Antiulcer mechanisms of the hydroalcoholic extract from Aztec marigolds' medicinal and edible flowers (Tagetes erecta L.).

The antiulcer mechanisms of the dry extract of T. erecta flowers (DETe) were studied here. The acute ulcers induced by acidified ethanol or indomethacin were reproduced in mice pretreated with DETe (3 - 300 mg/kg). The antiulcer activity of DETe was also verified in mice pretreated with NEM, L-NAME, indomethacin, or yohimbine. The antisecretory effect of DETe was verified in rats, and its anti-Helicobacter pylori activity was determined in vitro. DETe (300 mg/kg, p.o) reduced the ethanol- or indomethacin-induced ulcer by 49 and 93%, respectively. The pre-treatment with L-NAME, NEM or yohimbine abolished the gastroprotective effect of DETe. However, DETe did not change the volume, acidity, or peptic activity in rats and did not affect H. pylori. This study expands knowledge about the antiulcerogenic potential of DETe, evidencing the role of nitric oxide, non-protein sulfhydryl groups, α2 adrenergic receptors, and prostaglandins, but not antisecretory or anti-H. pylori properties.

Tumor-neutrophil crosstalk promotes in vitro and in vivo glioblastoma progression.

Introduction: The tumor microenvironment (TME) of glioblastoma (GB) is characterized by an increased infiltration of immunosuppressive cells that attenuate the antitumor immune response. The participation of neutrophils in tumor progression is still controversial and a dual role in the TME has been proposed. In this study, we show that neutrophils are reprogrammed by the tumor to ultimately promote GB progression. Methods: Using in vitro and in vivo assays, we demonstrate the existence of bidirectional GB and neutrophil communication, directly promoting an immunosuppressive TME. Results and discussion: Neutrophils have shown to play an important role in tumor malignancy especially in advanced 3D tumor model and Balb/c nude mice experiments, implying a time- and neutrophil concentration-dependent modulation. Studying the tumor energetic metabolism indicated a mitochondria mismatch shaping the TME secretome. The given data suggests a cytokine milieu in patients with GB that favors the recruitment of neutrophils, sustaining an anti-inflammatory profile which is associated with poor prognosis. Besides, glioma-neutrophil crosstalk has sustained a tumor prolonged activation via NETs formation, indicating the role of NFκB signaling in tumor progression. Moreover, clinical samples have indicated that neutrophil-lymphocyte ratio (NLR), IL-1ß, and IL-10 are associated with poor outcomes in patients with GB. Conclusion: These results are relevant for understanding how tumor progression occurs and how immune cells can help in this process.

Cytotoxicity, antinociceptive and gastroproiltective potential of the Abuta selloana Eichler: a fruit plant from Catarinense flora, Brazil.

This study evaluated some biological activities of extracts from Abuta selloana. The gastroprotective potential was determined against ethanol/HCl- and indomethacin-induced gastric ulcers, whereas the antinociceptive effect was evaluated by acetic acid-induced abdominal contortions in mice. The cytotoxicity activity was measured against human cancer cell lines: U251 (glioma), MCF-7 (breast cancer) and NCI-H460 (lung cancer). The radical scavenger potential was verified; and preliminary phytochemical analyses were performed. The phytochemical screening revealed higher levels of phenolic compounds in all extracts. Moreover, the methanolic extract from pulp fruit (MEPu), peel fruit (MEPe), branches (MEB) and leaves (MEL) scavenged the DPPH radical at 100 µg/mL. Besides, only MEL presented GI50 < 30 µg/mL in all tested cells. Besides, MEPu, MEPe, MEB or MEL at 10 mg/kg (i.p) reduced the abdominal contortions at 47.22%, 63.31%, 84.59% and 37.76%, respectively. The MEPu, MEPe, MEB and MEL reduced the ethanol/HCl- and indomethacin- induced ulcer at 250 mg/kg (p.o). In conclusion, A. selloana had interesting biological activities; presenting the leaves as a promising source for compounds with cytotoxic potential, however, further studies should be performed to confirm its antitumoral activity. Besides, the whole plant can be an important source of bioactive compounds associated with gastroprotective and antinociceptive properties.

Involvement of Anti-Inflammatory and Stress Oxidative Markers in the Antidepressant-like Activity of Aloysia citriodora and Verbascoside on Mice with Bacterial Lipopolysaccharide- (LPS-) Induced Depression.

Aloysia citriodora Palau is popularly used to treat nervous disorders. Experimental evidence has indicated that verbascoside (VBS) isolated from A. citriodora has pharmacological potential. In this study, we evaluated the antidepressant-like effects of a hydroalcoholic extract of A. citriodora (HEAc) and VBS against lipopolysaccharide- (LPS-) induced depressive-like behavior in mice. In the pretreatment protocol (performed to evaluate the preventive potential), mice were pretreated with HEAc (3, 30, or 300 mg/kg) or VBS (30 mg/kg) before the administration of LPS. In the posttreatment protocol (performed to evaluate the therapeutic potential), mice were initially administered LPS and were subsequently given HEAc (3, 30, or 300 mg/kg) or VBS (30 mg/kg). In both treatments, the mice were submitted to an open-field test and tail suspension test (TST) at 6 and 24 h after LPS administration. The posttreatment evaluation revealed that HEAc (30 or 300 mg/kg) and VBS produced an antidepressant-like effect, as indicated by a reduction in the time spent with no movement in the TST. Moreover, HEAc (30 or 300 mg/kg) was found to reduce interleukin-6 (IL-6) levels and N-acetyl-glycosaminidase activity in the hippocampus, increase glutathione (GSH) levels in the hippocampus and cortex, and enhance IL-10 in the cortex and, at a dose of 300 mg/kg, reduced myeloperoxidase activity in the cortex. Contrastingly, no comparable effects were detected in mice subjected to the pretreatment protocol. Administration of VBS similarly reduced the levels of IL-6 in the hippocampus and increased GSH levels in the cortex. Our observations indicate that both HEAc and VBS show promising antidepressant-like potential, which could be attributed to their beneficial effects in reducing neuroinflammatory processes and antioxidant effects in the central nervous system.

Sonchus oleraceus L. Promotes Gastroprotection in Rodents via Antioxidant, Anti-Inflammatory, and Antisecretory Activities.

Sonchus oleraceus L. is an edible and medicinal plant used to treat stomachache and gastric ailments around the world. Thus, this study aimed to determine the gastroprotective mode of action of hydroalcoholic extract of S. oleraceus (HES). Mice were treated with HES before induction of gastric ulceration by ethanol/HCl. The area and histological appearance of ulcers were quantified, and mucus was measured histochemically. The effects of HES on inflammatory and oxidative markers were assessed in the ulcerated tissue. In addition, we investigated the gastric acid antisecretory activity of HES in pylorus-ligated rats. Chemical analyses of HES and its antioxidant activity were also performed in vitro. The HES (30 or 300 mg/kg) reduced the ulceration by 71.5 and 76.2%, respectively, compared with vehicle (p < 0.001), and the histological analysis confirmed the macroscopic results with elevation in mucin levels by 361.4 and 477.5%, respectively, compared with vehicle (p < 0.001). Moreover, the gastroprotection was accompanied by increases in GSH levels and in SOD, CAT, and GST activities; in parallel to a reduction in MPO activity and TNF levels. Furthermore, HES reduced the total acidity, and pepsin activity of the gastric juice of rats by 61 and 63%, respectively, compared to the vehicle. Phytochemical analysis indicated that luteolin-7-O-ß-D-glucoside is the main active compound annotated in HES. Was also found that HES scavenged the DPPH radical with an IC50 of 15.41 µg/mL. In conclusion, the gastroprotective effects of HES involve reductions in oxidative stress and inflammatory injury, in conjunction with an increase in mucus layer and inhibition of gastric secretion. This study advances in elucidating the modes of the antiulcer potential of S. oleraceus and contributes to the prospection of new gastroprotective molecules.

Gastroprotective Effects of the Aqueous Extract from Taraxacum officinale in Rats Using Ultrasound, Histology, and Biochemical Analysis.

Taraxacum officinale F.H. Wigg. belonging to the family Asteraceae is an edible medicinal plant distributed worldwide. This study aimed to determine the gastroprotective effects of aqueous extract of T. officinale (AETo) in rats using ultrasound, histological, and biochemical analyses. In this study, gastric ulceration was induced by ethanol or piroxicam. Rats were then treated with AETo (3, 30, or 300 mg/kg). The area and histological appearance of gastric ulcers were quantified, and histochemical analysis was performed. The activity of AETo on inflammatory and oxidative stress markers was assessed in the ulcerated tissue. In addition, we investigated the thickness of the gastric wall using the ultrasound technique. Moreover, chemical analyses of AETo were performed. In rats with ethanol- or piroxicam-induced ulcers, AETo reduced the ulceration area, elevated mucin level, and the gastroprotective effect was confirmed by histological analysis. The gastroprotective effect was accompanied by increased activities of SOD, CAT, and GST, as well as an increase in GSH level and reduction in MPO activity. Furthermore, AETo reduced the thickness of the gastric wall in rats. Phytochemical analysis of AETo indicated phenolic acids and flavonoids as the main active compounds. In conclusion, the gastroprotective effect of AETo involves reduction in oxidative stress and inflammatory injury and increase in mucin content. This study advances in the elucidation of mechanisms of gastric protection of T. officinale, contributes to the prospection of new molecules gastroprotective, and proposes the ultrasonographic analyses as a new gastroprotective assessment tool in preclinical studies.

Recent Advances in the Knowledge of Naturally-derived Bioactive Compounds as Modulating Agents of the Renin-angiotensin-aldosterone System: Therapeutic Benefits in Cardiovascular Diseases.

BACKGROUND: One of the biggest challenges to public health worldwide is to reduce the number of events and deaths related to the cardiovascular diseases. Numerous approaches have been applied to reach this goal, and drug treatment intervention has been indispensable along with an effective strategy for reducing both cardiovascular morbidity and mortality. Renin-angiotensin-aldosterone system (RAAS) blockade is currently one of the most important targets of cardiovascular drug therapy. Many studies have proven the valuable properties of naturally-derived bioactive compounds to treat cardiovascular diseases. METHODS: The goal of this review, therefore, is to discuss the recent developments related to medicinal properties about natural compounds as modulating agents of the RAAS, which have made them an attractive alternative to be available to supplement the current therapy options. RESULTS: Data has shown that bioactive compounds isolated from several natural products act either by inhibiting the angiotensin-converting enzyme or directly by modulating the AT1 receptors of angiotensin II, which consequently changes the entire classical axis of this system. CONCLUSION: While there are a few evidence about the positive actions of different classes of secondary metabolites for the treatment of cardiovascular and renal diseases, data is scarce about the clinical assays established to demonstrate their value in humans.

Chemical composition and diuretic, natriuretic and kaliuretic effects of extracts of Mimosa bimucronata (DC.) Kuntze leaves and its majority constituent methyl gallate in rats.

OBJECTIVES: Some species of the genus Mimosa showed promising results in previous investigations, which include diuretic effect; however, no chemical analyses or animal model has been conducted so far to evaluate the biological properties of M. bimucronata. METHODS: Male Wistar rats received the oral treatment with vehicle; hydrochlorothiazide; methanolic extract from M. bimucronata (MEMB), dichloromethane (DCM) and ethyl acetate (EA) fractions or methyl gallate (MG). The cumulative urine volume, electrolytes excretion, pH and osmolality were determined at the end of the experiment. KEY FINDINGS: The chemical studies demonstrated that the phenolic compounds are the majorities in the plant, with the MG being the main substance identified. We showed that MEMB and EA fraction, but not DCM, exhibited diuretic and saluretic effects. Similarly, the MG also revealed diuretic, natriuretic and kaliuretic properties to both normotensive and spontaneously hypertensive rats. Atropine, a muscarinic receptor antagonist, fully prevented MG-induced diuresis and saluresis. In addition, MG did not alter the viability of A7r5 and L929 cell lines and neither stimulated nitric oxide generation. CONCLUSIONS: These findings suggest that M. bimucronata extracts and its majority compound MG present diuretic, natriuretic and kaliuretic properties, which was dependent on the activation of muscarinic acetylcholine receptor.

Anandamide reverses depressive-like behavior, neurochemical abnormalities and oxidative-stress parameters in streptozotocin-diabetic rats: Role of CB1 receptors.

The pathophysiology associated with increased prevalence of depression in diabetics is not completely understood, although studies have pointed the endocannabinoid system as a possible target. Then, we aimed to investigate the role of this system in the pathophysiology of depression associated with diabetes. For this, diabetic (DBT) male Wistar rats were intraperitoneally treated with cannabinoid CB1 (AM251, 1mg/kg) or CB2 (AM630, 1mg/kg) receptor antagonists followed by anandamide (AEA, 0.005mg/kg) and then submitted to the forced swimming test (FST). Oxidative stress parameters, CB1 receptor expression and serotonin (5-HT) and noradrenaline levels in the hippocampus (HIP) and prefrontal cortex (PFC) were also performed. It was observed that DBT animals presented a more pronounced depressive-like behavior and increase of CB1 receptor expression in the HIP. AEA treatment induced a significant improvement in the depressive-like behavior, which was reversed by the CB1 antagonist AM251, without affecting the hyperglycemia or weight gain. AEA was also able to restore the elevated CB1 expression and also to elevate the reduced level of 5-HT in the HIP from DBT animals. In addition, AEA restored the elevated noradrenaline levels in the PFC and induced a neuroprotective effect by restoring the decreased reduced glutathione and increased lipid hydroperoxides levels along with the decreased superoxide dismutase activity observed in HIP or PFC. Together, our data suggest that in depression associated with diabetes, the endocannabinoid anandamide has a potential to induce neuroadaptative changes able to improve the depressive-like response by its action as a CB1 receptor agonist.

Identification of a dicaffeoylquinic acid isomer from Arctium lappa with a potent anti-ulcer activity.

Leaves of Arctium lappa contain several mono- and dicaffeoylquinic acids, as evaluated by liquid chromatography-mass spectrometry. In order to investigate the protection on gastric mucosa against ulcers, rats were treated with fractions from leaf extract prior to ethanol-induced ulcers. The original fraction obtained as ethanol soluble fraction from hot aqueous extract was able to protect de gastric mucosa, and this effect was retained in the ethyl acetate fraction, obtained from liquid/liquid fractionation. The main compound in this fraction was isolated and chemically characterized by nuclear magnetic resonance and mass spectrometry, assisted by isopropylidene derivatization which gave rise a mass increment of 40 units. Therefore, the underivatized compound that had m/z 515.119 [M-H](-) was shifted to m/z 555.151, being confirmed as 1,3-O-dicaffeoylquinic acid, which presented an ED50 of 57 µg kg(-1) on gastric protection, lesser than the therapeutic concentration of omeprazole (40 mg kg(-1)).

Antidepressant-like effect of celecoxib piroxicam in rat models of depression.

Beyond the current hypothesis of depression, several new biological substrates have been proposed for this disorder. The present study investigated whether the anti-inflammatory drugs celecoxib and piroxicam have antidepressant activity in animal models of depression. After acute administration, we observed antidepressant-like effects of celecoxib (10 mg/kg) and piroxicam (10 mg/kg) in the modified forced swim test in rats. Piroxicam increased serotonin and norepinephrine levels in the hippocampus. Prolonged (21-day) treatment with celecoxib (10 mg/kg) and piroxicam (10 mg/kg) rescued sucrose preference in a chronic mild stress model of depression. Additionally, the chronic mild stress-induced reduction of hippocampal glutathione was prevented by treatment with celecoxib and piroxicam. Superoxide dismutase in the hippocampus was increased after chronic mild stress compared with the non-stressed saline group. The non-stressed celecoxib and piroxicam groups and stressed piroxicam group exhibited an increase in hippocampal superoxide dismutase activity compared with the stressed saline group. Lipid hydroperoxide was increased in the stressed group treated with vehicle and non-stressed group treated with imipramine but not in the stressed groups treated with celecoxib and piroxicam. These results suggest that the antidepressant-like effects of anti-inflammatory drugs might be attributable to enhanced antioxidant defenses and attenuated oxidative stress in the hippocampus.

Increased oxidative stress in prefrontal cortex and hippocampus is related to depressive-like behavior in streptozotocin-diabetic rats.

Depression is a common comorbid in diabetic patients. The pathophysiologic mechanisms that relate this comorbidity is not completely elucidated yet, although several lines of evidence point out that increased oxidative stress resulting from hyperglycemia may have a crucial role. Thus, the effect of prolonged treatment with insulin (INS), the antioxidant vitamin E (VIT E) or the antidepressant imipramine (IMI) was evaluated in animals submitted to forced swimming test. Oxidative stress parameters (lipid peroxidation product levels, reduced gluthatione levels and catalase and superoxide dismutase activities) were also evaluated in brain areas related to depression, prefrontal cortex (PFC) and hippocampus (HIP). Our data show that treatment of streptozotocin-induced diabetic (DBT) rats with INS (6 UI/day, s.c.) prevented the blood glucose increase, reduced the immobility time, an antidepressant-like behavior, and normalized the reduced weight gain. Although the VIT E treatment (300 mg/kg, p.o.) had not altered the blood glucose levels, this treatment was able to reduce the immobility time and to reestablish the reduced weight gain in DBT rats. Differently, treatment with IMI (15 mg/kg, i.p.) induced antidepressant-like behavior in normoglycemic besides DBT animals. While VIT E and IMI treatments restored only specific oxidative stress parameters, INS was able to prevent all changed parameters evaluated in both PFC and HIP from DBT animals. Therefore, our data provide further evidence of the importance of oxidative stress in PFC and HIP in the pathophysiology of depression related to diabetes.

Gastroprotective bio-guiding fractionation of hydro-alcoholic extracts from green- and black-teas (Camellia sinensis).

Hydro-alcoholic extracts from leaves of Camellia sinensis (green- and black-tea leaves) were submitted to a fractionation, promoting the compound separation according to their polarity, and analyzed by ultra-high performance liquid chromatography-mass spectrometry. A wide range of compounds could be identified, such as catechins and their gallate (esters) or oxidation derivatives (theaflavins), glycosylated flavonoids and other phenolics, as well as lipids, saponins and alkaloids. Also have been developed, via bio-guided examination, the gastroprotective property of the compounds identified. The samples were assayed using the model of acute gastric lesions induced in rats by ethanol. Hydro-alcoholic extracts of green-tea and black-tea protected the gastric mucosa with ED50=3.6 and 10.2mg/kg, respectively, with participation of gastric mucus and reduced glutathione (GSH). The ethyl acetate fraction from green-tea and aqueous fraction from black-tea were, respectively, 6 and 10 times more effectiveness than the initial extracts. Moreover, the epigallocatechin gallate (EGCG, 0.204mg/kg), a main component of ethyl acetate fraction from green tea, reduced the gastric lesion by 56% and restored the mucus levels, however the rutin (0.0133mg/kg), a flavonoid found in the most active fraction of black-tea, was less significant at the natural concentrations. These results have confirmed that the different compounds present in green- and black-tea hydro-alcoholic extracts and partitioned fractions produce relevant gastroprotection mainly via maintenance of the protective factors, mucus and GSH.

Gastroprotective effect and structure of a rhamnogalacturonan from Acmella oleracea.

The plant Acmella oleracea (L.) R.K.Jansen (Asteraceae), locally known as jambu, is widely used in Legal Amazon in local dishes and in folk medicine. A polysaccharide (SC) was isolated from this plant, following aqueous extraction, which contained uronic acid, galactose, arabinose, rhamnose, and glucose in a 15:2:1:1:0.5 molar ratio and had a M(w) 226,000 g/mol. Methylation analysis and NMR spectroscopy indicated that SC is a rhamnogalacturonan composed of a long chain of →4)-6-OMe-α-D-GalpA-(1→, interspersed with some α-L-Rhap residues, partly substituted by side-chains of type II arabinogalactans. SC significantly inhibited ethanol-induced gastric ulcers in rats with an ED50 of 1.5 mg/kg, indicating that SC acts as gastroprotective agent.

Isolation of a gastroprotective arabinoxylan from sugarcane bagasse.

After industrial processing, one-third of sugarcane culms is converted into residual bagasse. The xylan-rich hemicellulose components of the bagasse were extracted with hot aqueous alkali (AX-CRUDE). Approximately 82% of the extracted hemicelluloses was precipitated with ethanol (AX-PET). Both AX-CRUDE and AX-PET contained an arabinoxylan as confirmed by 13C NMR and methylation analysis. Fraction AX-PET was fed to female Wistar rats with ethanol-induced gastric lesions. Oral administrations of 30, 100, and 300 mg/kg reduced the gastric lesion area by over 50%, and replenished ethanol-induced depletion of glutathione. The polysaccharide also increased mucus production by over 70%, indicating its cytoprotective action on experimentally induced gastric ulcers. These findings are significant, since a biologically active compound can be extracted in high yields from an abundant, readily available residue.