RESUMO
The use of various herbs and their compounds has been a strategy widely used in the fight against various human diseases. For example, rosmarinic acid, a bioactive phenolic compound commonly found in Rosemary plants (Rosmarinus officinalis Labiatae), has multiple therapeutic benefits in different diseases, such as cancer. Therefore, the study aimed to evaluate in silico and in vitro the inhibition potential of the enzyme Elastase from the porcine pancreas by rosmarinic acid isolated from the plant species R. officinalis Linn. Through Molecular Docking, the mechanism of action was investigated. In addition, rosmarinic acid presented a range of 5-60 µg/mL and significantly inhibited Elastase. At 60 µg/mL, there was an inhibition of 55% on the enzymatic activity. The results demonstrate the inhibition of Elastase by rosmarinic acid, which can lead to the development of new enzyme inhibitors that can be an inspiration for developing various drugs, including anticancer drugs.
Assuntos
Ácido Rosmarínico , Rosmarinus , Humanos , Elastase Pancreática , Simulação de Acoplamento Molecular , Extratos Vegetais/farmacologia , Cinamatos/farmacologia , Depsídeos/farmacologiaRESUMO
Methyl phydroxycinnamate (MH), an esterified derivative of pCoumaric acid exerts antiinflammatory effects on lipopolysaccharide (LPS)stimulated RAW264.7 macrophages. Based on these effects, the present study investigated the protective role of MH in a mouse model of LPSinduced acute respiratory distress syndrome (ARDS). The results demonstrated that administration of LPS (5 mg/kg intranasally) markedly increased the neutrophil/macrophage numbers and levels of inflammatory molecules (TNFα, IL6, IL1ß and reactive oxygen species) in the bronchoalveolar lavage ï¬uid (BALF) of mice. On histological examination, the presence of inflammatory cells was observed in the lungs of mice administered LPS. LPS also notably upregulated the secretion of monocyte chemoattractant protein1 and protein content in BALF as well as expression of inducible nitric oxide synthase in the lungs of mice; it also caused activation of p38 mitogenactivated protein kinase (MAPK) and NFκB signaling. However, MH treatment significantly suppressed LPSinduced upregulation of inflammatory cell recruitment, inflammatory molecule levels and p38MAPK/NFκB activation, and also led to upregulation of heme oxygenase1 (HO1) expression in the lungs of mice. In addition, the ability of MH to induce HO1 expression was confirmed in RAW264.7 macrophages. Taken together, the findings of the present study indicated that MH may exert protective effects against airway inflammation in ARDS mice by inhibiting inflammatory cell recruitment and the production of inflammatory molecules.
Assuntos
Anti-Inflamatórios/farmacologia , Cinamatos/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Síndrome do Desconforto Respiratório/tratamento farmacológico , Animais , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/patologia , Transdução de SinaisRESUMO
Picrorhiza kurroa has a long medicinal history as a traditional medicinal plant in China and India that is widely used in clinical treatments. It is a common treatment for liver diseases, fever, diarrhoea, indigestion, and some other diseases. Modern pharmacological studies proved that P. kurroa rhizomes have high levels of picroside I and II, which were identified as main constituents with anti-inflammatory and hepatoprotective activities. In our study, we used picroside I and II as the lead compounds to generate derivatives by reactions with Boc-valine or Boc-proline, which underwent dehydration and condensation with the hydroxyl groups in the lead compounds in the presence of coupling reagent N,N'-dicyclohexylcarbodiimide. We synthesized 11 derivatives and examined their hepatoprotective effects in vitro by assessing the proliferation rates of H2 O2 -exposed HepG2 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. We found that some derivatives promoted higher proliferation rates in HepG2 cells than the natural compounds before derivatization, suggesting that those derivatives possessed an improved hepatoprotective capacity. The novel derivatization strategy for picrosides had the additional benefit that the esterification of their hydroxyl groups created derivatives not only with increased stability but also with improved pharmacokinetic properties and potentially prolonged half-life.
Assuntos
Aminoácidos/química , Cinamatos/química , Glucosídeos Iridoides/química , Substâncias Protetoras/química , Proliferação de Células/efeitos dos fármacos , Cinamatos/isolamento & purificação , Cinamatos/farmacologia , Células Hep G2 , Humanos , Peróxido de Hidrogênio/farmacologia , Glucosídeos Iridoides/isolamento & purificação , Glucosídeos Iridoides/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Picrorhiza/química , Picrorhiza/metabolismo , Plantas Medicinais/química , Plantas Medicinais/metabolismo , Substâncias Protetoras/farmacologiaRESUMO
Cadmium (Cd) is an environmental pollutant that can get entry into human body via ingestion of contaminated foods causing multiple organ damage. This study aimed at monitoring Cd residues in 20 foodstuffs of animal origin that are commonly consumed in Egypt. Health risk assessment was conducted via calculation of Cd dietary intakes and non-carcinogenic target hazard quotient. An in vitro approach was performed to investigate the constitutive effects of Cd on human hepatoma (HepG2) cells under food-relevant concentrations. Trials to reduce Cd-induced adverse effects on HepG2 cells were done using rosmarinic (RMA) and ascorbic acids (ASA). The achieved results indicated contamination of the tested foodstuffs with Cd at high levels with potential human health hazards. Cd at food-relevant concentrations caused significant cytotoxicity to HepG2 cells. This may be attributed to induction of oxidative stress and inflammation, as indicated by the overexpression of stress and inflammatory markers. At the same time, Cd downregulated xenobiotic transporters and upregulated the proliferation factors. Co-exposure of HepG2 cells to Cd and micronutrients such as RMA and ASA led to recovery of cells from the oxidative damage, and subsequently cell viability was strongly improved. RMA and ASA ameliorated the biological responses of HepG2 cells to Cd exposure.
Assuntos
Ácido Ascórbico/farmacologia , Cádmio/química , Sobrevivência Celular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Cádmio/análise , Cinamatos/química , Cinamatos/farmacologia , Depsídeos/química , Depsídeos/farmacologia , Egito , Células Hep G2 , Humanos , Medição de Risco , Ácido RosmarínicoRESUMO
This study was undertaken to estimate the concentrations of the formed polycyclic aromatic hydrocarbons (PAHs) in heat-treated (boiled, pan-fried and grilled) meats collected from Egypt. Dietary intakes and cancer risks of PAHs among Egyptian adults were calculated. Benzo[a]pyrene (B[a]P)-induced mutagenicity and oxidative stress in human colon (CaCo-2) cell line and mechanisms behind such effects were also investigated. Finally, protection trials using rosmarinic (RMA) and ascorbic acids (ASA) were carried out. The results indicated formation of PAHs at high levels in the heat-treated meats. Calculated incremental life time cancer risk among Egyptian adults were 7.05179E-07, 7.00604 E-06 and 1.86069 E-05 due to ingestion of boiled, pan-fried and grilled meats, respectively. B[a]P-exposed CaCo-2 cells had high abilities for mutagenicity (490.05⯱â¯21.37 Hisâ¯+â¯revertants) and production of reactive oxygen species. RMA and ASA protected CaCo-2 cells via reduction of B[a]P-induced mutagenicity and oxidative stress and upregulation of phase II detoxification enzymes and xenobiotic transporters.
Assuntos
Ácido Ascórbico/farmacologia , Benzo(a)pireno/análise , Benzo(a)pireno/toxicidade , Cinamatos/farmacologia , Depsídeos/farmacologia , Temperatura Alta , Carne/análise , Estresse Oxidativo/efeitos dos fármacos , Adulto , Células CACO-2 , Colo/patologia , Citoproteção/efeitos dos fármacos , Egito , Humanos , Mutagênicos/análise , Mutagênicos/toxicidade , Medição de Risco , Ácido RosmarínicoRESUMO
GDC-0810 was under development as an oral anti-cancer drug for the treatment of estrogen receptor-positive breast cancer as a single agent or in combination. In vitro data indicated that GDC-0810 is a potent inhibitor of OATP1B1/1B3. To assess clinical risk, a PBPK model was developed to predict the transporter drug-drug interaction (tDDI) between GDC-0810 and pravastatin in human. The PBPK model was constructed in Simcyp® by integrating in vitro and in vivo data for GDC-0810. The prediction of human pharmacokinetics (PK) was verified using GDC-0810 phase I clinical PK data. The Simcyp transporter DDI model was verified using known OATP1B1/1B3 inhibitors (rifampicin, cyclosporine and gemfibrozil) and substrate (pravastatin), prior to using the model to predict GDC-0810 tDDI. The effect of GDC-0810 on pravastatin PK was then predicted based on the proposed clinical scenarios. Sensitivity analysis was conducted on the parameters with uncertainty. The developed PBPK model described the PK profile of GDC-0810 reasonably well. In the tDDI verification, the model reasonably predicted pravastatin tDDI caused by rifampicin and gemfibrozil OATP1B1/3 inhibition but under-predicted tDDI caused by cyclosporine. The effect of GDC-0810 on pravastatin PK was predicted to be low to moderate (pravastatin Cmax ratios 1.01-2.05 and AUC ratio 1.04-2.23). The observed tDDI (Cmax ratio 1.20 and AUC ratio 1.41) was within the range of the predicted values. This work demonstrates an approach using a PBPK model to prospectively assess tDDI caused by a new chemical entity as an OATP1B1/3 uptake transporter inhibitor to assess clinical risk and to support development strategy.
Assuntos
Cinamatos/farmacologia , Indazóis/farmacologia , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Modelos Biológicos , Pravastatina/farmacocinética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Área Sob a Curva , Ciclosporina/farmacologia , Interações Medicamentosas , Genfibrozila/farmacologia , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Rifampina/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismoRESUMO
Sideritis montana L. endemic of Turkey was screened for its polyphenols content and antioxidant activity. Factor analysis and experimental design have been applied to understand the structure of the separation process, to determine the effective parameters, and to accomplish the performance improvement. Face-centred composite design (FCD) of response surface methodology (RSM) was applied to evaluate the influences of solvent concentration, solvent amount, extraction time, and stirring speed of homogenizer-assisted extraction (HAE) as well as to model and to optimize the HAE. Quadratic models were highly significant (pâ¯<â¯0.0001) for the responses studied with high coefficients of determination (R2) of 0.9440, 0.9415 and 0.9521. The result of the study suggests that 15.02â¯mL of 22.69% EtOH solution (v/v), 70.16â¯s, and 9524.52â¯rpm of mixing speed are the optimal conditions to obtain the highest yield of total polyphenols (TPC) and flavonoids (TFC), and the best antioxidant activity (AA). Rosmarinic acid was identified as the most abundant component.
Assuntos
Antioxidantes/isolamento & purificação , Fracionamento Químico/métodos , Extratos Vegetais/isolamento & purificação , Polifenóis/isolamento & purificação , Sideritis/química , Antioxidantes/farmacologia , Fracionamento Químico/instrumentação , Cinamatos/isolamento & purificação , Cinamatos/farmacologia , Depsídeos/isolamento & purificação , Depsídeos/farmacologia , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Química Verde/economia , Química Verde/instrumentação , Química Verde/métodos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Solventes/química , Ácido RosmarínicoRESUMO
In this study, a series of rosmarinic acid and analogs were investigated for their anti-inflammatory potential against LPS-induced alveolar macrophages (MH-S). Our results showed that, among the test compounds, ethyl rosmarinate (3) exhibited the most potent inhibitory effect on NO production in LPS-induced MH-S cells, with low cytotoxicity. Compound 3 exhibited remarkable inhibition of the production of PGE2 in LPS-induced MH-S cells. The inhibitory potency of compound 3 against LPS-induced NO and PGE2 release was approximately two-fold higher than that of dexamethasone. Compound 3 significantly decreased the mRNA and protein expression of iNOS and COX-2 and suppressed p65 expression in the nucleus in LPS-induced MH-S cells. These results suggested that compound 3 inhibited NO and PGE2 production, at least in part, through the down-regulation of NF-κB activation. Analysis of structure-activity relationship revealed that the free carboxylic group did not contribute to inhibitory activity and that the alkyl group of the corresponding alkyl ester analogs produced a strong inhibitory effect. We concluded that compound 3, a structurally modified rosmarinic acid, possessed potent inhibitory activity against lung inflammation, which strongly supported the development of this compound as a novel therapeutic agent for the treatment of macrophage-mediated lung inflammatory diseases, such as COPD.
Assuntos
Cinamatos/farmacologia , Depsídeos/farmacologia , Dinoprostona/biossíntese , Lipopolissacarídeos/farmacologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Óxido Nítrico/biossíntese , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Macrófagos Alveolares/citologia , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ácido RosmarínicoRESUMO
The main objective of this work is to evaluate the phytotoxicity of olive mill solid wastes (OMW) produced in two different centrifugation technologies and also the toxicity associated with specific phenolic compounds. Two samples of waste were collected in two-phase (2P-OMW) and three-phase (3P-OMW) centrifugation olive oil production processes, and cress bioassays with Lepidium sativum L. were employed to evaluate phytotoxicity. Although both OMW have similar total phenolic content (TPh), results confirmed that 2P-OMW is more phytotoxic than 3P-OMW. When extracts from 2P-OMW at liquid to solid ratio of 10 L kg-1 were applied none of the seeds germinated, i.e. germination index (GI) was 0%, while for 3P-OMW GI was 94.3%. Growth tests in soil and mixtures with OMW also led to more favorable results for 3P-OMW, whereas worse results than those obtained in the control experiments were observed. In order to discriminate the individual influence of eleven phenolic compounds, gallic acid, protocatechuic acid, cinnamic acid, syringic acid, 3,4,5-trimethoxybenzoic acid, 4-hydroxybenzoic acid, vanillic acid, p-coumaric acid, caffeic acid, veratric acid and phenol were tested in the concentration range of 5-500 mg L-1. Results showed that cinnamic acid is the most phytotoxic, with EC50 of 60 mg L-1, which is related with its hydrophobicity. Moreover, increasing -OH and -OCH3 groups in these molecules seem to reduce phytotoxicity. Tests with a mixture of six phenolic compounds demonstrated there are neither synergistic nor additive effects. The phytotoxicity appears to be determined by the presence of the most lipophilic phenolic molecule.
Assuntos
Resíduos Industriais/análise , Lepidium sativum/efeitos dos fármacos , Olea/química , Fenóis , Resíduos Sólidos , Centrifugação , Cinamatos/análise , Cinamatos/farmacologia , Germinação/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Lepidium sativum/crescimento & desenvolvimento , Fenóis/análise , Fenóis/química , Fenóis/farmacologia , Sementes/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Androgen receptor plays multiple physiological and pathological roles in human organism. In the current paper, we describe construction and characterization of a novel stably transfected human reporter cell line AIZ-AR for assessment of transcriptional activity of human androgen receptor. Cell line AIZ-AR is derived from human prostate carcinoma epithelial cell line 22Rv1 that was transfected with reporter plasmid containing 3 copies of androgen response regions (ARRs) followed by a single copy of androgen response element (ARE) from the promoter region of human prostate specific antigen (PSA) gene. AIZ-AR cells remained fully functional for more than 60 days and over 25 passages in the culture and even after cryopreservation. Time-course analyses showed that AIZ-AR cells allow detection of AR ligands as soon as after 8 hours of the treatment. We performed dose-response analyses with 23 steroids in 96-well plate format. We observed activation of AR by androgens, but not by estrogens and mineralocorticoids. Some glucocorticoids and progesterone also induced luciferase, but their potencies were 2-3 orders of magnitude weaker as compared to androgens. Taken together, we have developed a rapid, sensitive, selective, high-throughput and reproducible tool for detection of human AR ligands, with potential use in pharmacological and environmental applications.
Assuntos
Genes Reporter , Receptores Androgênicos/genética , Transcrição Gênica , Transfecção , Antagonistas de Receptores de Andrógenos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cinamatos/farmacologia , Células Clonais , Criopreservação , Di-Hidrotestosterona/farmacologia , Relação Dose-Resposta a Droga , Humanos , Higromicina B/análogos & derivados , Higromicina B/farmacologia , Luciferases/metabolismo , Receptores Androgênicos/metabolismo , Esteroides/farmacologia , Fatores de Tempo , Transcrição Gênica/efeitos dos fármacosRESUMO
This study aimed to assess the phototoxic potential of combined UV-filters and retinyl palmitate (RP) in the presence or not of bemotrizinol (BMTZ), employing photostability and in vitro and in vivo phototoxicity assays. The formulations tested contained octocrylene (OCT), octyl methoxycinnamate (OMC), benzophenone-3 (BZP-3) and RP (photostable) or octocrylene (OCT), octyl methoxycinnamate (OMC), avobenzone (AVO) and RP (less photostable). Both formulations were supplemented with bemotrizinol. Photostability was evaluated by exposing, or not, formulations spread on a glass plate to UVA/UVB irradiation. The resulting products were quantified by HPLC analysis. In vitro phototoxicity of UV-filters and combinations were evaluated using 3T3 viable monolayer fibroblast cultures submitted, or not, to irradiation according to OECD TG 432. In vivo photoallergy and photoxicity were assessed by clinical studies (photopatch test). Photostability assays showed that UV-filter bemotrizinol was a better photostabilizer for RP/benzophenone-3 than for RP/avobenzone. The in vitro phototoxicity of the combination RP/avobenzone was reduced by bemotrizinol. Clinical studies did not indicate phototoxic or photoallergenic potentials in all formulations tested. It is concluded that the 3T3 NRU phototoxicity test may be considered a supplementary assay in formulation developments, since it can detect chemically unstable and potentially phototoxic combinations. However, extrapolation of in vitro positive results to human photopatch tests may be performed only to a limited extent.
Assuntos
Dermatite Fotoalérgica/etiologia , Dermatite Fototóxica/etiologia , Fenóis/efeitos adversos , Protetores Solares/efeitos adversos , Triazinas/efeitos adversos , Vitamina A/análogos & derivados , Células 3T3 , Acrilatos/efeitos adversos , Acrilatos/farmacologia , Acrilatos/efeitos da radiação , Adolescente , Adulto , Idoso , Animais , Benzofenonas/efeitos adversos , Benzofenonas/farmacologia , Benzofenonas/efeitos da radiação , Cinamatos/efeitos adversos , Cinamatos/farmacologia , Cinamatos/efeitos da radiação , Diterpenos , Método Duplo-Cego , Interações Medicamentosas , Estabilidade de Medicamentos , Humanos , Camundongos , Pessoa de Meia-Idade , Vermelho Neutro/metabolismo , Fenóis/farmacologia , Fenóis/efeitos da radiação , Ésteres de Retinil , Medição de Risco , Protetores Solares/farmacologia , Protetores Solares/efeitos da radiação , Triazinas/farmacologia , Triazinas/efeitos da radiação , Raios Ultravioleta , Vitamina A/efeitos adversos , Vitamina A/farmacologia , Vitamina A/efeitos da radiação , Adulto JovemRESUMO
Considering the controversial results concerning the antimutagenicity of some phenolic compounds recorded in the literature, the antigenotoxic effects of four selected phenolic compounds, myricetin, quercetin, rutin, and rosmarinic acid, against DNA damage induced by alkylation with ethyl methanesulfonate (EMS), were evaluated in Drosophila melanogaster males using the sex-linked recessive lethal (SLRL) test. To assess the protective effects against DNA damage, D. melanogaster males were exposed to a monofunctional alkylating agent EMS in concentration of 0.75 ppm, 24 h prior to one of the selected phenolic compounds in the concentration of 100 ppm. The possible differences in mechanisms of protection by selected compounds were determined by molecular docking, after which structure-based 3-D pharmacophore models were generated. EMS induced considerable DNA damage as shown by significant increase in the frequency of germinative mutations. The frequency decreased with high significance (p<0.001***) after post-treatments with all selected phenolic compounds. Further, docking analysis revealed EMS pre-bond conformations against guanine and thymine as a necessary condition for alkylation, after which resulting O6-ethylguanine and O4-ethylthimine were docked into the active site of O6-alkylguanine-DNA alkyltransferase to confirm that particular lesions are going to be repaired. Finally, myricetin and quercetin protected dealkylated nucleotides from further EMS alkylation by forming the strong hydrogen bonds with O6-guanine and O4-thymine via B ring hydroxyl group (bond lengths lower than 2.5 Å). On the other side, rutin and rosmarinic acid encircled nucleotides and by fulfilling the EMS binding space they made an impermeable barrier for the EMS molecule and prevented further alkylation.
Assuntos
Antimutagênicos/farmacologia , Cinamatos/farmacologia , Depsídeos/farmacologia , Flavonoides/farmacologia , Quercetina/farmacologia , Rutina/farmacologia , Alquilantes/química , Alquilantes/toxicidade , Animais , Antimutagênicos/química , Sítios de Ligação , Domínio Catalítico , Cinamatos/química , Dano ao DNA/efeitos dos fármacos , Depsídeos/química , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Metanossulfonato de Etila/toxicidade , Flavonoides/química , Guanina/análogos & derivados , Guanina/química , Guanina/metabolismo , Masculino , Simulação de Acoplamento Molecular , Método de Monte Carlo , Mutação , O(6)-Metilguanina-DNA Metiltransferase/química , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Quercetina/química , Rutina/química , Timina/análogos & derivados , Timina/química , Timina/metabolismo , Ácido RosmarínicoRESUMO
Patients with lung adenocarcinoma are often diagnosed with metastasizing symptoms and die of early and distal metastasis. Metastasis is made up of a cascade of interrelated and sequential steps, including cell adhesion, extracellular matrix degradation, cell movement, and invasion. Hence, substances carrying the ability to stop one of the metastasis-associated steps could be a potential candidate for preventing tumor cells from metastasizing and prolonging the life of cancer patients. Cinnamic acid (CA) was demonstrated to be such a candidate for human lung adenocarcinoma cells. Nevertheless, the effectiveness of CA derivatives on invasion of lung cancer cells is still unclear. The aims of this study were to explore the mechanisms underlying several select CA derivatives against invasion of human lung adenocarcinoma A549 cells. The results revealed that caffeic acid (CAA), chlorogenic acid (CHA), and ferulic acid (FA) can inhibit phorbol-12-myristate-13-acetate (PMA)-stimulated invasion of A549 cells at a concentration of ≥100 µM. The MMP-9 activity was suppressed by these compounds through regulating urokinase-type plasminogen activator (uPA), tissue inhibitor of metalloproteinase (TIMP)-1, plasminogen activator inhibitor (PAI)-1, and PAI-2; the cell-matrix adhesion was decreased by CAA only. The proposed molecular mechanism involved not only decreasing the signaling of MAPK and PI3K/Akt but also inactivating NF-κB, AP-1, and STAT3. In the present study, we selected CAA, CHA, and FA as potential inhibitors for invasive behaviors of human lung adenocarcinoma cells and disclosed the possible mechanisms. The association between structural features and anti-invasive activity of these compounds cannot be determined here and needs to be further verified.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Cinamatos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Antineoplásicos Fitogênicos/química , Ácidos Cafeicos/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ácido Clorogênico/farmacologia , Cinamatos/química , Ácidos Cumáricos/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Transdução de Sinais/efeitos dos fármacosRESUMO
The investigation deals with antifungal, antiaflatoxin and antioxidant efficacy of Zanthoxylum alatum Roxb. essential oil (EO), its two major constituents and their comparison with five commonly used organic acid preservatives. The chemical profile of EO, characterized through GC and GC-MS analysis, revealed linalool (56.10%) and methyl cinnamate (19.73%) as major components. The EO, linalool and methyl cinnamate completely inhibited the growth of a toxigenic strain of A. flavus (LHP-10) as well as aflatoxin B(1) secretion at different concentrations. Methyl cinnamate was found to be more efficacious than EO, linalool and five organic acid preservatives, showing antifungal and antiaflatoxigenic efficacy at a low concentration (0.6 µl/ml) and the nature of its toxicity was fungicidal. However, EO showed strong antioxidant activity with an IC(50) value at 5.6 µl/ml. Moreover, EO was found to have negligible mammalian toxicity as its LD(50) value, determined through oral administration on mice, was calculated to be 6124µl/kg body weight during safety profile assessment. During in vivo investigation on fruit systems, the Zanthoxylum EO, when tested as fumigant, provided 66.27% and 86.33% protection respectively at 1.25 µl/ml and 2.5 µl/ml against fungi infesting Piper nigrum L. fruits demonstrating its practical efficacy as a plant based antimicrobial for post harvest application.
Assuntos
Aspergillus flavus/efeitos dos fármacos , Óleos Voláteis/farmacologia , Piper nigrum/microbiologia , Zanthoxylum , Monoterpenos Acíclicos , Aflatoxina B1/biossíntese , Aflatoxinas/antagonistas & inibidores , Animais , Anti-Infecciosos/farmacologia , Antifúngicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Aspergillus flavus/metabolismo , Cinamatos/farmacologia , Microbiologia de Alimentos , Conservantes de Alimentos/farmacologia , Inocuidade dos Alimentos , Fumigação , Cromatografia Gasosa-Espectrometria de Massas , Camundongos , Modelos Animais , Monoterpenos/farmacologia , Óleos Voláteis/química , Óleos Voláteis/toxicidadeRESUMO
The antiviral activity of quercetin, morin and trans-cinnamic acid was evaluated in vitro against equid herpesvirus 1 (EHV-1) by determining the virucidal activity and using the time of addition assay to test inhibition of the viral replication cycle. The cytotoxicity of each substance was assessed using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]. Quercetin showed virucidal action and inhibition of the viral replication cycle at 0 and 1h. Morin showed potential virucidal and viral replication cycle inhibition at 0 h. Trans-cinnamic acid did not show virucidal activity but inhibited the viral replication cycle at -1 and 0 h. This study demonstrates the potential of these compounds as future antiviral candidates in relation to viruses of importance in veterinary medicine.
Assuntos
Antivirais/farmacologia , Cinamatos/farmacologia , Flavonoides/farmacologia , Herpesvirus Equídeo 1/efeitos dos fármacos , Quercetina/farmacologia , Animais , Chlorocebus aethiops , Células VeroRESUMO
UNLABELLED: Mints (Mentha spp.), aromatic crops grown largely for their essential oils, also are rich sources of nonvolatile antiinflammatory agents. Identification and quantitation of the constituents responsible for their antiinflammatory activity is challenging owing to the lack of suitable chromatographic methodology. In the present research, the simultaneous quantitation of antiinflammatory constituents rosmarinic acid, oleanolic acid, and ursolic acid in mints was attained by using a unique tandem HPLC column system coupled with an electrospray ionization mass detection (MRM mode). The ion mode optimization for rosmarinic acid under negative and triterpenoid acids under positive was achieved by setting 2 time segments in a single run where the polarity mode was switched from negative (0 to 10 min) to positive (10 to 40 min). For the investigated concentration ranges of antiinflammatory agents in mints, good linearities (r² ≥ 0.998) were obtained for each calibration curve. Validation of precision and accuracy for this method showed that intra- and inter-day repeatabilities for all analytes were less than 5.51%, and the recoveries varied from 97.8% to 99.3%. The developed LC/MS/MS assay provides a suitable quality control method for the determination of antiinflammatory constituents in Mentha spp. There is a wide range of diversity in the natural product composition for these acids across the Mentha germplasm collection evaluated. The presence of these antiinflammatory acids in post-distilled mints shows that value-added nutraceutical enriched products can be developed with proper processing and recovery systems in addition to the distillation and capture of the valuable volatile essential oils. PRACTICAL APPLICATION: Results from this research would benefit both commercial farmers growing mint for essential oil and those in the food industry where value-added phytopharmaceutical enriched products can be developed with proper processing, quality control, and recovery systems during mint essential oil distillation.
Assuntos
Anti-Inflamatórios não Esteroides/análise , Cinamatos/análise , Depsídeos/análise , Mentha/química , Ácido Oleanólico/análise , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Triterpenos/análise , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/economia , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular Transformada , Fenômenos Químicos , Cromatografia Líquida de Alta Pressão , Cinamatos/química , Cinamatos/economia , Cinamatos/farmacologia , Depsídeos/química , Depsídeos/economia , Depsídeos/farmacologia , Destilação , Resíduos Industriais/análise , Resíduos Industriais/economia , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Óleos Voláteis/economia , Ácido Oleanólico/química , Ácido Oleanólico/economia , Ácido Oleanólico/farmacologia , Reprodutibilidade dos Testes , Especificidade da Espécie , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Triterpenos/química , Triterpenos/economia , Triterpenos/farmacologia , Ácido Rosmarínico , Ácido UrsólicoRESUMO
The systemic treatment with angiogenesis inhibitor has been shown to result in weight reduction and adipose tissue loss in various models of obesity. To verify the mechanism of CKD-732 (TNP-470 analog) against obesity, we evaluated CKD-732's peripheral and central anti-obesity effects. CKD-732 was injected subcutaneously (s.c.) for 7 days in various animal models and intracerebroventricularly (i.c.v.) in arcuate nucleus (ARC) lesion mice, ob/ob mice, and normal littermates. Modulation of the hypothalamic neuropeptide mRNAs after i.c.v. injection was evaluated in ARC lesion mice and normal littermates. A conditioned taste aversion (CTA) was performed using lithium chloride (LiCl) as a positive control agent in Long-Evans Tokushima Otsuka and Otsuka Long-Evans Tokushima fatty (OLETF) rats. As a result, 7 days of CKD-732 s.c. injection reduced the cumulative food intake and the body weight significantly in both treated obese (e.g. 114.8 +/- 13.4 g vs 170.7 +/- 20.6 g, 7.9 +/- 0.5% decrease vs 0.3 +/- 2.2% decrease; in treated OLETF rat versus control OLETF rat, P < 0.01 respectively) and non-obese models. Epididymal and mesenteric fat pads, and the size of adipocytes were significantly decreased in treated rats. A single i.c.v. injection decreased food intake and body weight in ARC lesion mice and ob/ob mice but not in normal littermates. Unexpectedly, the hypothalamic neuropeptide mRNAs were not altered by single i.c.v. injection. CKD-732 also induced a dose-dependent CTA comparable with LiCl injection, which is a commonly used agent to produce a CTA. In conclusion, CKD-732 causes significant body weight and appetite reduction, possibly by decreasing adiposity directly and inducing central anorexia, which is partly explained by a CTA. These results should be carefully verified to assess the utility of CKD-732 as an anti-obesity drug.
Assuntos
Fármacos Antiobesidade/farmacologia , Cinamatos/farmacologia , Cicloexanos/farmacologia , Compostos de Epóxi/farmacologia , Obesidade/tratamento farmacológico , Sesquiterpenos/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Tecido Adiposo/efeitos dos fármacos , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/uso terapêutico , Núcleo Arqueado do Hipotálamo/patologia , Peso Corporal/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Cinamatos/administração & dosagem , Cinamatos/uso terapêutico , Cicloexanos/administração & dosagem , Cicloexanos/química , Cicloexanos/uso terapêutico , Ingestão de Alimentos/efeitos dos fármacos , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/uso terapêutico , Hipotálamo/metabolismo , Cloreto de Lítio/farmacologia , Masculino , Camundongos , Camundongos Obesos , Neuropeptídeos/metabolismo , O-(Cloroacetilcarbamoil)fumagilol , Ratos , Ratos Endogâmicos OLETF , Sesquiterpenos/administração & dosagem , Sesquiterpenos/química , Sesquiterpenos/uso terapêutico , Paladar/efeitos dos fármacosAssuntos
Anti-Infecciosos/uso terapêutico , Indústria Farmacêutica/tendências , Animais , Anti-Infecciosos/economia , Antivirais/uso terapêutico , Biofilmes/efeitos dos fármacos , Cinamatos/farmacologia , Indústria Farmacêutica/economia , Resistência a Medicamentos , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Helicobacter pylori , Humanos , Rhinovirus/efeitos dos fármacos , Ésteres do Ácido Sulfúrico/farmacologia , TerrorismoRESUMO
Growth and Differentiation Factor-15 (GDF-15, NAG-1, MIC-1) is induced by several apoptosis-inducing agents including the retinoid-related molecule (RRM) 6-[3-(1-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437). It has been suggested that GDF-15 may be involved in the induction of apoptosis by CD437 in H460 lung cancer cells. The present study was designed to probe this hypothesis more directly. Several RRMs (CD437, ST1926 and MX3350-1) but not the retinoids all-trans- retinoic acid and 4HPR were able to induce GDF-15 in H460 cells. A similar differential effect of these retinoids was observed for the induction of p53, which has been reported to regulate GDF-15 expression. In H460 cells transfected with a neo vector control (H460-Neo), treatment with RRMs but not ATRA or 4HPR resulted in increases in p53, GDF-15 and apoptosis evidenced by poly(ADP ribose) polymerase (PARP) cleavage. In contrast, RRMs failed to increase p53 or induce apoptosis in H460 cells in which p53 was inactivated by transfection of the human papillomavirus E6-6 (H460-E6-6). The increase in GDF-15 by RRMs was also compromised in the H460-E6-6 cells. Because PARP cleavage was only evident when GDF-15 levels where elevated it appeared that GDF-15 was mediating the pro-apoptotic effects of RRMs. However, silencing of GDF-15 induction by RNA interference failed to decrease the ability of CD437 and ST1926 to induce apoptosis. These results demonstrate that GDF-15 is dispensable for the pro-apoptotic activity of CD437 and ST1926.
Assuntos
Adamantano/análogos & derivados , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cinamatos/farmacologia , Citocinas/metabolismo , Neoplasias Pulmonares/metabolismo , Retinoides/farmacologia , Adamantano/farmacologia , Western Blotting , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/patologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator 15 de Diferenciação de Crescimento , Humanos , Neoplasias Pulmonares/patologia , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , RNA Interferente Pequeno/farmacologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Tretinoína/farmacologia , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
UNLABELLED: GOAL, SCOPE, BACKGROUND: The traditional solution for keeping unwanted organisms from attaching to submerged surfaces is to apply anti-fouling coatings. The most common antifoulant was tributyltin (TBT). TBT systems were highly effective but were also toxic to non-target organisms. The use of the TBT based coatings will be completely banned by January 1, 2008. Therefore, there is an urgent need to seek out suitable non-toxic alternatives. METHODS: The aim of this work was to evaluate the effectiveness of capsaicin and zosteric acid as natural product antifoulants (NPAs) in deterring bacterial attachment. Two fresh water bacteria systems Pseudomonas putida (Pp) and bacteria isolated from Lake Erie (LE) were used to assess the attachment when the NPAs dispersed in the water. Effectiveness was ascertained based on the decrease in microbial attachment, limited toxicity, and minimum alteration of the coatings properties. RESULTS AND DISCUSSION: A significant inhibition of bacteria attachment was achieved when aqueous capsaicin concentration was increased from 0 to 40 mg/L. For instance, after 14 days the LE system depicted 93.5% and 98.5% less biofilm coverage for 20 mg/L and 40 mg/L capsaicin, respectively when pared to systems without NPA. Biofilm coverage was reduced by 92.5% and 98.2%, respectively with 50 mg/L and 500 mg/L zosteric acid. CONCLUSIONS: Both capsaicin and zosteric acid was effective at preventing bacteria attachment. As the NPA aqueous concentration increased, biofilm formation decreased. Evaluating changes in aqueous pH, conductivity, dissolved oxygen, aqueous microbial population and biofilm formation suggested that the primary antifoulant mechanism of these two NPAs was to block the bacteria's active sites versus posing a lethal level. RECOMMENDATION AND PERSPECTIVE: From the attachment study, zosteric acid appeared to be more effective in preventing bacterial attachment when the NPAs were dispersed in the aqueous environment. For practical applications, the antifoulant needs to be incorporated into a coating and have a slow release rate. Thus the ability to successfully incorporate zosteric acid into a coating, without deterring bacterial attachment, needs to be investigated.