Xanthones and Cancer: from Natural Sources to Mechanisms of Action.

Xanthones are a class of heterocyclic natural products that have been widely studied for their pharmacological potential. In fact, they have been serving as scaffolds for the design of derivatives focusing on drug development. One of the main study targets of xanthones is their anticancer activity. Several compounds belonging to this class have already demonstrated cytotoxic and antitumor effects, making it a promising group for further exploration. This review therefore focuses on recently published studies, emphasizing their natural and synthetic sources and describing the main mechanisms of action responsible for the anticancer effect of promising xanthones.

Chrysophyllum cainito (apple-star): a fruit with gastroprotective activity in experimental ulcer models.

The gastroprotective potential of the methanolic extracts from peels (MEPe), seeds (MESe) and pulp (MEPu) of Chrysophyllum cainito L. (Sapotaceae) fruits was evaluated in mice using ethanol/HCl- and indomethacin-induced ulcer, as well as the antiulcer effect of the juice and flour from this fruit. The lowest oral gastroprotective dose of MEPe, MESe and MEPu against ethanol/HCl was 3, 3 and 10 mg/kg, respectively. Moreover, all extracts increased mucin secretion at 176, 198 and 193%. Intraperitoneal administration of MEPe (0.3 mg/kg), MESe (0.3 mg/kg) and MEPu (1 mg/kg) also promoted gastroprotection against ethanol/HCl. In addition, MEPe (3 mg/kg, p.o), MESe (3 mg/kg, p.o) and MEPu (10 mg/kg, p.o) reduced indomethacin-induced gastric ulcer in mice by 78, 70 and 50%, respectively. Regarding the mode of action, the gastroprotective effect of MEPe was decreased by the pre-administration of N-ethylmaleimide (NEM, a sulfhydryl group chelator, 10 mg/kg, i.p), glibenclamide (a potassium channel blocker, 10 mg/kg, i.p), yohimbine (10 mg/kg, i.p, an alpha-adrenergic receptor antagonist, 10 mg/kg, i.p) and indomethacin (a cyclooxygenase inhibitor, 10 mg/kg, i.p). The gastroprotective effect of MESe was reduced by the pre-administration of NEM, glibenclamide, N-Nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor, 70 mg/kg, i.p) and yohimbine, while MEPu had the gastroprotective effect decreased in animals pretreated with NEM and L-NAME. However, the extracts did not reduce gastric acid secretion. The supplementation with the flour from C. cainito fruit at 10% by 7 days, but not the juice intake, displayed gastroprotective potential, evidencing the fruit as a promising functional food. Together, the antiulcer effect of extracts of the C. cainito fruit in different experimental models was confirmed by the favoring of mucosal protective mechanisms among different, but complementary, modes of action. In parallel, the gastroprotective effects of the flour from C. cainito fruit were also described.

Metabolomics of cancer cell cultures to assess the effects of dietary phytochemicals.

Cancer is a multi-factorial disease and is a major cause of morbidity and mortality worldwide. Dietary phytochemicals have been used for the treatment of cancer throughout history due to their safety, low toxicity, and general availability. Several studies have been performed to elucidate the effects of dietary phytochemicals on cancer metabolism, and many molecular targets of phytochemicals have been discovered. In spite of remarkable progress, their effects on cancer metabolism have not yet been fully clarified. Recent developments in metabolomics allowed to probe much further the metabolism of cancer, highlighting altered metabolic pathways and offering a new powerful tool to investigate cancer disease. In this review, we discuss the main metabolic alterations of cancer cells and the potentiality of phytochemicals as promising modulators of cancer metabolism. We will focus on the application of nuclear magnetic resonance-based metabolomics on breast and hepatocellular cancer cell lines to evaluate the impact of curcumin and resveratrol on cancer metabolome with the aim to demonstrate the premise of this approach to provide useful information for a better understanding of impact of diet components on cancer disease.

Effects of 1,3,5-triphenyl-4,5-dihydro-1H-pyrazole derivatives on cell-cycle and apoptosis in human acute leukemia cell lines.

Pyrazoline is an important 5-membered nitrogen heterocycle that has been extensively researched. Ten derivatives were synthesized and tested for antileukemic effects on 2 human acute leukemia cell lines, K562 and Jurkat. The most cytotoxic of these derivatives, compound 21, was chosen for investigation of cytotoxicity mechanisms. The results obtained with selectivity calculations revealed that compound 21 is more selective for acute leukemia (K562 and Jurkat cell lines) than for other tumor cell lines. Moreover, compound 21 was not cytotoxic to normal cell lines, indicating a potential use in clinical tests. Compound 21 caused a significant cell cycle arrest in the S-phase in Jurkat cells and increased the proportion of cells in the sub G0/G1 phase in both cell lines. Cells treated with compound 21 demonstrated morphological changes characteristic of apoptosis in the EB/AO assay, confirmed by externalization of phosphatidylserine by the annexin V - fluorescein isothiocyanate method and by DNA fragmentation. An investigation of cytotoxicity mechanisms suggests the involvement of an intrinsic apoptosis pathway due to mitochondrial damage and an increase in the ratio of mitochondrial Bax/Bcl2. Pyrazoline 21 obeyed Lipinski's "rule of five" for drug-likeness. Based on these preliminary results, the antileukemic activity of compound 21 makes it a potential anticancer agent.

Heteropterys tomentosa A. Juss: Toxicological and adaptogenic effects in experimental models.

BACKGROUND: The constant pursuit of improved athletic performance characterizes high-performance sport and the use of medicinal plants as dietary supplements is becoming widespread among athletes to enhance long-term endurance performance. AIM: The present study evaluated the toxicity of Heteropterys tomentosa (HEHt) and its acute adaptogenic effects. METHODS: The in vitro safety profile was evaluated on CHO-k1 cells using the alamar Blue assay, at concentrations ranging from 3.125 to 200 µg/mL. In vivo acute oral toxicity was conducted in male and female mice with oral administration of graded doses of HEHt from 400 to 2000 mg/kg. A subchronic oral toxicity study was completed by oral administration of HEHt (50, 200 or 1000 mg/kg) and vehicle for 30 days in male Wistar rats. Clinical observations and toxicological related parameters were determined. Blood was collected for biochemical and hematological analyses, while histological examinations were performed on selected organs. Thereafter, an adaptogenic test consisting of progressive loads until exhaustion was conducted in rats ( n = 5/group) orally pre-treated with the vehicle and HEHt (25, 100 or 400 mg/kg). RESULTS: HEHt exhibited no cytotoxic effects on the CHO-k1 cells and, apparently, no acute toxicity in mice and no subchronic toxicity in rats. An ergogenic effect was observed only at the dose of 25 mg/kg compared with the vehicle in relation to time to exhaustion and exercise load ( p = .011 and .019, respectively). HEHt is safe at up to 400 mg/kg, contains astilbin and taxifolin as the major phytochemical compounds, and exhibited a potential adaptogenic effect. CONCLUSIONS: These results justify its anecdotal usage as a tonic, show that the hydroethanolic maceration of the root does not cause toxicity, and provide scientific evidence of its potential as a source of new adaptogenic substance(s).

A magnetic nanogel based on O-carboxymethylchitosan for antitumor drug delivery: synthesis, characterization and in vitro drug release.

This paper studied the synthesis, characterization and use of the magnetic chitosan nanogel for carrying meleimidic compounds. The hydrogel polymer was prepared using O-carboxymethylchitosan, which was crosslinked with epichlorohydrin for subsequent incorporation of iron oxide magnetic nanoparticles. The characterization revealed that the magnetic material comprises about 10% of the hydrogel. This material is comprised of magnetite and maghemite and exhibits ferro-ferrimagnetic behavior. The average particle size is 4.2 nm. There was high incorporation efficiency of maleimides in the magnetic nanogel. The release was of sustained character and there was a greater release when an external magnetic field was applied. The mathematical model that best explained the process of drug release by the magnetic hydrogel was that of Peppas-Sahlin. The magnetic nanogel proved to be an excellent candidate for use in drug-delivery systems.

3-Demethyl-2-geranyl-4-prenylbellidifoline, a natural xanthone with diuretic and kidney protective properties.

OBJECTIVES: The diuretic and kidney protective effect of the 3-demethyl-2-geranyl-4-prenylbellidifoline (DGP) were evaluated in rats. METHODS: The normotensive (NTR) and spontaneously hypertensive rats (SHR) received, once a day for 7 days, oral treatment with DGP (0.1 mg/kg), hydrochlorothiazide (10 mg/kg), or vehicle (10 ml/kg). Urine, blood, and kidney samples were collected for further analysis. KEY FINDINGS: The urine and Na+ elimination content were significantly higher in the groups that received DGP. Furthermore, a Ca2+-sparing action was detected in the urine of DGP-treated groups, which was consistent with the reduction in calcium oxalate crystal formation. Relevantly, the treatment did not change the parameters examined in the blood. Concerning the renal analyses, DGP treatment recovered the morphological damages of the kidney corpuscle area of SHR. In addition to the differences observed between the NTR and SHR vehicle groups, DGP augmented the amount of reduced glutathione and the activity of glutathione S-transferase GST while reducing the catalase and N-acetyl-ß-D-glucosaminidase activity and nitrite levels. CONCLUSION: Together, this study displayed the prolonged diuretic action of DGP and its natriuretic, Ca2+-sparing, and antiurolytic effects. The antioxidative and anti-inflammatory effects of DGP were evidenced in SHR kidneys, opening perspectives for further studies regarding the benefits of this xanthone.

N-antipyrine-3, 4-dichloromaleimide, an effective cyclic imide for the treatment of chronic pain: the role of the glutamatergic system.

BACKGROUND: In recent years, cyclic imides have attracted the attention of the scientific community because of their promising therapeutic potential. Studies with the compound N-antipyrine-3,4-dichloromaleimide (NA-3,4-DCM) also demonstrated an antinociceptive effect in formalin or capsaicin models of nociception, and that it reduced acetic acid-induced abdominal writhing in mice. METHODS: In this study, we examined the effects of NA-3,4-DCM on mechanical hypernociception in persistent pain-like behavioral models in mice. We also investigated the peripheral, topical, spinal, and supraspinal antinociceptive properties of NA-3,4-DCM and evaluated the involvement of the glutamatergic system on the antinociceptive effects of NA-3,4-DCM in mice. RESULTS: NA-3,4-DCM, dosed systemically (intraperitoneally or per os), was capable of interfering with the development of mechanical hypernociception induced by intraplantar injection of carrageenan and complete Freund adjuvant in mice. Interestingly, repeated intraperitoneal or per os treatment with NA-3,4-DCM, administered after the induction of hypernociception, also reversed the mechanical sensitization induced by complete Freund adjuvant injection or partial ligation of the sciatic nerve in mice, with lower doses than gabapentin, a drug used clinically to treat chronic pain. When administered systemically, locally, spinally, or supraspinally, NA-3,4-DCM was able to inhibit the overt nociception of both phases of the formalin test. The systemic administration of NA-3,4-DCM also reduced the nociception induced by intraplantar or intrathecal injection of glutamate in mice. Furthermore, NA-3,4-DCM caused marked inhibition of the nociceptive response induced by intrathecal injection of a group I metabotropic glutamate receptors agonist (1S,3R)-aminocyclopentane-trans-1,3-dicardboxylic acid (ACPD) or N-methyl-d-aspartate (NMDA), without interfering with nociception induced by other non-NMDA receptor agonists (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid and kainate) or by substance P. Notably, in the same range of doses, the antinociception caused by the compound NA-3,4-DCM was not associated with nonspecific effects such as changes in locomotor activity or motor coordination. CONCLUSION: These results provide strong evidence that NA-3,4-DCM produces antihypernociception in mice at peripheral, spinal, and supraspinal sites, and that interaction with the group I metabotropic glutamate receptors and NMDA receptors contributes to the mechanisms underlying its effect.

Protocols for in vitro culture and phytochemical analysis of Phyllanthus species (euphorbiaceae).

We developed reproducible protocols for micropropagation, callus culture, and root culture of the medicinal plant Phyllanthus urinaria, P. niruri, P. tenellus, P. corcovadensis, P. caroliniensis, P. stipulatus, and P. fraternus by using single node explants. Genotype-linked differences are visible among the Phyllanthus species concerning shoot culture, callus culture, and root culture growth. The protocols developed for phytochemical screening of callus and root extracts of P. urinaria, P. caroliniensis, P. stipulatus, and P. fraternus have shown the production of sterols and triterpenes. Both compounds are known to account for the antinociceptive activity of the methanolic extracts as glochidone and stigmasterol have strong activity against neurogenic and inflammatory pain. Similarly, methanolic callus extracts of P. tenellus, P. niruri and P. corcovadensis have potent analgesic properties, however phenolics are major compounds isolated from these species. The optimized micropropagation, callus culture, and root culture protocols offer the possibility to use cell/root culture techniques for vegetative propagation and secondary metabolite studies.

Mechanisms underlying Eugenia mattosii D. Legrand leaves extract, fractions and compounds induce relaxation of the aorta from normotensive and hypertensive rats.

The present study aimed to verify the effect of methanolic extract, fractions, and phenolic compounds of Eugenia mattosii D. Legrand leaves on the aorta relaxation. Isometric tensions were measured on the aorta of normotensive (NTR) and spontaneously hypertensive rats (SHR). The results showed that both methanolic extracts of leaves and stems, as well as, fractions obtained from leaves were able to induce a concentration-dependent relaxation in both endothelium-intact and -denuded aortas. The methanolic extract of leaves (ME-leaves) was the most effective since the maximal relaxation (≈ 83%) obtained was at the concentration of 300 µg/mL. As the endothelium-dependent relaxation was more significant, we investigated the mechanisms by which ME-leaves induced this effect. After the pretreatment with LNAME, ME-leaves-induced relaxation was decreased in the aorta of NTR and SHR. However, the pretreatment with methylene blue only reduced the relaxation in the aorta of NTR. Furthermore, pretreatment with ME-leaves decreased phenylephrine-induced contraction in preparation Ca2+-free only in aortic rings from NTR. This study also reveals that both compounds, cryptostrobin isolated from chloroform fraction and catechin from the ethyl acetate fraction induced a marked relaxation in endotheliumintact aortic rings of NTR. In conclusion, ME-leaves induces relaxation in the rat aorta involves the modulation of NO/cGMP dependent signaling pathway, this mechanism may at least, in part, explain the endothelium-dependent relaxation. Furthermore, cryptostrobin and catechin also induced relaxation, which may contribute synergistically to the vasorelaxation effect of the ME-leaves.

Effect of Libidibia ferrea bark and seed in maternal reproductive and biochemical outcomes and fetal anomaly in rats.

BACKGROUND: Unhealthy pregnant women living in underdeveloped regions are usually treated by traditional healers, inadvertent of the potential toxic effects of plant-derivative substances. Thus, we investigated whether exposure to a hydroalcoholic extract of bark and seed of Libidibia ferrea during pregnancy results in fetotoxicity and maternal toxicity. The main constituents of both extracts were analyzed by High Performance Liquid Chromatography (HPLC). METHODS: Pregnant rats were divided into three groups: control (C), group exposed to extract of bark (Lfb-1.0 g/kg/day), and group exposed to extract of the seed (Lfs-1.0 g/kg/day). Biochemical parameters, reproductive capacity, morphological effects in the offspring were analyzed. RESULTS: HPLC fingerprint confirmed the presence of ellagic in both bark and seed extracts, and the absence of detectable concentrations of gallic and catechin. Fetuses exposed to L. ferrea extracts presented shorter mean lengths for head and body sections when compared to those in C and exhibited visceral and skeletal anomalies. Pregnant rats exposed to Lfs extracts show alterations in serum creatinine levels and yield amniotic fluid with abnormal biochemical composition. CONCLUSION: Bark or seed extracts of L. ferrea do not exhibit safety level compatible to be used in the gestational period.

Antidepressant-like effect and toxicological parameters of extract and withanolides isolated from aerial parts of Solanum capsicoides All. (Solanaceae).

The present work describes the evaluation of the antidepressant-like activity of the extract, fractions, and compounds obtained from the aerial parts of Solanum capsicoides. The methanolic extract (MESC) obtained by conventional maceration was partitioned with solvents of increasing polarities yielding the respective fractions of hexane (HE), dichloromethane (DCM), and ethyl acetate (EA). The dichloromethane and ethyl acetate fractions were submitted to chromatographic and spectroscopic techniques, leading to the isolation and identification of cilistadiol (1), astragalin (2), and cilistol A (3). In relation to the antidepressant activity, the extract was active against the forced swimming test (FST) at a concentration of 300 mg/kg an ED50 (deffective dose that reduces 50% of immobility time) of 120.3 (117.3-123.4) mg/kg. Similar values were observed when evaluated in the tail suspension test (TST). In addition, the results showed no influence on motor behavior when evaluated in the open field test (OFT). Based on the observed profile of the MESC, dichloromethane fraction presenting the best profile, in both FST and TST test. Likewise, the fraction also did not present motor impairment when evaluated by the OFT test. Considering that the dichloromethane fraction was more effective, the isolated compounds cilistadiol and cilistol A were evaluated in the same experimental models. In FST, both compounds had a significant antidepressant-like effect, with ED50 values of 0.22 (0.16-0.28) and 1.03 (0.89-1.18) µmol/kg, respectively. When evaluated in the TST, showed ED50 values of 0.30 (0.18-0.52) and 1.49 (1.27-1.73) µmol/kg, respectively. The isolated compounds also did not present significant differences in the motor behavior when evaluated on OFT test in comparison with the control group. No toxicological parameters were observed until the highest dose of MESC (2000 mg/kg), demonstrating safety in the use of this plant.

Anti-inflammatory effects of hydroalcoholic extract and two biflavonoids from Garcinia gardneriana leaves in mouse paw oedema.

Garcinia gardneriana (Planch. & Triana) Zappi (Clusiaceae) is widely distributed in Brazil and used in folk medicine to treat inflammation, pain, and urinary tract and other infections. However, very few studies have analyzed these therapeutic effects. In this study, the anti-inflammatory effects of the hydroalcoholic extracts from Garcinia gardneriana (HEGG) and some of its isolated biflavonoids were evaluated. The results showed that HEGG from the leaves, bark and seeds reduced carrageenan-induced mouse paw inflammation, in addition to diminishing the myeloperoxidase activity in the stimulated tissues. The reduction of neutrophil infiltration by treatment with the HEGG from leaves was confirmed by histology. The leaf extract also reduced the paw oedema evoked by bradykinin, histamine, prostaglandin E2 and 12-O-tetradecanoylphorbol acetate. However, it partially decreased substance P and compound 48/80-caused paw oedema, without any influence on the arachidonic acid-induced oedema. Both of the isolated compounds, fukugetin and GB-2a, prevented the carrageenan-induced paw oedema. In conclusion, this study showed important anti-inflammatory effects of HEGG through its interaction with different intracellular signaling pathways, without interfering with the formation of arachidonic acid (AA) metabolites. These characteristics, in addition to the wide distribution and culturing ease of the plant, confirm its popular use and highlight its promise in the development of new anti-inflammatory drugs.

Quercetin: further investigation of its antinociceptive properties and mechanisms of action.

The antinociceptive action of quercetin, a common bioactive flavonoid present in many medicinal plants, was assessed in different models of chemical and thermal nociception in mice. Quercetin (10-60 mg/kg, i.p. or 100-500 mg/kg, p.o.) dose-dependently inhibited nociceptive behavior in the acetic acid-induced pain test. Moreover, quercetin (10-60 mg/kg, i.p.) inhibited both phases of formalin-induced pain, with ID50 values of 374.1 (68.0-402.0) mmol/kg and 103.0 (45.0-201.0) mmol/kg, for the neurogenic and inflammatory phases, respectively. Quercetin (10-60 mg/kg) also inhibited the nociception induced by glutamate and capsaicin by 68.2% and 75.5%, respectively. Its analgesic action was significantly reversed by p-chlorophenylalanine methyl ester, katanserin, methysergide, a GABA(A) antagonist (bicuculline), or a GABA(B) antagonists (baclofen). Its action was also modulated by tachykinins, but was not affected by adrenal-gland hormones. Furthermore, the antinociceptive effects did not result from muscle-relaxant or sedative action. Together, these results indicate that quercetin produces dose-related anti-nociception in several models of chemical pain, through mechanisms that involve interaction with L-arginine-nitric oxide, serotonin, and GABAergic systems. These results confirm and extend other investigations on the analgesic effect of quercetin and its mechanisms of action.

Antiproliferative effects of a series of cyclic imides on primary endothelial cells and a leukemia cell line.

The present study describes the cytotoxic properties of a series of 15 cyclic imides observed against different endothelial cells and K562 leukemic cells. Initially, eight structurally unrelated compounds were evaluated against cultured bone marrow endothelial cells (BMEC) and human umbilical vein endothelial cells (HUVEC). Only two imides showed cytotoxic activity at 10 microM. In continuation of our screening, eight compounds, structurally related to the compound with the higher cytotoxic activity, were assayed against endothelial cells and the K562 leukemic cell line. All of these new compounds except two exhibited cytotoxic and antiproliferative activities at concentrations below 10 microM against BMEC and HUVEC, respectively. The K562 leukemia cell line was only affected by concentrations of 100 microM. Preliminary SAR analysis indicated that the cytotoxic activity of these compounds was related to the presence of a planar imide ring directly bound to an aromatic ring.

Assessment of toxicity and differential antimicrobial activity of methanol extract of rhizome of Simaba ferruginea A. St.-Hil. and its isolate canthin-6-one.

ETHNOPHARMACOLOGICAL RELEVANCE: Simaba ferruginea A. St.-Hil., Simaroubaceae, popularly known as "calunga" is a typical subtropical shrub used in Central Brazil mainly for infection, anti-inflammatory, analgesic and gastric duodenal-ulcers. It presents in its composition the alkaloid canthin-6-one, an alkaloid indole ß-carboxylic. AIM: This study aims to investigate the toxicity, antimicrobial activities of methanol extract of Simaba ferruginea (MESf) and canthin-6-one by using different experimental models. METHODS: The present study evaluated the phytochemical analysis by high performance liquid chromatography (HPLC), toxicological potential of MESf and canthin-6-one, using the cytotoxicity, genotoxicity assays with CHO-K1 cells and in vivo acute test in mice. Antimicrobial activity was evaluated by the broth microdilution assays, while the antimicrobial mechanism of action was also assessed using different in vitro bacterial and fungal models. RESULTS: The HPLC analysis of MESf revealed the presence of canthin-6-one, kaempferol and morin. Differential in vitro toxicities were observed between MESf and canthin-6-one. In the cytotoxicity assay, MESf presented toxicity against CHO-K1, while canthin-6-one did not. In the case of in vitro genotoxicity, both showed to be potentially genotoxic. In the in vivo toxicity study, both MESf (up to 1000 mg/kg) and cantin-6-one (up to 100 mg/kg) caused no toxicologically relevant alterations and are thus considered not to be toxic. MESf was shown to be relatively safe with NOAEL (100 mg/kg) when administrate in mice. Both MESf and canthin-6-one also showed differential antimicrobial activities. On one hand, MESf demonstrated good spectrum of antibacterial action against Staphylococcus aureus (MIC 12.5 µg/mL) and Escherichia coli (MIC 25 µg/mL) and moderate activity against Enterococcus faecalis and Shigella flexneri (MIC 200 µg/mL) but no antifungal effect. On the hand, canthin-6-one showed no antibacterial activity, except against Staphylococcus aureus (100 µg/mL), but potent in vitro fungicidal activity against clinically important Aspergillus niger and Candida species at MFC intervals ranging from 3.12 to 25 µg/mL. Both MESf and canthin-6-one were bacteriostatic in action. MESf antimicrobial mechanism of actions are associated with changes in the permeability of bacterial membranes, evidenced by the increased entry of hydrophobic antibiotic in Shigella flexneri, intense K+ efflux (Shigella flexneri, Staphylococcus aureus) and nucleotides leakage (Staphylococcus aureus). In the antifungal mode of action, canthin-6-one inhibited Saccharomyces cerevisiae growth and including alteration in the cell membrane of Neurospora crassa. CONCLUSION: The results of this work demonstrated the differential antimicrobial activities of MESf and its alkaloid isolate, canthin-6-one with antibacterial and antifungal activities, respectively. The present study support the popular use of Simaba ferruginea in combatting afflictions related to bacterial infections, and demonstrate that canthin-6-one as a promising antifungal agent. Both MESf and canthin-6-one are considered non-toxic based on the in vitro toxicological study.

Evaluation of the antiulcerogenic activity of Maytenus robusta (Celastraceae) in different experimental ulcer models.

Maytenus robusta (Celastraceae) is used in folk medicine for the treatment of stomach ulcers and is very well adapted to the South of Brazil. Maytenus ilicifolia is the main species of the Celastraceae family, and is used in the treatment of gastric ulcers. However, Maytenus ilicifolia is presently at the stage of extinction, due to indiscriminate use in Brazil. Thus, the use of Maytenus robusta in phytotherapeutic preparations, instead of Maytenus ilicifolia, is suggested. However, there have been no reports regarding the antiulcer activity of Maytenus robusta extract. Therefore, this study was carried out to evaluate the antiulcerogenic property of the hydroalcoholic extract of aerial parts of Maytenus robusta. The antiulcer assays were performed using the following protocols: nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, ethanol-induced ulcer, and stress-induced ulcer. The effects of the extract on gastric content volume, pH and total acidity, using the pylorus ligated model, were also evaluated. In the ethanol-induced ulcer model, it was observed that the treatment with Maytenus robusta extract significantly reduced the lesion index in 75.1 +/- 8.6, 85.0 +/- 9.2, 86.6 +/- 7.4 and 75.5 +/- 5.3 for the groups treated with 50, 250 and 500 mg/kg of Maytenus robusta and positive control (omeprazole 30 mg/kg), respectively. Also were observed significant inhibition in lesion index in the indomethacin-induced ulcer model, being the decrease of the 62.5 +/- 7.1, 62.5 +/- 6.1, 63.6 +/- 5.5 and 96.2 +/- 3.6 for groups treated with 50, 250 and 500 mg/kg of Maytenus robusta and positive control (cimetidine 100 mg/kg), respectively. Results similar were observed in the stress-induced ulcer model, where the inhibition of ulcer lesions were 71.3 +/- 5.5, 72.7 +/- 6.3, 76.5 +/- 7.1 and 92.3 +/- 7.5 for the groups treated with 50, 250 and 500 mg/kg of Maytenus robusta and positive control (cimetidine 100 mg/kg), respectively. Regarding the model of gastric secretion, a reduction in the volume of gastric juice volume and total acidity was observed, as well as an increase in gastric pH. The results of the present study showed that Maytenus robusta hydroalcoholic extract displays gastroprotective activity. These results were similar to those obtained in studies carried out with Maytenus ilicifolia, which indicate that this species could be used in phytotherapeutic preparations as a substitute for Maytenus ilicifolia. This work also corroborates the traditional indication of Maytenus robusta, contributing to its pharmacological validation.

Gastroprotective potential of methanolic extract and dimethyl cardamonin from Campomanesia reitziana fruits in mice.

This study evaluated the gastroprotective potential of methanolic extract from fruits of Campomanesia reitziana (MECR) and its isolated chalcone dimethyl cardamonin (DMC). The phenolic compound in the extract, and the free radical scavenging activity of MECR and DMC, were quantified. The gastroprotective activity of MECR (30-300 mg/kg, p.o) and DMC (1 and 3 mg/kg, p.o) was determined by ethanol/HCl-induced gastric ulcers in mice. Histological, histochemical, and biochemical analyses were performed in the ulcerated tissue. MECR showed a high content of phenolic compounds, including DMC, and was able to scavenge DPPH radicals by 29.58% at 1000 µg/mL. However, DCM (1-1000 µg/mL) did not reduce DPPH radicals. Pre-treatment with MECR at doses of 100 and 300 mg/kg reduced the gastric lesions by 35.07 and 79.47%, respectively (ulcerated-vehicle group 10.72 ± 0.88 mm2). Moreover, the extract increased the mucin content by 1044.44% and superoxide dismutase activity by 20.04%, and decreased the lipoperoxide levels by 39.39%, compared to the ulcerated-vehicle group (0.27 ± 0.04 pixels × 103/field; 57.37 ± 1.59 U SOD/mg of protein and 29.57 ± 2.99 mmol LOOH/mg of tissue, respectively). However, MECR did not prevent the depletion of reduced glutathione or the decrease in catalase activity. Pre-treatment with DMC, at 1 and 3 mg/kg, also reduced the gastric ulcers by 53.83 and 52.64%, respectively. In summary, these findings confirm the gastroprotective activity of MECR and DMC, and open an interesting field concerning the gastroprotective potential of dimethyl cardamonin, given its potent antinociceptive and anti-inflammatory activity already described.

The validation of Calophyllum brasiliense ("guanandi") uses in Brazilian traditional medicine as analgesic by in vivo antinociceptive evaluation and its chemical analysis.

Calophyllum brasiliense is used as anti-inflammatory and analgesic in Brazilian traditional medicine. Thus, the main purpose of this study is to evaluate the antinociceptive effect of the chloroform fraction of C. brasiliense (CFCB) roots and to investigate its main mechanism of action. The antinociceptive effect of CFCB was evaluated in mice using acetic acid-induced writhing, formalin-induced paw licking, and hot-plate tests and capsaicin- and glutamate-induced nociception. Brasiliensic acid and 1,2-dimethoxyxanthone were isolated and evaluated in writhing test. The amount of 1,2-dimethoxyxanthone was determined in the fraction by UPLC-DAD. CFCB inhibited abdominal constrictions induced by acetic acid up to 97%, with an ID50 of 9.4 mg/kg (i.p.) and 131.8 mg/kg (p.o.). In the formalin test, CFCB impaired paw licking with an ID50 of 26.3 mg/kg for the first phase and 27.5 mg/kg for the second phase (i.p.). The painful response evoked by capsaicin and glutamate was significantly reduced (ID50 26.7 and 47.9 mg/kg, i.p.). The latency time was increased up to 76% at 60 mg/kg (i.p.) in the hot-plate test. 1,2-Dimethoxyxanthone was almost three times more potent (ID50 27.6 µmol/kg, i.p.) than brasiliensic acid (72.0 µmol/kg) in acetic acid-induced writhing test. The amount of the xanthone was estimated as 92.5 mg/g in the extract. CFCB inhibited the nociceptive response associated to several agents. TRPV1 channels play an important role in the mechanism of action of the fraction. In addition, 1,2-dimethoxyxanthone largely contributes to the antinociceptive effect of CFCB.

Biomonitored UHPLC-ESI-QTOF-MS2 and HPLC-UV thermostability study of the aerial parts of Sphagneticola trilobata (L.) Pruski, Asteraceae.

As the temperature of extraction and processing could impact the biological effects of herbal extracts, which have wide chemical diversity, the aim of this work were to investigate the thermostability of herbal derivatives of the aerial parts of Sphagneticola trilobata, a reputed medicinal plant; to biomonitor its oral anti-hyperalgesic effect; and to elucidate the degradation pathways of the major components by UHPLC-ESI-QTOF-MS. The lipophilic markers (kaurenoic acid-KA) and hydrophilic markers [chlorogenic acids; measured as total phenolic compounds (PC), expressed in caffeic acid] were also monitored through a validated HPLC-UV methodology, suitable for quality control and stability studies. The soft extract (drug:solvent ratio of 1:10, ethanol 60% v/v) was exposed to high temperatures (50-180°C). PC showed high thermolability (27.4% of degradation at 150°C), compared to KA (16.5%, at 180°C). These results suggest that the loss of oral anti-hyperalgesic activity observed in the spray-dried extracts (dried at 170°C), compared with the soft and the lyophilized extract may be related to degradation of the active components, especially the polar compounds, i.e. chlorogenic acid derivatives and the four oleanane type triterpenoid saponins. These latter degraded at temperatures above 150°C and vanished at 180°C, as demonstrated in the UHPLC-ESI-QTOF-MS analyses. These results provide a relevant guide for the extraction process of S. trilobata, aimed at preserving the antinociceptive effect.