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1.
Zhongguo Zhong Yao Za Zhi ; 45(4): 932-936, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32237496

RESUMO

Cerebral ischemia-reperfusion(I/R) injury is an important cause of acute ischemic stroke. Timely elimination of damaged proteins and organelles by regulating autophagy during cerebral ischemia-reperfusion plays an important role in relieving brain damage. In order to investigate whether ß-caryophyllene(BCP) could protect neurons from cerebral I/R injury by regulating auto-phagy, C57 BL/6 J male mice were randomly divided into sham operation group, model group, and drug-administered group. After intra-gastric administration was given for 5 days, the middle cerebral artery occlusion(MCAO) model was established by suture method. Twenty four hours after surgery, the infarct volume and neurological function were assessed; the pathological changes of cortical tissue were observed by HE staining; Western blot was used to detect the expression of autophagy-related proteins beclin1, p62, LC3 B and apoptosis-related protein Bcl-2; immunofluorescence was used to observe the expression of LC3 B in the ischemic cortex. The autophagy of cortical tissue in the ischemic area was observed by transmission electron microscopy. The experimental results showed that as compared with the model group, the BCP pretreatment significantly reduced the neurological deficit, decreased the percentage of cerebral infarction volume, reduced the death of brain tissue cells in the ischemic area, up-regulated the expression of beclin1, LC3 B and Bcl-2 protein, down-regulated p62 protein expression, and significantly increased the number of autophagosomes in the cortical tissue of the ischemic area. It was finally determined that BCP could protect neurons from cerebral ischemia-reperfusion injury by activating autophagy.


Assuntos
Autofagia , Isquemia Encefálica/tratamento farmacológico , Sesquiterpenos Policíclicos/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Infarto da Artéria Cerebral Média , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória
4.
PLoS Negl Trop Dis ; 14(2): e0008073, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32101555

RESUMO

The Aedes aegypti mosquito serves as a major vector for viral diseases, such as dengue, chikungunya, and Zika, which are spreading across the globe and threatening public health. In addition to increased vector transmission, the prevalence of insecticide-resistant mosquitoes is also on the rise, thus solidifying the need for new, safe and effective insecticides to control mosquito populations. We recently discovered that cinnamodial, a unique drimane sesquiterpene dialdehyde of the Malagasy medicinal plant Cinnamosma fragrans, exhibited significant larval and adult toxicity to Ae. aegypti and was more efficacious than DEET-the gold standard for insect repellents-at repelling adult female Ae. aegypti from blood feeding. In this study several semi-synthetic analogues of cinnamodial were prepared to probe the structure-activity relationship (SAR) for larvicidal, adulticidal and antifeedant activity against Ae. aegypti. Initial efforts were focused on modification of the dialdehyde functionality to produce more stable active analogues and to understand the importance of the 1,4-dialdehyde and the α,ß-unsaturated carbonyl in the observed bioactivity of cinnamodial against mosquitoes. This study represents the first investigation into the SAR of cinnamodial as an insecticide and antifeedant against the medically important Ae. aegypti mosquito.


Assuntos
Aedes/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Inseticidas/farmacologia , Sesquiterpenos Policíclicos/farmacologia , Animais , Feminino , Inseticidas/síntese química , Inseticidas/química , Larva/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Controle de Mosquitos , Sesquiterpenos Policíclicos/síntese química , Sesquiterpenos Policíclicos/química , Conformação Proteica , Canal de Cátion TRPA1/química , Canal de Cátion TRPA1/metabolismo
5.
Artigo em Inglês | MEDLINE | ID: mdl-31931331

RESUMO

Ptaquiloside (PTA) is an illudane glycoside partly responsible for the carcinogenicity of bracken ferns (Pteridium sp.). The PTA analogues ptesculentoside (PTE) and caudatoside (CAU) have similar biochemical reactivity. However, both compounds are highly under-investigated due to the lack of analytical standards and appropriate methods. This study presents a robust method for preparation of analytical standards of PTE, CAU, PTA, the corresponding hydrolysis products: pterosins G, A and B, and an LC-MS based method for simultaneous quantification of the six compounds in bracken. The chromatographic separation of analytes takes 5 min. The observed linear range of quantification was 20-500 µg/L for PTA and pterosin B, and 10-250 µg/L for the remaining compounds (r > 0.999). The limits of detection were 0.08-0.26 µg/L for PTE, CAU and PTA and 0.01-0.03 µg/L for the pterosins, equivalent to 2.0-6.5 µg/g and 0.25-0.75 µg/g in dry weight, respectively. The method was applied on 18 samples of dried fern leaves from 6 continents. Results demonstrated high variation in concentrations of PTE, CAU and PTA with levels prior to hydrolysis up to 3,900, 2,200 and 2,100 µg/g respectively. This is the first analytical method for simultaneous and direct measurement of all six compounds. Its application demonstrated that bracken ferns contain significant amounts of PTE and CAU relative to PTA.


Assuntos
Cromatografia Líquida/métodos , Glicosídeos , Indanos , Pteridium/química , Sesquiterpenos , Glicosídeos/análise , Glicosídeos/química , Indanos/análise , Indanos/química , Limite de Detecção , Modelos Lineares , Espectrometria de Massas/métodos , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/química , Extratos Vegetais/química , Sesquiterpenos Policíclicos/análise , Sesquiterpenos Policíclicos/química , Reprodutibilidade dos Testes , Sesquiterpenos/análise , Sesquiterpenos/química
6.
Artigo em Inglês | MEDLINE | ID: mdl-31707089

RESUMO

Compounds having insecticidal activity can be used to control Aedes aegypti mosquitoes, a major worldwide vector, and several plants have a source of such molecules. A principal component analysis (PCA) was carried out to determine the criterion to select larvicidal metabolites. The insecticidal activity of seven selected metabolites by PCA was validated by determining its lethal concentrations 50 (LC50) by probit analysis. Six of the seven evaluated molecules presented LC50 values <100 ppm. The effects of these six molecules on acetylcholinesterase and the respiratory chain complexes of the mitochondria of Ae. aegypti were evaluated. Four metabolites presenting the highest inhibition effects on these targets were mixed in 11 different combinations, and the percentage of mortality of each mixture on Ae. aegypti larvae were determined. Secondary metabolites such as geranyl acetate, α-humulene, ß-caryophyllene, geraniol, nerol, and n-octanol presented LC50 values under 100 ppm (44, 41, 48, 84, 87, and 98 ppm, respectively), whereas 1,8-cineole presented a LC50 value of 183 ppm. We found that, geranyl acetate, α-humulene, ß-caryophyllene, nerol, n-octanol, and geraniol inhibited at least one of the six targets with an efficiency between 25 and 41%. Overall, the evaluation of the different mixtures revealed a synergistic effect between geranyl acetate and geraniol, and an antagonistic effect between α-humulene and ß-caryophyllene compounds.


Assuntos
Aedes/metabolismo , Inseticidas/toxicidade , Mitocôndrias/metabolismo , Controle de Mosquitos/métodos , Metabolismo Secundário , Acetatos/toxicidade , Monoterpenos Acíclicos/toxicidade , Animais , Sesquiterpenos Monocíclicos/toxicidade , Oxirredução , Sesquiterpenos Policíclicos/toxicidade
7.
Fitoterapia ; 140: 104415, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31704260

RESUMO

Four new sesquiterpenoids, phellinignins A-D (1-4), together with four known ones (5-8), were isolated from cultures of the fungus Phellinus igniarius. The structures were established by extensive spectroscopic methods including MS, NMR, and the single crystal X-ray diffraction. Compounds 1-3 and 5-8 are tremulane sesquiterpenoids, while compound 4 possesses a new carbon skeleton that might derive from an illudane framework. Compounds 1, 2, 4, and 5 showed certain cytotoxicities to three human cancer cell lines.


Assuntos
Antineoplásicos/farmacologia , Basidiomycota/química , Sesquiterpenos/farmacologia , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , China , Humanos , Estrutura Molecular , Sesquiterpenos Policíclicos , Sesquiterpenos/isolamento & purificação
8.
Food Chem Toxicol ; 135: 110876, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31610257

RESUMO

Two independent 90-day GLP-compliant studies were conducted in Sprague-Dawley rats with ß-caryophyllene or ß-caryophyllene epoxide, two common flavoring and fragrance materials. Dietary concentrations of ß-caryophyllene were 3500; 7000; and 21,000 ppm for males and 3500; 14,000; and 56,000 ppm for females. Dietary concentrations of ß-caryophyllene epoxide were 1750; 10,500; and 21,000 ppm. There were no deaths or clinical toxicity attributable to either substance administration. Statistically significant, dose-dependent reductions in body weight, body weight gain, food consumption, and food efficiency at the highest dietary concentrations of ß-caryophyllene, but not of ß-caryophyllene epoxide, were attributed to palatability issues. Neither ß-caryophyllene nor ß-caryophyllene epoxide influenced estrus cyclicity or sperm parameters. Macroscopic and microscopic findings were primarily related to changes in the kidneys of male rats, consistent with α2u-globulin nephropathy, and in the liver of male and female rats, including hepatocyte hypertrophy at the middle and high intake levels. These changes correlated with increased absolute and relative organ weights. Since the kidney findings were a species- and sex-specific effect, the NOAEL in each study was based on hepatocyte hypertrophy at the two highest dietary concentrations and were determined to be 222 mg/kg bw/day for ß-caryophyllene and 109 mg/kg bw/day for ß-caryophyllene epoxide.


Assuntos
Sesquiterpenos Policíclicos/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Compostos de Epóxi/administração & dosagem , Feminino , Masculino , Nível de Efeito Adverso não Observado , Sesquiterpenos Policíclicos/química , Sesquiterpenos Policíclicos/toxicidade , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade
9.
Nat Prod Res ; 34(6): 851-854, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30417666

RESUMO

The chemical composition, and antioxidant activity of the essential oils of the endemic Phlomis leucophracta P. H. Davis et Hub.-Mor. was investigated. The major compounds of the essential oil were linalool (36.4%), spathulenol (8.4%) and caryophyllene oxide (8.4%). The composition of the oil differs with published data, suggesting other chemotype. Moreover, the oil of this species was analysed for its antioxidant activity for the first time and results indicate it possess strong antioxidant activity comparable with already known antioxidants, such as ascorbic acid, BHT, or Trolox. Presented results suggest that this endemic species has strong potential to be used in food and pharmacological industries, and therefore they need to be further investigated.


Assuntos
Antioxidantes , Óleos Voláteis/química , Phlomis/química , Monoterpenos Acíclicos/análise , Antioxidantes/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Sesquiterpenos Policíclicos/análise , Sesquiterpenos/análise , Turquia
10.
Nat Prod Res ; 34(3): 441-444, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30600707

RESUMO

The hydro-distilled essential oil from aerial parts of Orthosiphon pallidus Royle, ex Benth (Lamiaceae) was investigated by using gas chromatography equipped with a flame ionisation detector (GC-FID) and gas chromatography coupled with a mass spectrometry (GC-MS). Fifty-two compounds, representing 98.4% of the total oil constituents, were identified. The major constituents were ß-caryophyllene (17.4%) and 7-epi-α-selinene (15.2%). The other minor constituents were terpinolene (6.9%), ß-pinene (6.8%), ß-elemene (5.1%), α-humulene (4.9%), α-copaene (4.8%), epi-cubebol (4.5%) and zonarene (3.9%). The oil was found to be rich in sesquiterpene hydrocarbon type constituents. Lamiaceae[Formula: see text].


Assuntos
Óleos Voláteis/análise , Orthosiphon/química , Monoterpenos Bicíclicos/análise , Monoterpenos Cicloexânicos/análise , Cromatografia Gasosa-Espectrometria de Massas , Lamiaceae/química , Sesquiterpenos Monocíclicos/análise , Óleos Voláteis/química , Sesquiterpenos Policíclicos/análise , Sesquiterpenos/análise
11.
J Nat Med ; 74(2): 476-481, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31863259

RESUMO

Upon screening compounds having Wnt signal inhibitory activity through evaluating TCF/ß-catenin transcriptional (TOP) activity, eight cadinane sesquiterpenoids, including three new compounds (1-3), were isolated from wood extracts of Santalum album (Santalaceae). Structures of compounds 1-3 were elucidated by spectral data to have a cadinane skeleton with an aromatic ring. Of the eight compounds isolated, compound 4, identified as mansonone I, was found to be active against TOP, having an IC50 of 1.2 µM.


Assuntos
Sesquiterpenos Policíclicos/química , Santalum/química , Via de Sinalização Wnt/genética , Sesquiterpenos/farmacologia
12.
J Pharmacol Sci ; 142(1): 26-33, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31786058

RESUMO

Cedrol, mainly derived from Juniperus virginiana L. essential oil, has been demonstrated the anxiolytic effect, although its mechanism of action is still not fully established. In the present study, male ICR mice were submitted to the elevated plus maze (EPM) and light-dark box (LDB) tests to investigate the putative mechanism of anxiolytic effect. WAY100635 (5-HT1A receptor antagonist), flumazenil (benzodiazepine receptor antagonist), SCH23390 (dopamine D1 receptor antagonist) or sulpiride (dopamine D2/D3 receptor antagonist) were used in the behavioral experiment to determine the mechanism of action of cedrol. Subsequently, the monoamine neurotransmitter levels were evaluated after behavioral tests. The data suggest that no significant effect in behavioral parameters were observed after sole intraperitoneal (i.p.) injection of antagonists compared to saline group. The anxiolytic effect of cedrol in behavioral procedures was blocked by either WAY100635 or flumazenil. The anxiolytic effect of cedrol (1200 mg/kg) was effectively antagonized by SCH23390 (0.125 mg/kg). Furthermore, cedrol decreased the DA and NE levels in hippocampus, striatum and hypothalamus. The present findings suggest that the dopaminergic system (D1 receptor) rather than serotoninergic or GABAergic system may potentially be involved in the modulation of cedrol-induced anxiolytic-like behaviors in mice.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Sesquiterpenos Policíclicos/farmacologia , Receptores Dopaminérgicos/metabolismo , Animais , Benzazepinas/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Flumazenil/farmacologia , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos ICR , Norepinefrina/metabolismo , Piperazinas/farmacologia , Piridinas/farmacologia , Antagonistas da Serotonina/farmacologia , Sulpirida/farmacologia
13.
Molecules ; 24(24)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842378

RESUMO

The aroma quality of citrus fruit is determined by volatile compounds, which bring about different notes to allow discrimination among different citrus species. However, the volatiles with various aromatic traits specific to different citrus species have not been identified. In this study, volatile profiles in the fruit peels of four citrus species collected from our previous studies were subjected to various analyses to mine volatile biomarkers. Principal component analysis results indicated that different citrus species could almost completely be separated. Thirty volatiles were identified as potential biomarkers in discriminating loose-skin mandarin, sweet orange, pomelo, and lemon, while 17 were identified as effective biomarkers in discriminating clementine mandarins from the other loose-skin mandarins and sweet oranges. Finally, 30 citrus germplasms were used to verify the classification based on ß-elemene, valencene, nootkatone, and limettin as biomarkers. The accuracy values were 90.0%, 96.7%, 96.7%, and 100%, respectively. This research may provide a novel and effective alternative approach to identifying citrus genetic resources.


Assuntos
Citrus/química , Frutas/química , Compostos Orgânicos Voláteis/análise , Cumarínicos/análise , Sesquiterpenos Policíclicos/análise , Sesquiterpenos/análise
14.
Mutat Res ; 782: 108276, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31843140

RESUMO

Bracken fern is carcinogenic when fed to domestic and laboratory animals inducing bladder and ileal tumours and is currently classified as a possible human carcinogen by IARC. The carcinogenic illudane, ptaquiloside (PTQ) was isolated from bracken fern and is widely assumed to be the major bracken carcinogen. However, several other structurally similar illudanes are found in bracken fern, in some cases at higher levels than PTQ and so may contribute to the overall toxicity and carcinogenicity of bracken fern. In this review, we critically evaluate the role of illudanes in bracken fern induced toxicity and carcinogenicity, the mechanistic basis of these effects including the role of DNA damage, and the potential for human exposure in order to highlight deficiencies in the current literature. Critical gaps remain in our understanding of bracken fern induced carcinogenesis, a better understanding of these processes is essential to establish whether bracken fern is also a human carcinogen.


Assuntos
Carcinógenos/toxicidade , Sesquiterpenos Policíclicos/toxicidade , Pteridium/toxicidade , Animais , Dano ao DNA/efeitos dos fármacos , Humanos , Indanos/toxicidade , Sesquiterpenos/toxicidade
15.
PLoS One ; 14(12): e0216104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31841509

RESUMO

Beta-caryophyllene is an odoriferous bicyclic sesquiterpene found in various herbs and spices. Recently, it was found that beta-caryophyllene is a ligand of the cannabinoid receptor 2 (CB2). Activation of CB2 will decrease pain, a major signal for inflammatory responses. We hypothesized that beta-caryophyllene can affect wound healing by decreasing inflammation. Here we show that cutaneous wounds of mice treated with beta-caryophyllene had enhanced re-epithelialization. The treated tissue showed increased cell proliferation and cells treated with beta-caryophyllene showed enhanced cell migration, suggesting that the higher re-epithelialization is due to enhanced cell proliferation and cell migration. The treated tissues also had up-regulated gene expression for hair follicle bulge stem cells. Olfactory receptors were not involved in the enhanced wound healing. Transient Receptor Potential channel genes were up-regulated in the injured skin exposed to beta-caryophyllene. Interestingly, there were sex differences in the impact of beta- caryophyllene as only the injured skin of female mice had enhanced re-epithelialization after exposure to beta-caryophyllene. Our study suggests that chemical compounds included in essential oils have the capability to improve wound healing, an effect generated by synergetic impacts of multiple pathways.


Assuntos
Sesquiterpenos Policíclicos/farmacologia , Receptor CB2 de Canabinoide/efeitos dos fármacos , Cicatrização/fisiologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Folículo Piloso/metabolismo , Inflamação/tratamento farmacológico , Queratinócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reepitelização , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Sesquiterpenos/metabolismo , Fatores Sexuais , Pele/metabolismo , Cicatrização/efeitos dos fármacos
16.
J Asian Nat Prod Res ; 21(12): 1161-1169, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31760800

RESUMO

Three new eremophilane-type sesquiterpenoids, alashanoids K-M (1-3), and one known analogue (4) were isolated from the peeled stems of Syringa pinnatifolia. All the compounds were isolated from the genus Syringa for the first time. Structures of these compounds were established using 1D and 2D NMR and MS data. The absolute configurations were determined by experimental and calculated electronic circular dichroism analysis, a modification of Mosher's method, and X-ray diffraction. Compounds 2 and 3 inhibited NO production in LPS-induced RAW264.7 macrophage cells with IC50 values of 14.23 and 12.20 µM, respectively, and showed cytotoxic activities against HepG2 cells with the IC50 values of 34.41 and 40.86 µM, respectively.


Assuntos
Sesquiterpenos , Syringa , Animais , Camundongos , Estrutura Molecular , Casca de Planta , Sesquiterpenos Policíclicos
17.
Int Immunopharmacol ; 77: 105923, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31711937

RESUMO

Multiple Sclerosis (MS) is one of the most common inflammatory diseases with the essential role of immune system in the demyelination, damage and inflammation of the central nervous system neurons (CNS). ß-Caryophyllene (BCP), a natural and selective CB2 agonist, possesses several protective effects. In the present study, we evaluated the protective effects of low dose of BCP (5 mg/kg), sphingomyelinase (SMase) inhibitor imipramine (IMP, 10 mg/kg), and the combination of BCP (2.5 and 5 mg/kg) with IMP in the treatment of experimental autoimmune encephalomyelitis (EAE) mice as a known model of chronic MS. These effects were assessed on the levels of pro- or anti-inflammatory cytokines as well as the polarization of spleen lymphocytes and microglia, in EAE mice. Our results indicated that low dose of BCP, IMP and BCP combined with a SMase inhibitor IMP exert protective effects in treatment of EAE mice. We also found that they reduced the clinical and pathological defects in EAE mice through modulation of both local (microglia) and systemic (lymphocytes and blood) immunity from inflammatory (Th1/Th17/M1) towards anti-inflammatory (Th2/Treg/M2) phenotypes. Therefore, it can be suggested that a low dose of BCP alone or combined with IMP as a known SMase inhibitor deserve a therapeutic position for treatment of MS.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Imipramina/uso terapêutico , Sesquiterpenos Policíclicos/uso terapêutico , Receptor CB2 de Canabinoide/agonistas , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Animais , Citocinas/sangue , Quimioterapia Combinada , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia
18.
Nutrients ; 11(11)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731718

RESUMO

Trans-ß-caryophyllene (BCP) is a natural sesquiterpene hydrocarbon with several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, and cardioprotective functions. These properties are mainly due to its selective interaction with the peripherally expressed cannabinoid receptor 2. In addition, BCP activates peroxisome proliferated activator receptors α and γ and inhibits the Toll-like receptor signaling pathway. Given the growing scientific interest in BCP, the aim of our study was to investigate the metabolic effects of a black pepper extract (PipeNig®-FL), containing a high standardized content of BCP. In particular our interest was focused on its potential activity on lipid accumulation and glucose uptake. The extract PipeNig®-FL was chemically characterized by gas chromatography-mass spectrometry (GC-MS) and gas chromatography with flame-ionization detection (GC-FID), confirming a high content (814 mg/g) of BCP. Experiments were performed on 3T3-L1 preadipocytes and on C2C12 myotubes. Lipid content following 3T3-L1 adipogenic differentiation was quantified with AdipoRed fluorescence staining. Glucose uptake and GLUT4 membrane translocation were studied in C2C12 myotubes with the fluorescent glucose analog 2-NBDG and by immunofluorescence analysis. Here we show that PipeNig®-FL reduces 3T3-L1 adipocyte differentiation and lipid accumulation. Moreover, acute exposure of C2C12 myotubes to PipeNig®-FL improves glucose uptake activity and GLUT4 migration. Taken together, these results reveal interesting and novel properties of BCP, suggesting potential applications in the prevention of lipid accumulation and in the improvement of glucose uptake.


Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Piper nigrum/química , Extratos Vegetais/farmacologia , Sesquiterpenos Policíclicos/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Extratos Vegetais/química
19.
Molecules ; 24(23)2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31766439

RESUMO

Interstitial cystitis (IC) is a chronic bladder disorder with unclear etiology. The endocannabinoid system has been identified as a key regulator of immune function, with experimental evidence for the involvement of cannabinoid receptors in bladder inflammation. This study used intravital microscopy (IVM) and behavioral testing in lipopolysaccharide-induced IC, to investigate the anti-inflammatory analgesic effects of a natural dietary sesquiterpenoid, beta-caryophyllene (BCP), which is present in cannabis among other plants, and has reported agonist actions at the cannabinoid 2 receptor (CB2R). BCP's anti-inflammatory actions were compared to the synthetic CB2R-selective cannabinoid, HU308, and to an FDA-approved clinical treatment (dimethyl sulfoxide: DMSO). IVM data revealed that intravesical instillation of BCP and/or HU308 significantly reduces the number of adhering leukocytes in submucosal bladder venules and improves bladder capillary perfusion. The effects of BCP were found to be comparable to that of the selective CB2R synthetic cannabinoid, HU308, and superior to intravesical DMSO treatment. Oral treatment with BCP was also able to reduce bladder inflammation and significantly reduced mechanical allodynia in experimental IC. Based on our findings, we believe that CB2R activation may represent a viable therapeutic target for IC, and that drugs that activate CB2R, such as the generally regarded as safe (GRAS) dietary sesquiterpenoid, BCP, may serve as an adjunct and/or alternative treatment option for alleviating symptoms of inflammation and pain in the management of IC.


Assuntos
Canabinoides/farmacologia , Cistite Intersticial/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Sesquiterpenos Policíclicos/farmacologia , Receptor CB2 de Canabinoide/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Cistite Intersticial/induzido quimicamente , Cistite Intersticial/metabolismo , Cistite Intersticial/patologia , Modelos Animais de Doenças , Feminino , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB C
20.
Physiol Res ; 68(Suppl 1): S51-S58, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31755290

RESUMO

Evaluation of possible interactions with enzymes of drug metabolism is an important part of studies on safety and, in general, on the properties of any drug or biologically active compound. Here, focus is given on interactions of three sesquiterpenes (beta-caryophyllene oxide (CAO), trans-nerolidol (tNER) and farnesol (FAR)) with CYP3A4. To determine the CYP3A4 activity, specific substrates testosterone (TES) and midazolam (MDZ) were used. In human liver microsomes, the CAO inhibited the MDZ 1´-hydroxylation by mixed type inhibition and K(i) 46.6 microM; TES 6beta-hydroxylation was inhibited more strongly by tNER by the same mechanism and with K(i) of 32.5 microM. Results indicated a possibility of different mode of interaction of both compounds within the active site of CYP3A4 and this was why the molecular docking study was done. The docking experiments showed that the studied sesquiterpenes (CAO and tNER) bound to the CYP3A4 active site cause a significant decrease of binding affinity of substrates tested which corresponded well to the inhibition studies. The inhibition observed, however, most probably does not pose a real harm to microsomal drug metabolism as the levels of sesquiterpenes in plasma (assuming the use of these compounds as spices or flavoring additives) does not usually exceed micromolar range. Hence, the interaction of drugs metabolized by CYP3A4 with sesquiterpenes is less probable.


Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/efeitos dos fármacos , Citocromo P-450 CYP3A/metabolismo , Sesquiterpenos Policíclicos/farmacologia , Sesquiterpenos/farmacologia , Domínio Catalítico , Citocromo P-450 CYP3A/química , Farneseno Álcool/química , Farneseno Álcool/farmacologia , Humanos , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Sesquiterpenos Policíclicos/química , Sesquiterpenos/química
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