerogenic effects of geraniol and to determine the possible mechanisms involved in this action. In the model of the ethanol-induced ulcer, treatment of rats with geraniol by oral route significantly inhibited gastric lesions by 70 % (7.50 mg/kg) to 99 % (200 mg/kg). Analysis of the gastric tissue of rats treated with geraniol (7.50 mg/kg) revealed that total glutathione content levels (GSH) increased and levels of myeloperoxidase (MPO) decreased in the gastric mucosa. Oral treatment with geraniol significantly decreased the number of ulcerative lesions induced by ischemia/reperfusion injury by 71 % and the duodenal ulcers induced by cysteamine by 68 %. The action of geraniol was mediated by the activation of defensive mucosa-protective factors such as the nitric oxide (NO) pathway, endogenous prostaglandins, increased mucus production, increased sulfhydryl compounds, antioxidant properties and the stimulation of calcitonin gene-related peptide (CGRP) release through the activation of transient receptor potential vanilloid (TRPV). The multifaceted gastroprotective mechanisms of geraniol represent a promising option for the treatment of gastric and duodenal mucosa injury.

Objectives: Syngonanthus macrolepis, popularly known in Brazil as 'sempre-vivas', is a plant from the family Eriocaulaceae, it is found in the states of Minas Gerais and Bahia. The species contains a variety of constituents, including flavonoids with gastroprotective effect. In this work, a flavonoid-rich fraction (Sm-FRF) obtained from scapes of S. macrolepis was investigated for preventing gastric ulceration in mice and rats., Methods: The activity was evaluated in models of induced gastric ulcer (absolute ethanol, stress, non-steroidal anti-inflammatory drugs and pylorus ligation). The cytoprotective mechanisms of the Sm-FRF in relation to sulfhydryl (SH) groups, nitric oxide (NO) and antioxidant enzymes were also evaluated., Key Findings: The Sm-FRF (100 mg/kg, p.o.) significantly reduced gastric injury in all models, and did not alter gastric juice parameters after pylorus ligation., Conclusions: The results indicate significant gastroprotective activity for the Sm-FRF, which probably involves the participation of both SH groups and the antioxidant system. Both are integral parts of the gastrointestinal mucosa's cytoprotective mechanisms against aggressive factors., (© 2013 Royal Pharmaceutical Society.)

Ethnopharmacological Relevance: An ethnopharmacological survey indicated that the bark from Qualea parviflora Mart. (Vochysiaceae) could be used to treat gastrointestinal disorders, such as diarrhea and intestinal inflammation. The objective of this study was to evaluate the effects of a methanolic extract from the bark of Qualea parviflora (QP) in an experimental model of diarrhea and intestinal inflammation induced in rodents., Material and Methods: The antidiarrheal and antispasmodic effects of QP were investigated by measuring intestinal motility, diarrhea, and intestinal fluid accumulation in rodents after challenging with a cathartic agent. In addition, the effects of QP on the contractility of the isolated mice-ileum preparation were determined. Acute intestinal inflammation was induced in male Wistar rats by the rectal administration of trinitrobenzenesulfonic acid (TNBS) in 50% ethanol (0.25 mL). QP was administered orally (for 5 days) prior to the induction of inflammation. The colonic injury and extent of inflammation were assessed by macroscopic damage scores and lesion length. The enhanced colonic mucosal injury, inflammatory response, and oxidative stress were evaluated by myeloperoxidase (MPO) activity; the tumor necrosis factor alpha (TNF-α), interleukin 1β (IL1-β), and malondialdehyde (MDA) levels; and the glutathione (GSH) content., Results: Oral treatment with QP (500 mg/kg) delayed the onset of diarrhea, reduced the amount of liquid stool, and decreased the severity of the diarrhea and the evacuation index in rodents challenged with castor oil (p<0.01). Additionally, QP (150-500 µg/mL) demonstrated effective antispasmodic activity against carbachol-induced contractions of mouse ileum in vitro. Oral treatment (25 and 50 mg/kg/day) with QP significantly reduced the intestinal inflammation induced by TNBS in rats (52% and 45%, respectively). Improvement of colonic mucosal injury by treatment with QP was demonstrated by a decrease in MDA levels and an increase in GSH content in colonic tissue. QP also prevented intestinal inflammation as evidenced by reduced cytokine levels (TNF-α and IL1-β) and low MPO activity., Conclusions: The ethnopharmacological usefulness of the bark from Qualea parviflora against diarrhea containing blood and mucus was supported by the observed antidiarrheal, antispasmodic, and intestinal antiinflammatory properties of this medicinal plant., (© 2013 Published by Elsevier Ireland Ltd.)