RESUMO
Glioblastoma is the most frequent primary malignant brain tumor without effective treatment, which makes this work extremely relevant. The study of the bioactive compounds from medicinal plants plays an important role in the discovery of new drugs.This research investigated the constituents of Tapirira guianensis and its antitumor potential (in vitro and in vivo) in glioblastoma. The T. guianensis extracts were characterized by mass spectrometry. The ethyl acetate partition (01ID) and its fractions 01ID-F2 and 01ID-F4 from T. guianensis showed potential antitumor treatment evidenced by selective cytotoxicity for GAMG with IC50 14.1 µg/mL, 83.07 µg/mL, 59.27 µg/mL and U251 with IC50 25.92 µg/mL, 37.3 µg/mL and 18.84 µg/mL. Fractions 01ID-F2 and 01ID-F4 were 10 times more selective when compared to TMZ and 01ID for the two evaluated cell lines. T. guianensis also reduced matrix metalloproteinases 2â-â01ID-F2 (21.84%), 01ID-F4 (29.6%) and 9â-â01ID-F4 (73.42%), ID-F4 (53.84%) activities, and induced apoptosis mainly through the extrinsic pathway. Furthermore, all treatments significantly reduced tumor size (01ID p < 0,01, 01ID-F2 p < 0,01 and 01ID-F4 p < 0,0001) and caused blood vessels to shrink in vivo. The present findings highlight that T. guianensis exhibits considerable antitumor potential in preclinical studies of glioblastoma. This ability may be related to the phenolic compounds and sesquiterpene derivatives identified in the extracts. This study deserves further in vivo research, followed by clinical investigation.
Assuntos
Antineoplásicos , Glioblastoma , Plantas Medicinais , Glioblastoma/tratamento farmacológico , Extratos Vegetais/química , Angiogênese , Plantas Medicinais/química , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular TumoralRESUMO
Annonacea species have been reported to possess antitumor properties. However, the in vitro and in vivo antitumor activities of Xylopia aromatica (Annonacea) have not yet been elucidated. This study aimed to investigate the effects of Xylopia aromatica leaves hexane fraction (XaHF) on Ehrlich ascites carcinoma cells lines (EAC), both in vitro and in vivo. In vitro assays revealed a significant cytotoxic effect with the two lower XaHF concentrations (62.5 and 32.3mg/mL). EAC (2.5x106 cells) were inoculated in the right flank of Swiss mice, and the animals were treated intraperitoneally with 32.3mg kg-1 of XaHF daily, for 20 days. Our findings indicate that XaHF suppressed the growth of EAC in vivo, with a significant decrease (46%) in tumor volume. There was also a decrease in the necrosis area (71%), inflammatory infiltrate, and MMP-2 expression. High-Performance Liquid Chromatography with Diode Array Detector (HPLC-DAD) identified secondary metabolites possibly related to phenolic acids, flavonoids, and alkaloids. Thus, the results confirmed the antitumoral activity that may be related to the presence of the identified metabolites in XaHF extract.
Assuntos
Carcinoma de Ehrlich/metabolismo , Proliferação de Células/efeitos dos fármacos , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta , Xylopia , Alcaloides/química , Animais , Aporfinas/química , Carcinoma de Ehrlich/patologia , Catequina/química , Linhagem Celular Tumoral , Ácido Clorogênico/química , Cromatografia Líquida de Alta Pressão , Regulação para Baixo , Flavonoides/química , Ácido Gálico/química , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Necrose , Fenóis/química , Extratos Vegetais/química , Quercetina/química , Rutina/química , Carga Tumoral/efeitos dos fármacosRESUMO
The species Annona nutans (R. E. Fries) is a plant found in Bolivia, Paraguay, Argentina and the Brazilian cerrado. Considering the anti-inflammatory and antinociceptive activities of the hydrometanolic fraction (FHMeOH) of A. nutans leaves previously reported, the present study aimed to evaluate in vivo anti-inflammatory and antinociceptive activities of a subfraction obtained from FHMeOH, the butanolic fraction (FBuOHf). Intraperitoneal (i.p.) treatment with FBuOHf (50 and 100 mg · kg-1) inhibited paw edema induced by carrageenan. Moreover, FBuOHf (100 mg · kg-1, i.p.) also suppressed polymorphonuclear (PMN) leukocyte migration in the footpad. Regarding the antinociceptive activity, FBuOHf (50, 100, and 200 mg · kg-1, i.p.) inhibited acetic acid-induced abdominal writhing. In the formalin test, this fraction (200 mg · kg-1, i.p.) reduced licking time only in the inflammatory phase. The FBuOHf contents flavonoids and cinnamic acid derivatives, such as quercetin-3-O-galactoside, quercetin-3-O-glucoside, isorhamnetin-3-O-galactoside, quercetin-3-O-ß-D-apio-furanosyl-(1â2)-galactopyranoside and chlorogenic acid, identified and quantified by LC-MS. The FBuOHf possesses anti-inflammatory and peripheral antinociceptive activities.
Assuntos
Annona , Annonaceae , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Carragenina , Edema/induzido quimicamente , Edema/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Folhas de PlantaRESUMO
A previous study reported the in vivo anti-inflammatory and antinociceptive activities of essential oil of the underground stem bark of Duguetia furfuracea, termed EODf. This study aimed to obtain a phenylpropanoid-enriched fraction from the D. furfuracea (EFDf) essential oil and to investigate its anti-inflammatory and antinociceptive effects. The chemical composition of the EFDf was determined by gas chromatography-mass spectrometry (GC-MS). The in vivo anti-inflammatory activity was evaluated with a lipopolysaccharide (LPS)-induced paw oedema model. The effects of the EFDf on the polymorphonuclear leukocyte recruitment and the inducible nitric oxide synthase (iNOS) expression were evaluated in mice footpads. Moreover, the in vivo antinociceptive effect was assayed using the formalin test and the LPS-induced thermal hyperalgesia model. In the EFDf, 8 major compounds were identified, with α-asarone (36.4%) and 2,4,5-trimethoxystyrene (27.8%) the main constituents. A higher concentration of phenylpropanoid derivatives was found in the EFDf, 64.2% compared to the EODf (38%). The oral (p.o.) treatment with the EFDf at a dose of 3 mg/kg significantly attenuated the paw oedema, polymorphonuclear leukocyte migration, iNOS expression, and tumour necrosis factor alpha (TNF-α) production. The EFDf (10 and 30 mg/kg) also inhibited both phases of the formalin test and caused a significant increase in the reaction time in the LPS-induced thermal hyperalgesia model. Finally, EFDf-treated animals did not show any alteration of motor coordination. The results suggest that the enrichment of 2,4,5-trimethoxystyrene and α-asarone enhances the anti-inflammatory activity of the EFDf compared to the EODf. In contrast, the antinociception promoted by the EFDf was similar to the EODf and was mediated via activation of adenosinergic and opioidergic receptors.
Assuntos
Analgésicos/farmacologia , Annonaceae/química , Anti-Inflamatórios/farmacologia , Extratos Vegetais/farmacologia , Analgésicos/isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , Modelos Animais de Doenças , Edema/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Lipopolissacarídeos , Masculino , Camundongos , Óleos Voláteis/isolamento & purificação , Óleos Voláteis/farmacologia , Medição da Dor , Fenilpropionatos/químicaRESUMO
Gliomas account for nearly 70% of the central nervous system tumors and present a median survival of approximately 12-17 months. Studies have shown that administration of novel natural antineoplastic agents is been highly effective for treating gliomas. This study was conducted to investigate the antitumor potential (in vitro and in vivo) of Miconia chamissois Naudin for treating glioblastomas. We investigated the cytotoxicity of the chloroform partition and its sub-fraction in glioblastoma cell lines (GAMG and U251MG) and one normal cell line of astrocytes. The fraction showed cytotoxicity and was selective for tumor cells. Characterization of this fraction revealed a single compound, Matteucinol, which was first identified in the species M. chamissois. Matteucinol promoted cell death via intrinsic apoptosis in the adult glioblastoma lines. In addition, Matteucinol significantly reduced the migration, invasion, and clonogenicity of the tumor cells. Notably, it also reduced tumor growth and angiogenesis in vivo. Moreover, this agent showed synergistic effects with temozolomide, a chemotherapeutic agent commonly used in clinical practice. Our study demonstrates that Matteucinol from M chamissois is a promising compound for the treatment of glioblastomas and may be used along with the existing chemotherapeutic agents for more effective treatment.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Cromonas/uso terapêutico , Glioblastoma/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Cromonas/isolamento & purificação , Cromonas/farmacologia , Glioblastoma/irrigação sanguínea , Humanos , Melastomataceae , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Extratos Vegetais , Folhas de PlantaRESUMO
Alpha-asarone has been found to possess many pharmacological activities, which can improve cognitive function and exert anti-oxidant, anxiolytic, anti-epileptic and protective effects against endothelial cell injury. The anti-inflammatory activity of α-asarone was evaluated using lipopolysaccharide (LPS)-induced paw oedema. Moreover, leukocyte migration, inducible nitric oxide synthase (iNOS) expression and tumour necrosis factor-alpha (TNF-α) levels were quantified in footpads. Formalin and LPS-induced thermal hyperalgesia models were generated using adenosinergic, opioidergic, serotonergic and muscarinic receptor antagonists. The effects on motor coordination were evaluated by means of the rota-rod test. Oral treatment (p.o.) with α-asarone (3 mg/kg) significantly inhibited paw oedema by 62.12 and 72.22%, 2 and 4 h post LPS injection, respectively. Alpha-asarone (3 mg/kg, p.o.) attenuated the inflammatory infiltrate 1, 3 and 6 h after LPS injection. Furthermore, α-asarone (3 mg/kg, p.o.) suppressed iNOS expression and TNF-α production, 6 and 1 h after inflammatory stimulus, respectively. Alpha-asarone (3, 10 and 30 mg/kg, p.o.) inhibited both phases of formalin-induced licking. In the hot-plate test, α-asarone (10 and 30 mg/kg, p.o.) increased the latency to response 3 and 5 h post LPS stimulus. Caffeine and naloxone abolished the central anti-nociceptive effect of α-asarone (neurogenic phase of formalin and hot plate tests), suggesting the participation of the adenosinergic and opioidergic systems. Furthermore, naloxone reversed the peripheral activity of α-asarone (inflammatory phase of formalin test), indicating the possible involvement of the opioidergic pathway. In the rota-rod test, α-asarone did not change motor coordination. These findings suggest that α-asarone has anti-inflammatory, peripheral and central anti-nociceptive effects and could represent a promising agent for future research.
Assuntos
Analgésicos/farmacologia , Anisóis/farmacologia , Anti-Inflamatórios/farmacologia , Leucócitos/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Derivados de Alilbenzenos , Animais , Modelos Animais de Doenças , Edema/tratamento farmacológico , Edema/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Dor/tratamento farmacológico , Dor/metabolismo , Medição da Dor/métodos , Extratos Vegetais/farmacologiaRESUMO
The medical importance of intra-abdominal candidiasis (IAC) contrasts with the limited number of pharmacological treatment options available and the increasing rate of resistance to antifungal drugs. Thus, the repositioning of compounds in clinical use can contribute to the broadening of treatment possibilities for this infection. Statins, a class of drugs used to reduce cardiovascular event risk, have shown antiparasitic, antibacterial, and antiviral activities; however, their antifungal effects remain poorly studied. In this context, the present study aimed to elucidate the antifungal potential of six statins in vitro, as well as to evaluate the therapeutic use of fluvastatin in a mouse model of IAC. The biological effects of statins were evaluated against Candida spp., through the determination of the minimum inhibitory concentration (MIC). For the statins that showed activity, the fungicidal concentration, toxicity/selectivity, synergism with azoles and polyenes, phenotypic effects, and activity against virulence factors were also determined. Atorvastatin, rosuvastatin and fluvastatin were highly active, especially against C. albicans (MIC < 1-128 µg.mL-1) and C. glabrata (MIC 32-64 µg.mL-1). Fluvastatin and atorvastatin were selective for C. albicans in baby hamster kidney (BHK) cells. Moreover, all active statins in the antifungal assay showed high selectivity for fungal cells over bacteria. The combination of atorvastatin, rosuvastatin, and fluvastatin with azoles was associated with a synergistic effect. Active statins do not act on the fungal membrane or wall, but instead stimulate farnesol-dependent pathogenicity factors such as yeast-to-hyphal transition and biofilm generation. Fluvastatin treatment was evaluated in a mouse model of IAC, showing stimulation of the extra-hepatic dissemination of C. albicans but improvements in renal, splenic, and hepatic histological aspects. In conclusion, statins have potent antifungal activity in vitro, but the therapeutic effect in vivo is restricted to their anti-inflammatory activity.
Assuntos
Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candidíase Invasiva/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Animais , Antifúngicos/farmacologia , Candida albicans/fisiologia , Candidíase Invasiva/patologia , Cricetinae , Relação Dose-Resposta a Droga , Feminino , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Mesocricetus , Camundongos , Testes de Sensibilidade Microbiana/métodos , Distribuição AleatóriaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Duguetia furfuracea (A. St. -Hil.) Saff. (Annonaceae) is commonly known in Brazil as "araticum-seco," and its root is used in folk medicine to treat inflammatory and painful disorders. However, no studies have been performed to evaluate these therapeutic activities. AIM OF THE STUDY: Investigate the chemical composition, anti-inflammatory and antinociceptive effects, and elucidate the possible antinociceptive mechanisms of action from the essential oil of D. furfuracea (EODf) underground stem bark. MATERIALS AND METHODS: Chemical composition was determined by gas chromatography and mass spectrometry (GC/MS). The paw edema induced by LPS, formalin-induced nociception, LPS-induced thermal hyperalgesia and rota-rod tests in vivo were used to evaluate the anti-inflammatory and antinociceptive effects in addition to the alteration on motor coordination. Histological analyses and an immunohistochemistry assay for iNOS were performed on mouse footpads of naive, control, 10â¯mg/kg EODf, and 10â¯mg/kg indomethacin (Ind) groups. The samples were removed at 1, 3, and 6â¯h after subplantar injection of LPS. In addition, the involvement of the adenosinergic, opioidergic, serotonergic, and cholinergic systems were investigated, in order to elucidate possible antinociceptive mechanisms. RESULTS: Twenty-four volatile constituents were detected and identified. (E)-asarone (21.9%), bicyclogermacrene (16.7%), 2,4,5-trimethoxystyrene (16.1%), α-gurjunene (15%), cyperene (7.8%), and (E)-caryophyllene (4.6%) were major compounds found in EODf. Oral treatment (p.o.) with EODf (1, 3, and 10â¯mg/kg) significantly inhibited the paw edema induced by LPS. At 10â¯mg/kg EODf promoted inhibition of tumor necrosis factor alpha (TNF-α) production, recruitment of polymorphonuclear (PMN) leukocytes and inducible nitric oxide synthase (iNOS) expression in paw tissue. EODf (10 and 30â¯mg/kg, p.o.) also reduced licking time in both phases of the formalin test and it had a significant effect on the LPS-induced thermal hyperalgesia model. The administration of caffeine (Caf) and naloxone (Nal) reversed the antinociceptive activity of EODf, in the first phase of the formalin test and in the LPS-induced thermal hyperalgesia model. Moreover, Nal was also able to abolish the antinociception caused by EODf, in the second phase of formalin test. In the rota-rod test, EODf-treated animals did not show any alteration of motor coordination. CONCLUSIONS: Our findings indicate that EODf underground stem bark produces anti-inflammatory and both central and peripheral antinociceptive effects. Furthermore, the antinociceptive activity of EODf underground stem bark is possibly mediated by adenosinergic and opioidergic pathways, and its properties do not induce effects on motor coordination. These results support the use of the folk medicine, D. furfuracea root, to treat inflammation and painful conditions.
Assuntos
Analgésicos , Annonaceae , Anti-Inflamatórios , Óleos Voláteis , Analgésicos/química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Annonaceae/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Edema/tratamento farmacológico , Edema/imunologia , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Masculino , Camundongos , Antagonistas de Entorpecentes/farmacologia , Óxido Nítrico Sintase Tipo II/imunologia , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Óleos Voláteis/uso terapêutico , Dor/tratamento farmacológico , Medição da Dor , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Raízes de Plantas/química , Antagonistas de Receptores Purinérgicos P1/farmacologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Plants of the Asteraceae family have been traditionally used as medicinal plants. The species Achyrocline satureioides and Achyrocline alata present anti-inflammatory properties and great chemical similarity. However, no study has been performed to evaluate the influence of these plants on skin wound healing in vivo. Here, we have assessed the effect of these plants extracts on skin wound healing in mice. Mice were randomly arranged into three groups (n = 10), an injury was performed on the dorsal area of the animals, which received the following topical treatment: group 1, control (ointment base); group 2, A. satureioides extract; group 3, A. alata extract. The solution for treatment was prepared as 10% (w/w) concentration. The wound area was measured on days 1, 4, 9, 15 and 17 after treatment and tissues of local lesion were collected on the ninth day for histological analysis. A. alata was more effective since it induced earlier wound closure associated with decreasing initial inflammatory response, faster reepithelialization and collagen remodeling. A. satureioides improved the collagen renovation, but induced slower closure, which may be due to different concentrations of phenolic compounds among the plants here studied. Both plants did not alter the ultrastructural characteristics of cells in the healing process. In conclusion, our findings suggest the potent wound healing capacity of A. alata extracts, as demonstrated by more efficient and faster induction of wound closure. We believe this plant is a potential wound healing treatment for humans and further studies are necessary to assess its clinical practice.
Assuntos
Achyrocline/metabolismo , Reparo do DNA/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Pele/efeitos dos fármacos , Pele/lesões , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Camundongos , Compostos Fitoquímicos/uso terapêuticoRESUMO
Cancer of the head and neck is a group of upper aerodigestive tract neoplasms in which aggressive treatments may cause harmful side effects to the patient. In the last decade, investigations on natural compounds have been particularly successful in the field of anticancer drug research. Our aim is to evaluate the antitumor effect of Tapirira guianensis Aubl. extracts on a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. Analysis of secondary metabolites classes in fractions of T. guianensis was performed using Nuclear Magnetic Resonance (NMR). Mutagenicity effect was evaluated by Ames mutagenicity assay. The cytotoxic effect, and migration and invasion inhibition were measured. Additionally, the expression level of apoptosis-related molecules (PARP, Caspases 3, and Fas) and MMP-2 was detected using Western blot. Heterogeneous cytotoxicity response was observed for all fractions, which showed migration inhibition, reduced matrix degradation, and decreased cell invasion ability. Expression levels of MMP-2 decreased in all fractions, and particularly in the hexane fraction. Furthermore, overexpression of FAS and caspase-3, and increase of cleaved PARP indicates possible apoptosis extrinsic pathway activation. Antiproliferative activity of T. guianensis extract in HNSCC cells lines suggests the possibility of developing an anticancer agent or an additive with synergic activities associated with conventional anticancer therapy.
Assuntos
Anacardiaceae/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/genética , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colágeno/química , Combinação de Medicamentos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Laminina/química , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Testes de Mutagenicidade , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteoglicanas/química , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Receptor fas/genética , Receptor fas/metabolismoRESUMO
Despite the large use of the Plantago major and Siparuna guianensis in traditional medicine, there are no studies demonstrating the effectiveness from extracts of these plants in the healing process by the present methodology. This study reported the effects and toxicity of the P. major and S. guianensis extracts in the wound healing compared with a commercial product used in Brazil by macroscopic and microscopic analysis. Following injury in cervical dorsal area of the mice, the extract from P. major and S. guianensis and ointment was applied after an injury in cervical dorsal area of the mice. Wound healing rates were calculated at 4, 9, 15 and 21 d after the wounding, and tissues were obtained on the ninth day for histological analysis. Moreover, mutagenic assay of extracts was performed. Mutagenicity studies carried out with plant extracts showed not mutagenic with or without metabolic activations. Reduction of the wound area occurred earlier in mice treated with P. major and control treatment. On the 15th day, the complete wound closure occurred in P. major-treated wounds. Throughout ointment and S. guianensis treatment it was not observed the wound closured. Microscopic analyses of the wound, on the ninth day, showed the more efficient formation of the neoepithelium and skin appendages in animals treated with S. guianensis and P. major, while ointment treatment presented no re-epithelialization and absent skin appendages in wound. Thus, P. major extract showed good effects on wound healing processes rendering it a promising candidate for the treatment of wounds what also justified its traditional usage in wound treatment.