Actions of sesquiterpene lactones isolated from Moquiniastrum polymorphum subsp. floccosum in MCF7 cell line and their potentiating action on doxorubicin.

BACKGROUND: In order to obtain better clinical results in anticancer therapies, polychemotherapy or combination therapies are used. For this, the combinations are required to increase the efficacy and reduce the adverse reactions of the associated chemotherapies. The aim of this study was to evaluate the cytotoxic, apoptotic and (anti)proliferative potential of two sesquiterpene lactones isolated from Moquiniastrum polymorphum, 11,13-diidrozaluzanin C (1) and gochnatiolide C (2), and their associations with chemotherapeutic agents irinotecan, tamoxifen, cisplatin, 5-fluouracyl and doxorubicin in the tumoral lineage of MCF-7 breast adenocarcinoma. METHODS: The analyses were performed by MTT cytotoxicity assays, drug combination index (CI), apoptosis morphological assay and cell proliferation assay. Treatments were evaluated with short exposure times (4 h), followed or not by recovery in drug-free medium for 24 h. For the cell viability assay the statistical analysis was performed using software INSTAT, and the ANOVA/Tukey test was applied. Combination Indices (CI) was made using CompuSyn software and demonstrated through isoboles. The assays that evaluated cell death and proliferation used statistical analysis SAS 9.4 (Statistical Analysis System), and the procedure adopted was PROC NPAR1WAY. The Wilcoxon test at 5% level was applied for comparing statistical differences. RESULTS: The results demonstrated that the compounds decrease cell viability and increase their action when associated with irinotecan, tamoxifen and doxorubicin (CI < 1 and CI = 1). In periods of 4 h-exposure, the compounds cause cell death by apoptosis and after 24 h, they increase the mean number of cells in programmed cell death, especially when treated with 2. In addition, the association with doxorubicin increases the apoptotic potential induced by tested compounds. Both isolates had effect on the reduction of the number of mitoses, especially when 2 at its highest concentration is associated with doxorubicin. CONCLUSIONS: Finally, these compounds are presented as potential agents in chemotherapy combined with doxorubicin, since they trigger the mechanism of apoptosis, which, through the mechanism of action of sesquiterpene lactones, leads to a reduction in toxicity. In addition, the tested compounds have the ability to exert a synergistic action with doxorubicin, possibly by down-regulating the drug resistance mechanisms.

Hydroethanolic extract of Baccharis trimera promotes gastroprotection and healing of acute and chronic gastric ulcers induced by ethanol and acetic acid.

Ethanol is a psychoactive substance highly consumed around the world whose health problems include gastric lesions. Baccharis trimera is used in folk medicine for the treatment of gastrointestinal disorders. However, few studies have evaluated its biological and toxic effects. To validate the popular use of B. trimera and elucidate its possible antiulcerogenic and cytotoxic mechanisms, a hydroethanolic extract of B. trimera (HEBT) was evaluated in models of gastric lesions. Rats and mice were used to evaluate the protective and antiulcerogenic effects of HEBT on gastric lesions induced by ethanol, acetic acid, and chronic ethanol consumption. The effects of HEBT were also evaluated in a pylorus ligature model and on gastrointestinal motility. The LD50 of HEBT in mice was additionally estimated. HEBT was analyzed by nuclear magnetic resonance, and a high-performance liquid chromatography fingerprint analysis was performed. Oral HEBT administration significantly reduced the lesion area and the oxidative stress induced by acute and chronic ethanol consumption. However, HEBT did not protect against gastric wall mucus depletion and did not alter gastric secretory volume, pH, or total acidity in the pylorus ligature model. Histologically, HEBT accelerated the healing of chronic gastric ulcers in rats, reflected by contractions of the ulcer base. Flavonoids and caffeoylquinic acids were detected in HEBT, which likely contributed to the therapeutic efficacy of HEBT, preventing or reversing ethanol- and acetic acid-induced ulcers, respectively. HEBT antiulcerogenic activity may be partially attributable to the inhibition of free radical generation and subsequent prevention of lipid peroxidation. Our results indicate that HEBT has both gastroprotective and curative activity in animal models, with no toxicity.

Sesquiterpene lactones of Moquiniastrum polymorphum subsp. floccosum have antineoplastic effects in Walker-256 tumor-bearing rats.

BACKGROUND AND AIM: This study aimed to evaluate the in vivo antitumor actions and toxicity of the dichloromethane fraction (F1B) of Moquiniastrum polymorphum subsp. floccosum (formerly Gochnatia polymorpha ssp. floccosa), composed of sesquiterpene lactones, against Walker-256 carcinosarcoma in rats. METHODS: Male Wistar rats received 100 mg kg(-1) F1B per day orally for 16 days after subcutaneous inoculation of Walker-256 cells in the pelvic limb. The tumor progression was monitored, and after treatment, tumor weight, oxidative stress, plasma biochemistry, inflammatory parameters, gene expression and histology of tumor and/or liver were evaluated. The toxicity of F1B was analyzed through the relative weight of organs. Additionally, an LD50 test was performed in mice. RESULTS: F1B treatment significantly reduced tumor volume and weight. There was no difference in oxidative stress in tumor tissue after treatment. F1B treatment modified hepatic glutathione and superoxide dismutase, and normalized plasma glucose, alkaline phosphatase, and amylase. F1B did not affect the activity of myeloperoxidase and N-acetylglucosaminidase or the nitric oxide levels in tumor tissue. However, F1B decreased the tumor necrosis factor (TNF)-α levels. Additionally, F1B increased apoptosis in the tumor, mediated by up-regulation of the p53 and Bax gene expression. No clinical signs of toxicity or death were observed in the rats treated with F1B. The LD50 calculated for mice was 1209 mg kg(-1). CONCLUSIONS: F1B, which is rich in sesquiterpene lactones, showed antitumor activity against Walker-256 carcinosarcoma. This effect may be, at least in part, related to the induction of apoptosis and inhibition of TNF-α signaling.

Anti-Inflammatory and Antihyperalgesic Activities of Ethanolic Extract and Fruticulin A from Salvia lachnostachys Leaves in Mice.

The anti-inflammatory and analgesic effects of the ethanolic extract (SLEE) and fruticulin A from the leaves of Salvia lachnostachys were evaluated in mice, using experimental models of inflammation (paw oedema and pleurisy induced by carrageenan injection) and hyperalgesia (electronic Von Frey). Oral administration of SLEE (30, 100, and 300 mg/kg) and fruticulin A (0.3 and 3.0 mg/kg) decreased the total leucocytes number in pleural lavage, protein extravasation, and paw oedema. SLEE (100 mg/kg) and fruticulin A (3 mg/kg) also exhibited antihyperalgesic activity in carrageenan induced mechanical hyperalgesia. In addition, fruticulin A (3 mg/kg) prevented mechanical hyperalgesia, inhibiting TNF but not L-DOPA-induced mechanical hyperalgesia. In conclusion, SLEE and fruticulin A display anti-inflammatory and analgesic properties. Therefore, fruticulin A is at least partially responsible for the activity observed in the ethanolic extract of Salvia lachnostachys.

Gochnatia polymorpha ssp. floccosa: bioprospecting of an anti-inflammatory phytotherapy for use during pregnancy.

ETHNOPHARMACOLOGICAL RELEVANCE: Gochnatia polymorpha ssp. floccosa is used in folk medicine to treat inflammation and infections. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly consumed medications during pregnancy in women with inflammatory diseases. However, the relationship between the use of NSAIDs and the risk of miscarriage and birth defects and/or benefits is not fully understood. Thus, an investigation regarding the use of Gochnatia polymorpha during gestation is of relevance for developing safe anti-inflammatory drugs for use during pregnancy. MATERIALS AND METHODS: The pregnant females were randomly divided into 5 groups. Control group received a hydroalcoholic solution (1.2%), via gavage, for at least 15 days prior to mating and throughout the gestational period. The pre-treatment group received Gochnatia polymorpha ethanol extract (GPEE), via gavage, at a dose of 100mg/kg body weight (b.w.) for at least 15 days prior to mating and up to the appearance of the vaginal plug. The organogenesis group received GPEE at a dose of 100mg/kg (b.w.), via gavage, on the 5-15th gestacional day. The pregnancy group received GPEE at a dose of 100mg/kg (b.w.), via gavage, throughout the gestational period (from the 1st to the 18th day of pregnancy). The pre+pregnancy group received GPEE at a dose of 100mg/kg (b.w.), via gavage, for at least 15 days prior to mating and throughout the entire gestational period. The clinical signals of maternal toxicity and teratogenesis were evaluated. Additional assays to evaluate chronic inflammation, antigenotoxicity and immunomodolatory activity were performed. RESULTS AND CONCLUSIONS: The results indicated that GPEE does not interfere with reproductive performance or embryo-fetal development but does correlate with reduced weight and fetal length. The extract was not teratogenic or mutagenic or an immunomodulator. However, GPEE did exhibit effective anti-inflammatory activity. Based on this study, it can be inferred that GPEE is an important, safe anti-inflammatory agent for use during pregnancy according to the experimental design we utilized, which opens up possibilities for the bioprospecting of a new anti-inflammatory phytotherapy for use during pregnancy.

Uncaria tomentosa exerts extensive anti-neoplastic effects against the Walker-256 tumour by modulating oxidative stress and not by alkaloid activity.

This study aimed to compare the anti-neoplastic effects of an Uncaria tomentosa (UT) brute hydroethanolic (BHE) extract with those of two fractions derived from it. These fractions are choroformic (CHCl3) and n-butanolic (BuOH), rich in pentacyclic oxindole alkaloids (POA) and antioxidant substances, respectively. The cancer model was the subcutaneous inoculation of Walker-256 tumour cells in the pelvic limb of male Wistar rat. Subsequently to the inoculation, gavage with BHE extract (50 mg.kg(-1)) or its fractions (as per the yield of the fractioning process) or vehicle (Control) was performed during 14 days. Baseline values, corresponding to individuals without tumour or treatment with UT, were also included. After treatment, tumour volume and mass, plasma biochemistry, oxidative stress in liver and tumour, TNF-α level in liver and tumour homogenates, and survival rates were analysed. Both the BHE extract and its BuOH fraction successfully reduced tumour weight and volume, and modulated anti-oxidant systems. The hepatic TNF-α level indicated a greater effect from the BHE extract as compared to its BuOH fraction. Importantly, both the BHE extract and its BuOH fraction increased the survival time of the tumour-bearing animals. Inversely, the CHCl3 fraction was ineffective. These data represent an in vivo demonstration of the importance of the modulation of oxidative stress as part of the anti-neoplastic activity of UT, as well as constitute evidence of the lack of activity of isolated POAs in the primary tumour of this tumour lineage. These effects are possibly resulting from a synergic combination of substances, most of them with antioxidant properties.

Anti-inflammatory activity of extracts and 11,13-dihydrozaluzanin C from Gochnatia polymorpha ssp. floccosa trunk bark in mice.

AIM OF THIS STUDY: Gochnatia polymorpha ssp. floccosa (Asteraceae), popularly known as "cambará", is well recognized in Brazilian traditional medicine to treat the respiratory tract inflammatory diseases and rheumatism. However, no scientific data have been published to support this ethnopharmacological use. This work aimed to evaluate the anti-inflammatory action of its ethanol (EEGP) extract, ethyl acetate (EA), dichloromethane (DCM), petroleum ether (PE) butanolic (BT) fractions, and the isolated compounds bauerenyl acetate (GPC1) and 11,13-dihydrozaluzanin C (GPC2). MATERIALS AND METHODS: The anti-inflammatory activities were evaluated in mice subjected to paw oedema and carrageenan-induced air pouch inflammation models. RESULTS: The oral administration of EEGP (30, 100 and 300 mg/kg), DCM (50 mg/kg), BT (20 mg/kg) and GPC2 (10 and 30 mg/kg), but not EP and EA fractions (both at 30 mg/kg) and GPC1 (1 and 10 mg/kg), significantly inhibited the paw oedema induced by carrageenan (41±13, 39±5 and 60±10% for EEGP at the three doses, respectively; 44,47±12.8 and 70.19±11.52% for DCM and BT, respectively; and 29.52±4.8 and 31.67±5.4%, for 11,13-dihydrozaluzanin C at 10 and 30mg/kg, respectively) compared to control group. The oral administration of EEGP (30, 100 and 300 mg/kg) inhibited the carrageenan-induced leukocyte migration in the air pouch model (37.2±12.5, 62.6±5.0 and 54.3±6.8%, respectively), as well as protein extravasation (47.9±12.5, 51.7±15.2 and 60.9±13.7%, respectively) compared to control group. In a similar way, DCM (50 mg/kg) or GPC2 (10 mg/kg), but not BT (20 mg/kg) given by oral route inhibited leukocyte infiltration into the pouch (29.5±10.6 and 54.4±21.8%, respectively). Also DCM and GPC2 significantly reduced the protein levels in the supernatants (52.4±15.0 and 51.83±16.9%, respectively). CONCLUSION: The results suggest that EEGP, and BT and DCM fractions from G. polymorpha possess anti-inflammatory activity and probably the compound 11,13-dihydrozaluzanin C was responsible, at least in part, for this action.