ABSTRACT
Two new triterpenes mayteneri A (1), mayteneri B (2), and seven known compounds (3-9) were isolated from stems of Maytenus hookeri Loes. The chemical structures of compounds 1 and 2 were established by 1D, 2D NMR, HRESIMS analysis, and calculating electronic circular dichroism (ECD). The structures of known compounds 3-9 were determined by comparison of their spectral with those reported. Compounds 4-7 showed significant inhibitory activity for NLRP3 inflammasome, with the IC50 values of 2.36-3.44 µM.
Subject(s)
Maytenus , Oleanolic Acid , Molecular Structure , Oleanolic Acid/chemistry , Oleanolic Acid/analogs & derivatives , Oleanolic Acid/isolation & purification , Oleanolic Acid/pharmacology , Maytenus/chemistry , Triterpenes/chemistry , Triterpenes/pharmacology , Triterpenes/isolation & purification , Plant Stems/chemistry , Animals , Mice , Inflammasomes/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitorsABSTRACT
The new flavonoid (-)-4'-O-methylepicatechin 5-O-ß-D-glucopyranoside (1), along with four known triterpenes (2-5), a steroid (6), and a flavonoid (7) were isolated from the ethyl acetate extract of Maytenus quadrangulata leaves. The chemical structures of the isolated compounds were determined through analysis of 1D NMR (1H and 13C) spectroscopic data, in addition to 2D NMR and spectrometric (MS) data for compound 1. This is the first report of the isolation of daucosterol (6) and (-)-4'-O-methylepigallocatechin (7) from this species. Compounds 1 and 7 were evaluated against the bacteria Staphylococcus aureus and Klebsiella pneumoniae, but neither exhibited activity even at the highest concentration tested.
Subject(s)
Acetates , Anti-Bacterial Agents , Flavonoids , Klebsiella pneumoniae , Microbial Sensitivity Tests , Plant Extracts , Plant Leaves , Staphylococcus aureus , Triterpenes , Plant Leaves/chemistry , Triterpenes/chemistry , Triterpenes/isolation & purification , Triterpenes/pharmacology , Flavonoids/isolation & purification , Flavonoids/chemistry , Flavonoids/pharmacology , Staphylococcus aureus/drug effects , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Klebsiella pneumoniae/drug effects , Acetates/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/chemistry , Maytenus/chemistry , Molecular StructureABSTRACT
Eleven densely functionalized new dihydro-ß-agarofuran sesquiterpenoid derivatives, named maytenoids A-K (1-11), as well as one known analog, were isolated and characterized from Maytenus austroyunnanensis. Their structures were assigned based on analysis of spectroscopic data and X-ray crystallography. Compounds 1-9 are macrocyclic sesquiterpene pyridine alkaloids generated by the respective acylation of the hydroxy groups at C-3 and C-13 of dihydro-ß-agarofuran sesquiterpenoids via diverse pyridine dicarboxylic acids. Compounds 1, 2, 5-10, and 12 exhibited significant inhibitory effects on NO production at 10 µM in lipopolysaccharide (LPS)-stimulated BV2 cells.
Subject(s)
Alkaloids , Maytenus , Sesquiterpenes , Maytenus/chemistry , Molecular Structure , Alkaloids/pharmacology , Alkaloids/chemistry , Sesquiterpenes/pharmacology , Sesquiterpenes/chemistry , Pyridines/chemistryABSTRACT
The relationship between oxidative stress and inflammation is well known, and exogenous antioxidants, primarily phytochemical natural products, may assist the body's endogenous defense systems in preventing diseases due to excessive inflammation. In this study, we evaluated the antioxidant properties of ethnomedicines from Peru that exhibit anti-inflammatory activity by measuring the superoxide scavenging activity of ethanol extracts of Maytenus octogona aerial parts using hydrodynamic voltammetry at a rotating ring-disk electrode (RRDE). The chemical compositions of these extracts are known and the interactions of three methide-quinone compounds found in Maytenus octogona with caspase-1 were analyzed using computational docking studies. Caspase-1 is a critical enzyme triggered during the activation of the inflammasome and its actions are associated with excessive release of cytokines. The most important amino acid involved in active site caspase-1 inhibition is Arg341 and, through docking calculations, we see that this amino acid is stabilized by interactions with the three potential methide-quinone Maytenus octogona inhibitors, hydroxytingenone, tingenone, and pristimerin. These findings were also confirmed after more rigorous molecular dynamics calculations. It is worth noting that, in these three compounds, the methide-quinone carbonyl oxygen is the preferred hydrogen bond acceptor site, although tingenone's other carbonyl group also shows a similar binding energy preference. The results of these calculations and cyclovoltammetry studies support the effectiveness and use of anti-inflammatory ethnopharmacological ethanol extract of Maytenus octogona (L'Héritier) DC.
Subject(s)
Maytenus , Superoxides , Maytenus/chemistry , Caspase 1 , Plant Extracts/pharmacology , Plant Extracts/chemistry , Antioxidants/pharmacology , Quinones , Anti-Inflammatory Agents/pharmacology , Inflammation , EthanolABSTRACT
The objective of this work was to identify and classify the plants species designated as medicinal by the population of Taboco in different categories of use and investigate the specie with higher value of use with medicinal potential in experimental models. The field research took place between June and November 2018, with periodic visits to the Taboco Village, Brazil. The community makes use of a diversity of native, cultivated and domesticated species, corresponding to 89 plant species, belonging to 44 families, for cure or prevention over 60 types of health problems. The species Maytenus ilicifolia, with the highest use value was evaluated in experimental models. In this treatment a higher keratin production, reconstitution of the epithelium and the structured dermis was observed, with thick collagen fibers rich in fibroblasts, which favored the healing of exposed wounds.
El objetivo de este trabajo fue identificar y clasificar las especies de plantas designadas como medicinales por la población de Taboco en diferentes categorías de uso e investigar la especie con mayor valor de uso con potencial medicinal en modelos experimentales. La investigación de campo se llevó a cabo entre junio y noviembre de 2018, con visitas periódicas a Villa de Taboco, Brasil. La comunidad hace uso de una diversidad de especies nativas, cultivadas y domesticadas, correspondientes a 89 especies vegetales, pertenecientes a 44 familias, para la curación o prevención de más de 60 tipos de problemas de salud. La especie Maytenus ilicifolia, con mayor valor de uso, fue evaluada en modelos experimentales. En este tratamiento se observó una mayor producción de queratina, reconstitución del epitelio y de la dermis estructurada, con espesas fibras de colágenoricas en fibroblastos, lo que favoreció la cicatrización de las heridas expuestas.
Subject(s)
Plants, Medicinal , Ethnobotany , Wound Healing , Brazil , Maytenus/chemistry , Medicine, TraditionalABSTRACT
Two new triterpenes, 3ß, 7ß-dihydroxyolean-12-en-11-one (1) and 3ß-O-acetyl-7ß-hydroxyolean-12-en-11-one (2), along with four known triterpenes 3ß-hydroxyolean-12-en-11-one (3), ß-amyrin (4), lup-20(29)-ene-1ß, 3ß-diol (5) and 1ß, 3ß-dihydroxy-urs-9(11)-12-diene (6), were isolated from the stems and leaves of Maytenus guangxiensis C. Y. Cheng et W. L. Sha. Their structures were elucidated using 1D and 2D NMR spectroscopy as well as MS and IR experiments. Compounds (3-6) were isolated from M. guangxiensis for the first time. Compounds 1-6 were evaluated for their antiproliferative activities against Eca-109, PANC-1, EJ and HeLa cell lines. The results showed that compounds 1-6 displayed a certain degree of inhibitory effects against the proliferation of various human cancer cell lines.
Subject(s)
Maytenus , Triterpenes , Humans , Triterpenes/chemistry , Maytenus/chemistry , HeLa Cells , Plant Leaves/chemistry , Magnetic Resonance Spectroscopy , Molecular StructureABSTRACT
Due to the widespread use of Maytenus ilicifolia leaves in the treatment of gastric ulcers, herbal medicines derived from such species are distributed by the national health system in Brazil. A related species, Maytenus aquifolium, is also used for the same disorders, and both are popularly known as Espinheira-santa. Due to their popular use, the quality and efficiency of the herbal medicines derived from these species is an important public health issue. The purpose of this study was to develop and test an analytical method that could quantify the content of catechin and epicatechin in dry Maytenus spp. leaves and simultaneously obtain their chemical profile to determine authenticity of the leaf samples. Ultra-high performance liquid chromatography coupled to mass spectrometry (UHPLC-MS) was used to quantify these isomers, in the selected ion monitoring (SIM) mode, while simultaneously analyzing the extract in full-scan mode. This approach was successfully applied to the analysis of commercial and authentic samples of Maytenus spp. Fewer than half the samples presented the minimum epicatechin content of 2.8 mg per g of dry leaf mass, as specified in the 6th Brazilian Pharmacopoeia (2019) for M. ilicifolia. Furthermore, by using untargeted metabolomics, it was observed that the chemical profile of most the samples was not compatible with M. ilicifolia leaves, indicating the need for stricter quality control of this material. The method described herein could be used for this control; moreover, its concept could be adapted and used for an ample variety of medicinal plant products.
Subject(s)
Catechin , Maytenus , Plants, Medicinal , Chromatography, High Pressure Liquid/methods , Mass Spectrometry , Maytenus/chemistry , Plant Extracts/chemistryABSTRACT
Free (epi) catechin, quercetin, (epi) gallocatechin, flavonol glycosides and condensed tannins were identified according to their molecular mass, characteristic product ions and retention times in extracts obtained from leaves and branches of Maytenus ilicifolia (Congorosa) by mass spectrometry. The in vitro anthelmintic activity against cattle gastrointestinal nematodes of Congorosa extract was determined using the Egg Hatch Inhibition Assay. Additionally, commercial quercetin, gallocatechin and epicatechin were evaluated. Although total phenolics, total tannins and condensed tannins contents were lower in branches extract than in leaves extract, the EC50 were 0.065 mg/mL and 0.890 mg/mL for branches and leaves extract, respectively. Moreover, the use of polyvinylpyrrolidone as a blocking agent of tannins, did not change significantly the EC50 for branches extract, but significantly changed for leaves extract. Quercetin and gallocatechin EC50 values were in the range 0.03-0.05 mg/mL and epicatechin showed 100% inhibition of the egg hatching process at 0.004 mg/mL.
Subject(s)
Anthelmintics , Catechin , Maytenus , Proanthocyanidins , Animals , Anthelmintics/pharmacology , Catechin/analysis , Cattle , Maytenus/chemistry , Phenols/analysis , Phenols/pharmacology , Plant Extracts/chemistry , Plant Leaves/chemistry , Proanthocyanidins/analysis , Quercetin/analysis , Quercetin/pharmacology , Tannins/analysisABSTRACT
The genus Maytenus is a member of the Celastraceae family, of which several species have long been used in traditional medicine. Between 1976 and 2021, nearly 270 new compounds have been isolated and elucidated from the genus Maytenus. Among these, maytansine and its homologues are extremely rare in nature. Owing to its unique skeleton and remarkable bioactivities, maytansine has attracted many synthetic endeavors in order to construct its core structure. In this paper, the current status of the past 45 years of research on Maytenus, with respect to its chemical and biological activities are discussed. The chemical research includes its structural classification into triterpenoids, sesquiterpenes and alkaloids, along with several chemical synthesis methods of maytansine or maytansine fragments. The biological activity research includes activities, such as anti-tumor, anti-bacterial and anti-inflammatory activities, as well as HIV inhibition, which can provide a theoretical basis for the better development and utilization of the Maytenus.
Subject(s)
Alkaloids/chemistry , Maytansine/analogs & derivatives , Maytenus/chemistry , Phytochemicals/chemistry , Sesquiterpenes/chemistry , Triterpenes/chemistry , Alkaloids/classification , Alkaloids/isolation & purification , Alkaloids/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Anti-HIV Agents/chemistry , Anti-HIV Agents/isolation & purification , Anti-HIV Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/pharmacology , Humans , Maytansine/isolation & purification , Maytansine/pharmacology , Maytenus/metabolism , Molecular Structure , Phytochemicals/classification , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Plants, Medicinal , Sesquiterpenes/classification , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacology , Structure-Activity Relationship , Triterpenes/classification , Triterpenes/isolation & purification , Triterpenes/pharmacologyABSTRACT
Maytenus roylanus (MEM) is a plant with anti-proliferative effects against prostate cancer. We aimed to explore the mechanism of action of MEM in prostate cancer (PCa) by employing an in vitro global proteome approach to get useful information of various signaling pathways and effected genes to define the mechanism of MEM action in prostate cancer. We conducted a global proteome analysis of CWR22Rv1after treatment with methanolic extract of MEM. The result of the proteomic profiling of in vitro PCa cells demonstrated the reduction in tumor protein D52 (TPD52) expression after treatment with methanolic extract of MEM. Down-regulation of TPD52 expression at mRNA level was observed by MEM treatment in CWR22Rν1 and C4-2 cells in a dose-dependent fashion probably by cleavage of Caspase 3 and PARP, or by modulation of cyclin-dependent kinases in CWR22Rν1 and C4-2 cells. The progressive character of the TRAMP model demonstrates a chance to evaluate the potential of chemo-preventive agents for both initial and late stages of prostate cancer development, and induction in TPD52 protein expression with development as well as the progression of prostate cancer was observed in the TRAMP model. Analyses of the tissue microarray collection of 25 specimens confirmed the clinical significance of our findings identifying TPD52 as a potential marker for PCa progression. We determined that knockdown of TPD52 (CWR22Rν1 cells), a considerable downregulation was seen at the protein level. Downregulation of TPD52 inhibited the migration and invasive behavior of prostate cancer cells as observed. Moreover, we observed that the siRNA-TPD52 transfection of CWR22Rν1 cells resulted in tumor growth inhibition with a marked reduction in the secretion of prostate-specific antigen (PSA) in the serum. Intraperitoneal injection of MEM considerably slowed tumor growth in athymic mice, inhibited TPD52 expression, and caused a marked reduction in PSA levels of serum as demonstrated by immunoblot screening and immune-histochemical staining. This report illustrates a molecular overview of pathological processes in PCa, indicating possible new disease biomarkers and therapeutic targets.
Subject(s)
Maytenus/chemistry , Neoplasm Proteins/metabolism , Plant Extracts/pharmacology , Prostatic Neoplasms/metabolism , Proteomics/methods , Tissue Array Analysis/methods , Animals , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Mice, Nude , Neoplasm Proteins/genetics , PC-3 Cells , Plant Extracts/administration & dosage , Plant Leaves/chemistry , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , RNA Interference , Xenograft Model Antitumor Assays/methodsABSTRACT
Maytenus ilicifolia or "Espinheira-Santa" is a renowned Brazilian medicinal plant usually used against intestinal and stomach ulcers. Other species with similar thorny leaves have raised great confusion in order to discern the authentic M. ilicifolia. Misidentifications can lead to product adulteration of authentic M. ilicifolia with other species, which can be found on the Brazilian market. The intake of misclassified herbal products potentially could be fatal, demanding faster reliable fingerprinting-based classification methods. In this study, the use of 1H HR-MAS NMR metabolomics fingerprinting and principal component analysis (PCA) allowed an evaluation of the authenticity for both collected and commercial M. ilicifolia samples, from the content of the flavanol, (-)-epicatechin (2), by observing variations in metabolic patterns. Plant specimen types from cultivated and natural habitats were analyzed by considering seasonal and topological differences. The interand intraplant topological metabolic profiles were found to be affected by seasonal and/or ecological trends such as sunlight, shade, rain, and the presence of pathogens. Moreover, several commercial samples, labeled as M. ilicifolia, were evaluated, but most of these products were of an inadequate quality.
Subject(s)
Maytenus/chemistry , Metabolome , Brazil , Catechin/analysis , Environment , Plant Leaves/chemistry , Plants, Medicinal/chemistry , SeasonsABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Maytenus ilicifolia Mart. ex Reissek, Celastraceae, is popularly known as "espinheira-santa" and used to treat pathologies related to the stomach. However, in popular culture, this species has also been used to treat other disorders such as diabetes, but without scientific evidence, requiring more phytochemical and pharmacological studies on the plant. AIM OF THE STUDY: This work aims to investigate the anti-hyperglycemic potential of ethanolic extracts obtained from leaves from two different accessions of Maytenus ilicifolia (MIA and MIB) in normal hyperglycemic rats. MATERIALS AND METHODS: The animals were divided into different experimental groups: normal hyperglycemic (negative control); MIA (treatment of Maytenus ilicifolia extract from access 116); MIB (treatment with Maytenus ilicifolia extract from access 122; and glipizide (positive control). At 30 min after treatment, all animals received glucose overload orally. Blood collection occurred at different periods for the assessment of blood glucose (0, 60, 90 and 210 min after treatment) and at the end of the experiment blood was collected through cardiac puncture and the liver, muscle, pancreas and intestine were dissected for further analysis. RESULTS: Chromatographic analysis identified oleic and palmitic acid as the most common constituents, and both extracts of Maytenus ilicifolia caused a reduction in blood glucose levels within 60 min after administration of glucose overload when compared to the normal hyperglycemic group. No significant changes were observed in hepatic and muscular glycogen levels, plasma insulin concentration and disaccharidases activity with none of the extracts in the model employed. However, hyperglycemic rats treated with the extracts showed a marked increase in triglyceride and HDL cholesterol levels. CONCLUSIONS: Our data suggest that Maytenus ilicifolia extracts from different locations showed differences in chemical composition which did not reflect significant differences in the results of biological tests. In addition, it was possible to conclude that the treatment with Maytenus ilicifolia had a discreet anti-hyperglycemic effect; however, it was not possible to identify the responsible mechanism, being necessary, therefore, new studies using different technologies in order to determine the possible mechanisms of action of the extract.
Subject(s)
Glucose/metabolism , Hyperglycemia/drug therapy , Maytenus/chemistry , Plant Extracts/chemistry , Plant Extracts/pharmacology , Alanine Transaminase/blood , Animals , Blood Glucose/drug effects , Disaccharides/metabolism , Ethanol/chemistry , Glipizide/pharmacology , Glipizide/therapeutic use , Glycogen/metabolism , Insulin/blood , Lipids/blood , Male , Oxidative Stress/drug effects , Plant Extracts/therapeutic use , Plant Leaves/chemistry , Rats, Wistar , Urea/bloodABSTRACT
Midazolam (MDZ) is routinely employed as a marker compound of cytochrome P450 3A (CYP3A) activity. Despite the many HPLC-UV methods described to quantify MDZ in plasma, all of them use acetonitrile (ACN) or a mixture of methanol-isopropanol as organic solvent of the mobile phase. Since the ACN shortage in 2008, efforts have been made to replace this solvent during HPLC analysis. A simple, sensitive, accurate and repeatable HPLC-UV method (220 nm) was developed and validated to quantify MDZ in rat plasma using methanol instead. The method was applied during a herb-drug interaction study involving Maytenus ilicifolia, a Brazilian folk medicine used to treat gastric disorders. Plasma samples were alkalinized and MDZ plus alprazolam (internal standard) were extracted with diethyl ether. After solvent removal, the residue was reconstituted with methanol-water (1:1). The analyte was eluted throughout a C18 column using sodium acetate buffer (10 mm, pH 7.4)-methanol (40:60, v/v). The precision at the lower limit of quantification never exceeded 19.40%, and 13.86% at the higher levels of quality control standards, whereas the accuracy ranged from -19.81 to 14.33%. The analytical curve was linear from 50 to 2,000 ng/ml. The activity of the hepatic CYP3A enzymes was not affected by the extract.
Subject(s)
Chromatography, High Pressure Liquid/methods , Herb-Drug Interactions , Maytenus/chemistry , Midazolam/blood , Animals , Cytochrome P-450 CYP3A/metabolism , Linear Models , Male , Methanol , Midazolam/administration & dosage , Midazolam/pharmacokinetics , Plant Preparations/administration & dosage , Plant Preparations/blood , Plant Preparations/pharmacokinetics , Rats , Rats, Wistar , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Maytenus robusta Reissek (Celesteraceae), popularly named as cafezinho do mato or coração de bugre, is employed to treat inflammatory digestive diseases in the south of Brazil. However, despite popular usage, the effects of this species on an experimental model of ulcerative colitis are unknown. AIM OF THE STUDY: To evaluate the effects of M. robusta extract (HEMR) on colon and liver from mice with colitis induced by dextran sulfate sodium (DSS). MATERIALS AND METHODS: Firstly, the cytotoxicity of HEMR and its effects on ROS and nitrite production in IEC-6 cells were evaluated. The experimental colitis was established by adding 3% DSS on drinking water of mice and the effects of HEMR (1-100 mg/kg, p.o, once a day by 7 days) in colonic and hepatic tissues were analyzed. RESULTS: The HEMR (1-100 µg/mL) did not alter the cell viability but reduced nitrite production of IEC-6 stimulated by LPS. Moreover, HEMR (100 mg/Kg) attenuates macro and microscopic alterations in the colon from mice exposed to DSS, as evidenced by a reduction of the colon shortening, attenuation of the epithelial erosion, submucosal edema and preservation of the Goblet cells integrity, as well as the restoration of mucin depletion. The treatment with HEMR increased GSH amount, reduced LOOH levels and normalizes CAT activity in the colon. The group treated with HEMR showed increased GST activity, reduced MPO activity and decreased inflammatory cytokines secretion (TNF and IL-6) in the colonic tissue. In the liver, HEMR increased GST activity, decreased the GPx activity and reduced IL-6 levels. Furthermore, the HEMR treatment reduced AST and ALT serum levels in mice exposed to DSS. Finally, the HEMR was able to reduce intestinal transit. CONCLUSIONS: HEMR treatment minimizes inflammation of the colon and maintaining the antioxidant homeostasis. In addition, HEMR may be a potential tool to prevent hepatic injury secondary to ulcerative colitis.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Colitis/prevention & control , Colon/drug effects , Gastrointestinal Agents/pharmacology , Intestinal Mucosa/drug effects , Liver/drug effects , Maytenus , Plant Extracts/pharmacology , Animals , Anti-Inflammatory Agents/isolation & purification , Antioxidants/pharmacology , Cell Line , Colitis/chemically induced , Colitis/metabolism , Colitis/pathology , Colon/metabolism , Colon/pathology , Cytokines/metabolism , Dextran Sulfate , Disease Models, Animal , Female , Gastrointestinal Agents/isolation & purification , Gastrointestinal Motility/drug effects , Inflammation Mediators/metabolism , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Liver/metabolism , Maytenus/chemistry , Mice , Oxidative Stress/drug effects , Plant Extracts/isolation & purification , RatsABSTRACT
BACKGROUND: Maytenus ilicifolia is a Brazilian popular medicine commonly used to treat ulcer and gastritis. Despite the absence of toxicity regarding its consumption, possible interactions when co-administrated with conventional drugs, are unknown. OBJECTIVE: This study aimed to evaluate the effects of M. ilicifolia extracts on Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) activities. METHODS: The extracts were obtained by infusion (MI) or turbo-extraction using hydro-acetonic solvent (MT70). The content of polyphenols in each extract was determined. To assess the modulation of M. ilicifolia on P-gp activity, the uptake of fexofenadine (FEX) by Caco-2 cells was investigated in the absence or presence of MI or MT70. The effect on CYP3A activity was evaluated by the co-administration of midazolam (MDZ) with each extract in male Wistar rats. The pharmacokinetic parameters of the drug were determined and compared with those from the control group. The content of total phenolic compounds, tannins, and flavonoids on MT70 extract was about double of that found in MI. RESULTS: In the presence of the extracts, the uptake of the P-gp marker (FEX) by Caco-2 cells increased from 1.7 ± 0.4 ng.mg-1 protein (control) to 3.5 ± 0.2 ng.mg-1 protein (MI) and 4.4 ± 0.5 ng.mg-1 protein (MT70), respectively. When orally co-administrated with MDZ (substrate of CYP3A), the extracts augmented the AUC(0-∞) (Control: 911.7 ± 215.7 ng.h.mL-1; MI: 1947 ± 554.3 ng.h.mL-1; MT70: 2219.0 ± 506.3 ng.h.mL-1) and the Cmax (Control: 407.7 ± 90.4 ng.mL-1; MI: 1770.5 ± 764.5 ng.mL-1; MT70: 1987.2 ± 544.9 ng.mL-1) of the drug in rats indicating a 50% reduction of the oral Cl. No effect was observed when midazolam was given intravenously. CONCLUSION: The results suggest that M. ilicifolia can inhibit the intestinal metabolism and transport of drugs mediated by CYP3A and P-gp, respectively, however, the involvement of other transporters and the clinical relevance of such interaction still need to be clarified.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Cytochrome P-450 CYP3A/metabolism , Maytenus/chemistry , Plant Extracts/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/agonists , Animals , Caco-2 Cells , Cell Line , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Drug Interactions , Humans , Ketoconazole/pharmacology , Male , Midazolam/pharmacokinetics , Quinolines/pharmacology , Rats , Rats, Wistar , Terfenadine/analogs & derivativesABSTRACT
Maytenus disticha (Hook F.), belonging to the Celastraceae family, is an evergreen shrub, native of the central southern mountains of Chile. Previous studies demonstrated that the total extract of M. disticha (MD) has an acetylcholinesterase inhibitory activity along with growth regulatory and insecticidal activities. ß-Dihydroagarofurans sesquiterpenes are the most active components in the plant. However, its activity in cancer has not been analyzed yet. Here, we demonstrate that MD has a cytotoxic activity on breast (MCF-7), lung (PC9), and prostate (C4-2B) human cancer cells with an IC50 (µg/mL) of 40, 4.7, and 5 µg/mL, respectively, an increasing Bax/Bcl2 ratio, and inducing a mitochondrial membrane depolarization. The ß-dihydroagarofuran-type sesquiterpene (MD-6), dihydromyricetin (MD-9), and dihydromyricetin-3-O-ß-glucoside (MD-10) were isolated as the major compounds from MD extracts. From these compounds, only MD-6 showed cytotoxic activity on MCF-7, PC9, and C4-2B with an IC50 of 31.02, 17.58, and 42.19 µM, respectively. Furthermore, the MD-6 increases cell ROS generation, and MD and MD-6 induce a mitochondrial superoxide generation and apoptosis on MCF-7, PC9, and C4-2B, which suggests that the cytotoxic effect of MD is mediated in part by the ß-dihydroagarofuran-type that induces apoptosis by a mitochondrial dysfunction.
Subject(s)
Apoptosis/drug effects , Maytenus/chemistry , Membrane Potential, Mitochondrial/drug effects , Mitochondria , Neoplasms , Plant Extracts/chemistry , Reactive Oxygen Species/metabolism , Sesquiterpenes/pharmacology , Humans , MCF-7 Cells , Mitochondria/metabolism , Mitochondria/pathology , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Sesquiterpenes/chemistryABSTRACT
BACKGROUND: Myrin®-p Forte is an anti-tuberclosis agent that can cause hepatic injuries in clinical settings. Maytenus royleanus (Celastraceae) is a medicinal plant, possesses antioxidant and anticancer activities. The hepatoprotective effect of the methanol extract of Maytenus royleanus leaves (MEM) against Myrin®-p Forte induced hepatotoxicity in mice was investigated. METHODS: Mice were randomly parted into six groups (n = 6). Fixed-dose combination of Myrin®-p Forte (13.5 mg/kg Rifampicin, 6.75 mg/kg Isoniazid, 36.0 mg/kg Pyrazinamide and 24.8 mg/kg Ethambutol; RIPE] was administered for 15 days to induce liver injury. In treatment groups MEM (200 mg/kg and 400 mg/kg doses) and Vitamin B6 (180mg/kg) were administered prior to RIPE. Control group received 2% DMSO. Serum liver function tests, DNA damage, tissue antioxidant enzymes and histopathological alterations were studied. HPLC analysis was performed to determine the chemical composition using standard compounds. RESULTS: The quercitin, gallic acid, luteolin, viteixin, apigenin, kaempherol, hyperoside and myricetin contents of all samples were determined by reverse-phase HPLC. Quercetin (0.217 mg/g dry weight) and luteolin (0.141 mg/g dry weight) were the major flavonoids identified in MEM. Myrin®-p Forte markedly (p < 0.05) deteriorated lipid profile and upregulated the concentration of LDH, AST, ALP, ALT and γ-GT in serum along with DNA fragmentation (37.13 ± 0.47%) and histopathological injuries in hepatic tissues of mice compared with the control group. Myrin®-p Forte increased (p < 0.001) lipid peroxidation and H2O2 while decreased (p < 0.001) the activity level of CAT, SOD, POD, GPx, GST, GSR, γ-GT and GSH. Co-administration of MEM (200 mg/kg; 400 mg/kg) or the vitamin B6 (180 mg/kg) to Myrin®-p Forte administered mice significantly ameliorated LDL, cholesterol, HDL and triglyceride content. Furthermore, MEM dose dependently corrected serum liver function tests, decrease % DNA fragmentation (17.82 ± 0.35 and 7.21 ± 0.32 respectively), DNA damage. MEM treated protect RIPE induced oxidative damage by enhancing antioxidants to oxidants balance. Histological examination comprehends biochemical findings. CONCLUSION: The antioxidant effects of MEM exerted the hepatoprotective potential against the Myrin®-p Forte induced hepatotoxicity in mice.
Subject(s)
Antineoplastic Agents/adverse effects , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/metabolism , Liver/drug effects , Maytenus/chemistry , Plant Leaves/chemistry , Animals , Chromatography, High Pressure Liquid , Glutathione/metabolism , Glutathione Peroxidase/metabolism , Glutathione Transferase/metabolism , Hydrogen Peroxide/metabolism , Lipid Peroxidation/drug effects , Liver/metabolism , Male , Mice , Oxidative Stress/drug effects , Peroxidase/metabolism , Superoxide Dismutase/metabolism , Thiobarbituric Acid Reactive Substances/metabolismABSTRACT
Natural triterpenes exhibit a wide range of biological activities. Since this group of secondary metabolites is structurally diverse, effects may vary due to distinct biochemical interactions within biological systems. In this work, we investigated the anticancer-related activities of the quinone-methide triterpene maytenin and its derivative compound 22-ß-hydroxymaytenin, obtained from Maytenus ilicifolia roots cultivated in vitro. Their antiproliferative and pro-apoptotic activities were evaluated in monolayer and three-dimensional cultures of immortalized cell lines. Additionally, we investigated the toxicity of maytenin in SCID mice harboring tumors derived from a squamous cell carcinoma cell line. Both isolated molecules presented pronounced pro-apoptotic activities in four cell lines derived from head and neck squamous cell carcinomas, including a metastasis-derived cell line. The molecules also induced reactive oxygen species (ROS) and down-regulated microRNA-27a and microRNA-20a/miR-17-5p, corroborating with the literature data for triterpenoids. Intraperitoneal administration of maytenin to tumor-bearing mice did not lead to pronounced histopathological changes in kidney tissue, suggesting low nephrotoxicity. The wide-ranging activity of maytenin and 22-ß-hydroxymaytenin in head and neck cancer cells indicates that these molecules should be further explored in plant biochemistry and biotechnology for therapeutic applications.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Maytenus/chemistry , Triterpenes/chemistry , Triterpenes/pharmacology , Acute Kidney Injury/chemically induced , Animals , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Agents, Phytogenic/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Down-Regulation/drug effects , Drug Screening Assays, Antitumor , Female , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/pathology , Humans , Keratinocytes/drug effects , Mice, SCID , MicroRNAs/genetics , Plant Extracts/chemistry , Plant Roots/chemistry , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/pathology , Triterpenes/adverse effects , Xenograft Model Antitumor AssaysABSTRACT
Medium and high polarity extracts from Maytenus species are known to contain polyphenolic compounds such as proanthocyanidins. The high polarity and structural complexity of these compounds make very difficult their isolation even by modern chromatographic techniques. Maytenus cajalbanica (Borhidi & O. Muñiz) Borhidi & O. Muñiz is endemic from Cuba. So far, there are reports neither of phytochemical work nor of biological evaluation of extracts from this subspecies. The goal of this work is to determine the polyphenolic profile and the antioxidant capacity of the ethanolic extract from the barks of Maytenus cajalbanica. FIA/ESI/IT/MSn analysis allowed the identification of 5 flavan-3-ol monomers, 33 proanthocyanidins, 2 free flavonoids and their respective glycosides as major compounds of the ethanolic extract, which showed a strong radical scavenging capacity and a significant ferric reduction power. FIA/ESI/IT/MSn technique led the rapid, effective and sensitive determination of the polyphenolic profile of Maytenus cajalbanica without previous separation.
Subject(s)
Antioxidants/pharmacology , Maytenus/chemistry , Plant Extracts/pharmacology , Polyphenols/analysis , Spectrometry, Mass, Electrospray Ionization/methods , Antioxidants/chemistry , Biphenyl Compounds/chemistry , Ethanol/chemistry , Flavonoids/analysis , Glycosides/analysis , Picrates/chemistry , Plant Bark/chemistry , Plant Extracts/chemistry , Polyphenols/chemistry , Proanthocyanidins/analysisABSTRACT
Leishmaniases, caused by Leishmania spp., are among the most prevalent infectious diseases in the world and their treatment may present high toxicity and side/adverse effects. This study evaluated the antileishmanial activity of the Hexanic Eluate subfraction from Maytenus guianensis bark (HEMg) incorporated in microparticles of PLGA. One batch of microparticles produced contained HEMg (HEMgP) and another contained the PLGA polymer alone (PCTE). The microparticles were characterized in regards to diameter, Zeta potential, encapsulation rate and morphology and their cytotoxicity was evaluated against J774 macrophages. The infection assay employing peritoneal macrophages witth L. amazonensis and cytokine dosages were performed on the cell supernatants. The groups of infected BALB/C mice were treated, euthanized and the parasite load and cytokine production were evaluated. The diameters and zeta potential were: 4⯵m and -11.6â¯mV (PCTE) and 7.8⯵m and -26.7â¯mV (HEMgP). The encapsulation rate was â 15% and the morphology of the particles was spherical and homogeneous. In the infection assay, HEMgP inhibited the amastigotes by 70% (24â¯h) and 59% (48â¯h) and induced IL-12 and TNF-α production. HEMg in solution reduced the number of parasites in the lymph nodes by 50% and HEMgP administration increased the levels of IL-12 and TNF-α cytokines in lymph nodes and in the lesion site. When encapsulated, HEMg maintained its antileishmanial activity, but in a more attenuated and sustained form over time, showing promise as complementary/alternative therapy against cutaneous leishmaniasis.