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1.
Food Chem ; 322: 126742, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32305872

RESUMO

Almond hulls, the main by-product of almond production, are considered a valuable source of bioactive phenolic compounds. This study aimed to characterize the phenolic composition, bioavailability of the phenolic-rich extracts from almond hulls (PEAH), and their protective effect on oxidative stressed Caco-2 cells induced by tert-butylhydroperoxide (t-BOOH). The ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) analysis detected 11 phenolic compounds in the PEAH with high total phenolic content and antioxidant activity. Oxidative Caco-2 cell damage was reduced by PEAH, especially at 5 µg/mL, through scavenging reactive oxygen species (ROS), modulating the cellular endogenous antioxidant system and cell redox at a predictable status. Also, in vitro digestion influenced the phenolic compounds' composition and antioxidant power of PEAH. These results suggested that almond hulls, rich in phenolic compounds, can meliorate the oxidative stressed Caco-2 cells and restore its impaired redox balance, and ultimately improve health benefits.


Assuntos
Estresse Oxidativo/efeitos dos fármacos , Fenóis/química , Extratos Vegetais/química , Substâncias Protetoras/farmacologia , Prunus dulcis/química , Antioxidantes/química , Disponibilidade Biológica , Células CACO-2 , Cromatografia Líquida de Alta Pressão , Análise Discriminante , Meia-Vida , Humanos , Análise dos Mínimos Quadrados , Espectrometria de Massas , Oxirredução , Fenóis/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/farmacocinética , Prunus dulcis/metabolismo , Espécies Reativas de Oxigênio/química , terc-Butil Hidroperóxido/toxicidade
2.
Curr Radiopharm ; 12(3): 211-219, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31612808

RESUMO

BACKGROUND: Nephrotoxicity is a prevalent consequence of cancer treatment using radiotherapy and chemotherapy or their combination. There are two methods; histological and biochemical, to assess the kidney damage caused by toxic agents in animal studies. Although these methods are used for the try-out of renoprotective factors, these methods are invasive and time-consuming, and also, lack the necessary sensitivity for primary diagnosis. Quantitative renal 99mTc-DMSA scintigraphy is a noninvasive, precise and sensitive radionuclide technique which is used to assess the extent of kidney damage, so that the extent of injury to the kidney will be indicated by the renal uptake rate of 99mTc-DMSA in the kidney. In addition, this scintigraphy evaluates the effect of the toxic agents by quantifying the alterations in the biodistribution of the radiopharmaceutical. CONCLUSION: In this review, the recent findings about the renoprotective agents were evaluated and screened with respect to the use of 99mTc-DMSA , which is preclinically and clinically used for animal cases and cancer patients under the treatment by radiotherapy and chemotherapy.


Assuntos
Neoplasias Renais/metabolismo , Rim/metabolismo , Substâncias Protetoras/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Ácido Dimercaptossuccínico Tecnécio Tc 99m/farmacocinética , Animais , Humanos , Rim/diagnóstico por imagem , Rim/efeitos dos fármacos , Rim/efeitos da radiação , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/radioterapia , Cintilografia
3.
Eur J Pharm Sci ; 138: 105033, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31382031

RESUMO

This study is to investigate pharmacokinetics (PK) and hemorheology (HR) of exogenous phosphocreatine (PCr), a cardio-protective agent, and its active metabolite creatine (Cr), with particular focus on the PK and PD comparison between PCr and Cr. A specific ion-pair reversed-phase HPLC-UV assay was used to simultaneously measure PCr, Cr and ATP concentrations in plasma and red blood cells (RBC) samples of rabbits. PK and HR parameters were calculated based on concentration-time (C-T) curves and effect-time (E-T) curves, respectively, obtained after i.v. dosing. Meanwhile the apparent pharmacological activity ratio (Rapp) and real pharmacological activity ratio (Rreal) of Cr to PCr were calculated. The PCr disappeared from plasma rapidly and in a biphasic manner; plasma PCr was converted to Cr fast and largely with the elimination rate limited metabolite disposition in vivo (Km < K). The i.v. administration of PCr led to a markedly elevated and long-lasting ATP level in RBC. After i.v. administration of preformed Cr, plasma Cr displayed similar elimination kinetics behaviors to that of Cr generated metabolically after i.v. PCr. The Cr could also raise ATP level in RBC, but to less extent than PCr. Approximately 43% of PCr-derived ATP came from Cr-derived ATP in RBC. PCr could significantly reduce whole blood viscosity and RBC osmotic fragility and Cr could do so, but weakly with estimated Rapp of 0.53-0.68 and Rreal of 0.38-0.48. PCr also inhibited platelet aggregation significantly, as opposed to Cr. The PCr-caused improvement of HR is related to the rise in ATP level in RBC. Cr is likely to partially mediate HR effect of PCr.


Assuntos
Creatina/metabolismo , Creatina/farmacocinética , Hemorreologia/fisiologia , Fosfocreatina/metabolismo , Fosfocreatina/farmacocinética , Trifosfato de Adenosina/metabolismo , Animais , Viscosidade Sanguínea/efeitos dos fármacos , Cinética , Masculino , Agregação Plaquetária/efeitos dos fármacos , Substâncias Protetoras/farmacocinética , Coelhos
4.
Pharmacol Rep ; 71(4): 703-712, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31207432

RESUMO

BACKGROUND: Silymarin, a known hepatoprotectant, owing to its poor oral bioavailability, has limited pharmacological effects. The present study was designed to improve its in vitro and in vivo hepatoprotection and increase its oral bioavailability against alcohol intoxication by formulating it in four different liposomal formulations namely conventional, dicetyl phosphate, stearyl amine and PEGylated liposomes. METHOD: The liposomes were prepared using phosphatidylcholine, cholesterol, and silymarin in addition to dicetyl phosphate, stearyl amine and DSPE mPEG 2000 by film hydration method with 5% sucrose as a cryo-protectant. The optimized formulations were studied for their release profile at pH 1.2 and 6.8. Liposomes were studied for in vitro protection on Chang liver cells and efficacious liposomes were selected for in vivo hepatoprotection study. Further, conventional liposomes were studied for bioavailability in alcohol intoxicated Wistar rats. RESULTS: The conventional liposomes increased in vitro release profile at pH 1.2 and 6.8 and also showed better in vitro protection compared to silymarin alone. Conventional and PEGylated liposomes showed better improvement in liver function, better efficacy in combating inflammatory conditions, better improvement in antioxidant levels and reversal of histological changes compared to silymarin alone. Conventional also showed an almost fourfold increase in area under the curve compared to silymarin suspension. CONCLUSION: Conventional and PEGylated liposomes of silymarin were found to be more efficacious as hepatoprotective against alcohol-induced hepatotoxicity by its free radical scavenging and anti-inflammatory effects. Conventional liposomes showed enhanced bioavailability compared to silymarin alone.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Etanol/toxicidade , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Silimarina/farmacologia , Animais , Disponibilidade Biológica , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Células Hep G2 , Humanos , Lipossomos , Fígado/metabolismo , Fígado/patologia , Masculino , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacocinética , Ratos Wistar , Silimarina/administração & dosagem , Silimarina/farmacocinética
5.
Eur J Med Chem ; 177: 198-211, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136894

RESUMO

A series of 3-amino-substituted rutacecarpine derivatives were synthesized to identify novel multitarget-directed ligands (MTDLs) for the treatment of Alzheimer's disease (AD). Biological evaluation showed that most of the synthesized compounds inhibited butyrylcholinesterase (BuChE) and exerted antioxidant effects. Among the synthesized compounds, 6n was subjected to further biological evaluation. Lineweaver-Burk plotting and molecular modeling illustrated that 6n bound simultaneously to the peripheral anionic site (PAS) and catalytic sites (CAS) of BuChE. Furthermore, 6n modulated Aß aggregation; chelated biometals; presented good absorption, distribution, metabolism, excretion, and toxicity properties; and showed remarkable neuroprotective activity. Previous research has shown that the optimized compound 6n has considerable potential for development as an MTDL for the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Substâncias Protetoras/farmacologia , Sulfonamidas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/química , Quelantes/farmacocinética , Quelantes/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Desenho de Fármacos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Substâncias Protetoras/síntese química , Substâncias Protetoras/química , Substâncias Protetoras/farmacocinética , Multimerização Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética
6.
J Ethnopharmacol ; 236: 161-172, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30802610

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Yin-Chen-Hao Tang (YCHT) has been a very popular, hepatoprotective three-herb formula with an unclear chemical base. AIM OF THIS STUDY: To reveal the hepatoprotective chemical base of oral-dosed YCHT, we bridged the hepatic disposition of six compounds in vivo and their hepatoprotection in vitro. MATERIALS AND METHODS: In vivo, following the oral administration of YCHT in normal and CCl4-induced liver injury rats, the determinations of chlorogenic acid, 4-hydroxyacetophenone, geniposide, genipin, rhein and emodin were conducted in the portal vein plasma, the liver, and the systemic plasma. In vitro, the hepatoprotective activities of these compounds were determined in the CCl4-induced HepG2 cells. RESULTS: Consistent with the highest content in YCHT, geniposide had the highest exposure in vivo. Inconsistent with the negligible content, rhein, 4-hydroxyacetophenone, emodin and genipin showed substantial hepatic accumulations. In contrast, chlorogenic acid, an ingredient that has a high content in YCHT, elicited no hepatic exposure. In normal rats, the hepatic disposition prevented the compounds entering into the systemic plasma from the portal vein plasma by 44.9-100%, except for rhein. CCl4-induced liver injury caused a decreased hepatic exposure of 4-hydroxyacetophenone, rhein and emodin by 50%. In vitro, all six compounds exerted the hepatoprotection by increasing cell viability, decreasing hepatic marker enzymes and inhibiting lipid peroxidation at varying levels. CONCLUSION: Geniposide, rhein, emodin, 4-hydroxyacetophenone and genipin directly resisted liver injury in oral-dosed YCHT, while chlorogenic acid likely played an indirect role. This study proved that YCHT exerted hepatoprotection through multiple components and multiple actions. However, close attention should be paid to the possible side effects and oral dosage of YCHT in clinics.


Assuntos
Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Medicamentos de Ervas Chinesas/uso terapêutico , Fígado/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Administração Oral , Animais , Área Sob a Curva , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Células Hep G2 , Humanos , Fígado/metabolismo , Testes de Função Hepática , Masculino , Fitoterapia , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacocinética , Ratos Sprague-Dawley , Distribuição Tecidual
7.
Sci Transl Med ; 11(473)2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30602537

RESUMO

Nerve agents are a class of organophosphorus compounds (OPs) that blocks communication between nerves and organs. Because of their acute neurotoxicity, it is extremely difficult to rescue the victims after exposure. Numerous efforts have been devoted to search for an effective prophylactic nerve agent bioscavenger to prevent the deleterious effects of these compounds. However, low scavenging efficiency, unfavorable pharmacokinetics, and immunological problems have hampered the development of effective drugs. Here, we report the development and testing of a nanoparticle-based nerve agent bioscavenger (nanoscavenger) that showed long-term protection against OP intoxication in rodents. The nanoscavenger, which catalytically breaks down toxic OP compounds, showed a good pharmacokinetic profile and negligible immune response in a rat model of OP intoxication. In vivo administration of the nanoscavenger before or after OP exposure in animal models demonstrated protective and therapeutic efficacy. In a guinea pig model, a single prophylactic administration of the nanoscavenger effectively prevented lethality after multiple sarin exposures over a 1-week period. Our results suggest that the prophylactic administration of the nanoscavenger might be effective in preventing the toxic effects of OP exposure in humans.


Assuntos
Nanopartículas/química , Agentes Neurotóxicos/toxicidade , Substâncias Protetoras/farmacologia , Administração Intravenosa , Animais , Feminino , Cobaias , Masculino , Nanopartículas/administração & dosagem , Paraoxon/toxicidade , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacocinética , Ratos Sprague-Dawley , Sarina/toxicidade , Análise de Sobrevida , Fatores de Tempo , Distribuição Tecidual
8.
Phytomedicine ; 54: 98-108, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668388

RESUMO

BACKGROUND: Although silybin serves as a well-known hepatoprotective agent with prominent anti-inflammatory, anti-oxidant and anti-fibrotic activities, its low bioavailability limits its application in the treatment of chronic liver diseases. However, novel formulation products with increased solubility were not sufficient to achieve pharmacologically meaningful concentrations of silybin in the clinical studies even used at high dosage. HYPOTHESIS/PURPOSE: We hypothesized that inhibiting efflux transporter(s) and/or glucuronidation by piperine might enhance the bioavailability and efficacy of silybin. METHODS: Pharmacokinetics of silybin given alone or in-combination with piperine was determined by a validated LC-MS method. A CCl4 induced rat model of liver injury was prepared and verified for comparing the effects of silybin and combination treatment. To investigate the underlying mechanism, the inhibition effects of piperine on transportation of silybin were performed in Caco-2 and transfected MDCKII cell lines as well as sandwich-cultured rat hepatocytes (SCH). Human liver microsomes incubation was used for exploring the modulation effects of piperine on the phase-2 metabolism of silybin. RESULTS: In the present study, we demonstrated for the first time that piperine as a bioenhancer increased the bioavailability of silybin (146%- 181%), contributing to a boosted therapeutic effect in CCl4-induced acute liver-injury rat model. The underlying mechanisms involved that piperine enhanced the absorption of silybin by inhibiting the efflux transporters including MRP2 and BCRP but not MDR1 in Caco-2 and transfected MDCKII cell lines. Moreover, piperine could inhibit the biliary excretion of silybin and conjugated metabolites in sandwich-cultured rat hepatocytes. Notably, we found that piperine did not affect the phase-2 metabolism of silybin. CONCLUSION: Efflux transporters play an important role in the pharmacokinetic behavior of flavolignans, and modulating these transporters by bioenhancer such as piperine could enhance the in vivo absorption of silybin, leading to more effective treatments.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Alcaloides/farmacocinética , Benzodioxóis/farmacocinética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Piperidinas/farmacocinética , Alcamidas Poli-Insaturadas/farmacocinética , Silibina/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Disponibilidade Biológica , Células CACO-2 , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Substâncias Protetoras/farmacocinética , Ratos Sprague-Dawley
9.
Phytomedicine ; 53: 182-192, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30668398

RESUMO

BACKGROUND: Herbal medicines (HMs) have been proven to be productive sources of leads for the development of drugs. To date approximately 150 lignans have been identified from Schisandra sphenanthera. Hepatoprotective activity is a well-known characteristic of schisandra lignans, yet the authentic types of active lignans are still not well known. PURPOSE: The present study aimed to develop a reliable and efficient strategy for identifying the hepatoprotective ingredients of schisandra lignan extract (SLE). METHODS: SLEs were prepared by extracting Schisandra sphenanthera powder using 10%, 50% and 90% ethanol (w/w 1:10) combining 5-fold volume of ethyl acetate. The schisandra lignans in SLEs were qualitatively analyzed based on liquid chromatography hybrid ion trap time-of-flight mass spectrometry (LCMS-IT-TOF). Preparative liquid chromatography (PLC) was used to collect ingredient fractions. The hepatoprotective activity of schisandra lignans was systematically investigated on in vivo and in vitro models. RESULTS: The SLE extracted by 50% ethanol and 5-fold volume of ethyl acetate (50%SLE) had the highest lignan content and exhibited significantly stronger hepatoprotective activity than other SLEs (P <  0.01). The hepatoprotective effect of 50%SLE mainly attributed to the SLE segment which collected from 12 to 22 min by PLC. Schisantherin A (Sth A) was confirmed as the most promising hepatoprotective drug in Schisandra sphenanthera due to high content in crude materials, high exposure level in vivo and high efficiency on APAP-induced hepatotoxicity. CONCLUSION: The hepatoprotective ingredients of SLEs were systematically investigated based on the presently developed approach, and Sth A was identified as the optimum hepatoprotective candidate in Schisandra sphenanthera.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacocinética , Substâncias Protetoras/farmacocinética , Schisandra/química , Animais , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cromatografia Líquida/métodos , Ciclo-Octanos/análise , Dioxóis/análise , Lignanas/análise , Lignanas/farmacocinética , Masculino , Espectrometria de Massas/métodos , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Substâncias Protetoras/química , Ratos Sprague-Dawley
10.
Int J Pharm ; 555: 63-76, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30448315

RESUMO

The first objective of this study was to optimize a supersaturatable self-nanoemulsifying drug delivery system (S-SNEDDS) containing silymarin through the investigation of the single and synergistic effect of either SNEDDS or a precipitation inhibitor on dissolution efficiency (DE) of silymarin. The bioavailability and hepatoprotective activity of S-SNEDDS were then compared to those of a branded product (Legalon®, Meda). SNEDDS containing silymarin was developed by titration technique, and Poloxamer 407 was selected as the optimal precipitation inhibitor by using casting film and solvent-shift method. The interaction of silybin (the major active constituent of silymarin) and the polymer was then determined by differential scanning calorimetry, powder X-ray diffractometry (PXRD), Fourier transforms infrared spectroscopy and 1H NMR analysis. The combination of two techniques including SNEDDS and addition of 10% of Poloxamer 407 remarkably increased DE4h (88.28%) compared to the reference product (6.41%). The relative bioavailability of S-SNEDDS versus Legalon® was about 760%. The hepatoprotective activity of S-SNEDDS in CCl4-induced mice was also superior to the commercial product in declining both the levels of serum transaminases (ALT, AST) and lipid peroxidation as well as glutathione and superoxide dismutase (SOD) activities under tested doses calculated as silybin (10, 25 and 50 mg/kg). These biopharmaceutical and pharmacological advantages of S-SNEDDS indicated prospects in the development of a novel product that offers lower strength of silymarin while enhancing therapeutic outcomes.


Assuntos
Sistemas de Liberação de Medicamentos , Hepatopatias/prevenção & controle , Nanopartículas , Silimarina/administração & dosagem , Animais , Disponibilidade Biológica , Tetracloreto de Carbono/toxicidade , Química Farmacêutica/métodos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Emulsões , Masculino , Camundongos , Poloxâmero/química , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacocinética , Substâncias Protetoras/farmacologia , Coelhos , Silibina/administração & dosagem , Silibina/química , Silimarina/farmacocinética , Silimarina/farmacologia , Solubilidade
11.
Nanomedicine ; 15(1): 175-187, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30300750

RESUMO

Lisofylline is an anti-inflammatory agent with proven anti-diabetic activity. Its high solubility and rapid metabolism results in poor bioavailability and short half-life, limiting its clinical utility. We have synthesized Lisofylline-Linoleic acid (LSF-LA) conjugate which self-assembled into micelles (156.9 nm; PDI 0.187; CMC 1 µg/mL; aggregation number 54) without any surfactant and showed enhanced cellular uptake. It protected MIN6 insulinoma cells from cytokine induced cell death and enhanced insulin production under inflammatory conditions. It also suppressed the proliferation of activated peripheral blood mononuclear cells and reduced the production of inflammatory cytokines, IFN-γ and TNF-α. LSF-LA micelles exhibited reduced protein binding, significantly higher half-life (5.7-fold) and higher apparent volume of distribution (5.3-fold) than free LSF. In T1D animals, reduced blood glucose levels were observed at a reduced dose (~15 mg/kg, once daily of LSF-LA micelles vs. 25 mg/kg, twice daily of free LSF) that was further confirmed by immunohistochemical analysis.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Insulinoma/tratamento farmacológico , Ácido Linoleico/química , Pentoxifilina/análogos & derivados , Substâncias Protetoras/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Mediadores da Inflamação/metabolismo , Secreção de Insulina , Insulinoma/metabolismo , Insulinoma/patologia , Masculino , Micelas , Pentoxifilina/química , Pentoxifilina/farmacocinética , Pentoxifilina/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/farmacocinética , Ratos , Ratos Wistar , Distribuição Tecidual
12.
Xenobiotica ; 49(2): 239-246, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29405807

RESUMO

1. Deoxyschizandrin and schizandrin B have diverse pharmacological effects, including hepatoprotective activity. We aim to study their hepatic uptake and their effects on the hepatic uptake of other clinical drugs mediated by OATP1B1 and OATP1B3. 2. Deoxyschizandrin exhibited a high affinity for OATP1B1 with Km of 17.61 ± 0.43 µM but a low affinity for OATP1B3. Similarly, schizandrin B also showed a strong affinity for OATP1B1 with Km of 18.45 ± 1.23 µM but a weak affinity for OATP1B3. 3. Atorvastatin and rifampicin could inhibit the uptake of deoxyschizandrin and schizandrin B mediated by OATP1B1. 4. Intriguingly, both deoxyschizandrin and schizandrin B significantly promoted the uptake of atorvastatin (with EC50 of 50.58 ± 8.08 and 24.70 ± 5.82 µM, respectively) and rosuvastatin (with EC50 of 13.46 ± 2.70 and 8.99 ± 4.73 µM, respectively) mediated by OATP1B1. Deoxyschizandrin could markedly promote the uptake of fluvastatin but inhibit the uptake of sodium taurocholate (TCNa) mediated by OATP1B1. 5. The promotion on hepatic uptake of statins mediated by OATP1B1 might lead to enhanced efficacy of cholesterol lowering and reduced risk of myopathy for hyperlipidemia patients when given statins together with deoxyschizandrin or schizandrin B.


Assuntos
Ciclo-Octanos/farmacocinética , Lignanas/farmacocinética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Fígado/metabolismo , Compostos Policíclicos/farmacocinética , Substâncias Protetoras/farmacocinética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Atorvastatina/efeitos adversos , Atorvastatina/farmacocinética , Ciclo-Octanos/metabolismo , Interações Medicamentosas , Células HEK293 , Humanos , Cinética , Lignanas/metabolismo , Compostos Policíclicos/metabolismo , Substâncias Protetoras/metabolismo , Rosuvastatina Cálcica/efeitos adversos , Rosuvastatina Cálcica/farmacocinética
13.
Eur. j. anat ; 22(6): 461-469, nov. 2018. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-182113

RESUMO

Polycystic ovary syndrome (PCOS) is a reproductive and metabolic disorder in which the level of oxidative elements in blood rises. Bougainvillea spectabilis is a plant with a potent antioxidant effect, since it contains flavonoids. The aim of this work is to explore the possible protective potency of Bougainvillea spectabilis leaves (BSL) extract on ovarian folliculogenesis using a rat model of estradiol valerate (EV) - induced PCOS. Thirty six mature female rats were divided into four groups: 1. Control group (six rats). 2. EV group (ten rats), singly injected with 2mg/kg EV subcutaneously. 3. BSL group (ten rats), given 100mg/kg BSL extract orally for 30 days. 4. EV + BSL group (ten rats), singly injected with EV subcutaneously and given 100mg/kg BSL extract orally for 30 days. Biochemical measurements of serum levels of estrogen, testosterone, LH, FSH, glucose, totals lipids, and total antioxidants were done using ELISA method. Histological (using hematoxylin & eosin and Masson's trichrome stains) and immunohistochemical (using anti cyclooxygenase 2 {COX 2}) studies were performed. This was followed by morphometric measurements and statistical analysis. PCOS caused massive primordial follicle loss and development of cystic follicles with increase in fibrosis, COX 2 immunoexpression. There was a significant reduction in LH, estrogen and glucose serum levels and increase in FSH and the antioxidant serum levels between the EV + BSL-extract-treated group compared to EV-treated group. Histomorphometric studies also showed the significant changes in the number of follicles and decreased cyst formation in the combined therapy group. There was a significant role of BSL extract in restoration of ovarian folliculogenesis and reduction of biochemical, histological and immunohistochemical changes in EV treated group


No disponible


Assuntos
Animais , Feminino , Ratos , Nyctaginaceae , Estradiol/efeitos adversos , Síndrome do Ovário Policístico , Ovário/ultraestrutura , Substâncias Protetoras/farmacocinética , Estradiol/administração & dosagem , Antagonistas de Estrogênios/uso terapêutico , Ovário/citologia , Ciclo-Oxigenase 2/imunologia
14.
Nutrients ; 10(10)2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30257423

RESUMO

The focus on nanotechnology for improved bioavailability and drug delivery is of increasing importance for control of different human diseases. Therefore, numerous nanoformulations have been developed for the oral bioavailability of different drugs. This review introduces applications of nanomedicine to enhance the biological activities of thymoquinone (TQ) to control different diseases in several in vivo studies as a preliminary investigation for human disease treatment with nano-TQ. Nano-TQ effectively augments the anticancer roles of doxorubicin by upregulation of P53 and downregulation of Bcl2 and potentiates paclitaxel's apoptosis in MCF-7 breast cancer cells. Moreover, nano-TQ protects against diabetes, inflammation, CNS, and hepatotoxicity, mainly by enhancement of organs' antioxidant status. We summarize the pros and cons of several FDA approved nanoparticle-based therapeutics and discuss the roadblocks in clinical translation, along with potential nano-TQ strategies to overcome these roadblocks. From this review, we can conclude that nano-TQ may be considered as a promising nutraceutical for human health.


Assuntos
Benzoquinonas/farmacocinética , Suplementos Nutricionais , Nanopartículas/uso terapêutico , Nanotecnologia/métodos , Substâncias Protetoras/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Benzoquinonas/química , Disponibilidade Biológica , Regulação para Baixo , Genes p53/efeitos dos fármacos , Humanos , Células MCF-7/efeitos dos fármacos , Nanopartículas/química , Substâncias Protetoras/química , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Regulação para Cima
15.
Clin. transl. oncol. (Print) ; 20(9): 1097-1018, sept. 2018. tab
Artigo em Inglês | IBECS | ID: ibc-173694

RESUMO

The association between venous thromboembolism (VTE) and cancer has been recognized for more than 100 years. Numerous studies have been performed to investigate strategies to decrease VTE incidence and to establish whether treating VTE impacts cancer progression and overall survival. Accordingly, it is important to understand the role of the hemostatic system in tumorigenesis and progression, as there is abundant evidence associating it with cell survival and proliferation, tumor angiogenesis, invasion, and dissemination, and metastasis formation. In attempts to further the scientific evidence, several studies examine survival benefits in cancer patients treated with anticoagulant therapy, specifically treatment with vitamin K antagonists, unfractionated heparin, and low-molecular-weight heparin. Several studies and meta-analyses have been conducted with a special focus on brain tumors. However, no definitive conclusions have been obtained, and more well-designed clinical trials are needed


No disponible


Assuntos
Humanos , Anticoagulantes/farmacocinética , Heparina/farmacocinética , Neoplasias/tratamento farmacológico , Taxa de Sobrevida , Tromboembolia Venosa/prevenção & controle , Substâncias Protetoras/farmacocinética , Vitamina K/antagonistas & inibidores , Heparina de Baixo Peso Molecular/farmacocinética
16.
Molecules ; 23(9)2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30135414

RESUMO

No scientific report proves the action of the phytochemicals from the mangrove tree Rhizophora mangle in the treatment of diabetes. The aim of this work is to evaluate the effects of the acetonic extract of R. mangle barks (AERM) on type 2 diabetes. The main chemical constituents of the extract were analyzed by high-performance liquid chromatography (HPLC) and flow injection analysis electrospray-iontrap mass spectrometry (FIA-ESI-IT-MS/MS). High-fat diet (HFD)-fed mice were used as model of type 2 diabetes associated with obesity. After 4 weeks of AERM 5 or 50 mg/kg/day orally, glucose homeostasis was evaluated by insulin tolerance test (kiTT). Hepatic steatosis, triglycerides and gene expression were also evaluated. AERM consists of catechin, quercetin and chlorogenic acids derivatives. These metabolites have nutritional importance, obese mice treated with AERM (50 mg/kg) presented improvements in insulin resistance resulting in hepatic steatosis reductions associated with a strong inhibition of hepatic mRNA levels of CD36. The beneficial effects of AERM in an obesity model could be associated with its inhibitory α-amylase activity detected in vitro. Rhizophora mangle partially reverses insulin resistance and hepatic steatosis associated with obesity, supporting previous claims in traditional knowledge.


Assuntos
Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/metabolismo , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Rhizophoraceae/química , Animais , Biomarcadores , Glicemia , Cromatografia Líquida de Alta Pressão , Dieta Hiperlipídica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Redes e Vias Metabólicas , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Polifenóis/química , Polifenóis/farmacocinética , Substâncias Protetoras/química , Substâncias Protetoras/farmacocinética , Substâncias Protetoras/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
17.
Acta Pharmacol Sin ; 39(10): 1670-1680, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29770798

RESUMO

Apatinib, a small-molecule inhibitor of VEGFR-2, has attracted much attention due to its encouraging anticancer activity in third-line clinical treatment for many malignancies, including non-small cell lung cancer (NSCLC). Its usage in second-line therapy with chemotherapeutic drugs is still under exploration. In this study we investigated the antitumor effect of apatinib combined with docetaxel against NSCLC and its cellular pharmacokinetic basis. A549 xenograft nude mice were treated with apatinib (100 mg/kg every day for 20 days) combined with docetaxel (8 mg/kg, ip, every four days for 5 times). Apatinib significantly enhanced the antitumor effect of docetaxel and alleviated docetaxel-induced liver damage as well as decreased serum transaminases (ALT and AST). LC-MS/MS analysis revealed that apatinib treatment significantly increased the docetaxel concentration in tumors (up to 1.77 times) without enhancing the docetaxel concentration in the serum, heart, liver, lung and kidney. Furthermore, apatinib decreased docetaxel-induced upregulation of P-glycoprotein in tumors. The effects of apatinib on the uptake, efflux and subcellular distribution of docetaxel were investigated in A549 and A549/DTX (docetaxel-resistant) cells in vitro. A cellular pharmacokinetic study revealed that apatinib significantly increased cellular/subcellular accumulation (especially in the cytosol) and decreased the efflux of docetaxel in A549/DTX cells through P-gp, while apatinib exerted no significant effect on the cellular pharmacokinetics of docetaxel in A549 cells. Consequently, the IC50 value of docetaxel in A549/DTX cells was more significantly decreased by apatinib than that in A549 cells. These results demonstrate that apatinib has potential for application in second-line therapy combined with docetaxel for NSCLC patients, especially for docetaxel-resistant or multidrug-resistant patients.


Assuntos
Docetaxel/uso terapêutico , Piridinas/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Docetaxel/farmacocinética , Sinergismo Farmacológico , Humanos , Fígado/efeitos dos fármacos , Masculino , Camundongos Nus , Substâncias Protetoras/farmacocinética , Substâncias Protetoras/uso terapêutico , Piridinas/farmacocinética , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Nutr. hosp ; 35(2): 318-325, mar.-abr. 2018. tab, graf
Artigo em Inglês | IBECS | ID: ibc-172742

RESUMO

Introduction: the excessive consumption of fructose can cause liver damage, characteristic of non-alcoholic fatty liver disease (NAFLD) associated with changes in lipid metabolism and antioxidant defenses. Açai, the fruit of Euterpe oleracea Mart., has demonstrated numerous biological activities, including anti-inflammatory, antioxidant, and lipid metabolism modulating action. Objective: we evaluated the benefits of açai supplementation on liver damage caused by replacing starch with fructose in rats. Methods: thirty male Fischer rats were divided into two groups, the control group (C, 10 animals), which consumed a standard diet (AIN-93M), and the fructose (F, 20 animals) group, which consumed a diet containing 60% of fructose. After eight weeks, 10 animals from the fructose group received 2% of lyophilized açai, and were called the açai fructose group (FA). The animals were fed ad libitum with these diets for another ten weeks. Serum, hepatic and fecal lipid profile, antioxidant enzymes and carbonylated protein were assessed and histopathological characterization of the liver was performed. Results: açai promoted the reduction of ALT activity in relation to the fructose group (F), reduced alkaline phosphatase to a level similar to that of the control group (C) in relation to the fructose group (F), and reduced catalase activity. The fruit also increased the ratio of total/oxidized glutathione (GSH/GSSG) and reduced the degree of macrovesicular steatosis and the number of inflammatory cells. Conclusion: the replacement of starch by fructose during this period was effective in promoting NAFLD. Açai showed attenuating effects on some markers of hepatic steatosis and inflammation


Introducción: el consumo excesivo de fructosa puede causar daño hepático, característico de la enfermedad hepática grasa no alcohólica (EHGNA), asociada con cambios en el metabolismo de los lípidos y defensas antioxidantes. El açai, fruto del Euterpe oleracea Mart., ha demostrado desempeñar numerosas actividades biológicas, incluidas acciones antiinflamatorias, antioxidantes y moduladoras del metabolismo lipídico. Objetivo: se evaluaron los beneficios de la suplementación con açai en el daño hepático causado por la sustitución del almidón por fructosa en ratas. Métodos: se distribuyeron 30 ratas Fischer macho en dos grupos: 10 ratas en el grupo control (C), que consumía una dieta estándar (AIN-93M), y 20 ratas en el grupo fructosa (F), que consumía una dieta que contenía un 60% de fructosa. Después de ocho semanas, diez animales del grupo fructosa recibieron un 2% de açai liofilizado, por lo que pasaron a integrar el grupo açai fructosa (FA). Los animales fueron alimentados ad libitum con estas dietas durante otras diez semanas. Se analizaron el perfil lipídico hepático y fecal, las enzimas antioxidantes y la proteína carbonilada, y se realizó la caracterización histopatológica del hígado. Resultados: el açai promovió la reducción de la actividad de ALT en relación al grupo de fructosa (F) y la reducción de la fosfatasa alcalina a niveles similares a los hallados en el grupo control (C) en relación con el grupo de fructosa (F). El fruto también aumentó la proporción de glutatión total/oxidado (GSH/GSSG) y redujo el grado de esteatosis macrovesicular y el número de células inflamatorias. Conclusión: la sustitución de almidón por fructosa durante este periodo fue eficaz en la promoción de NAFLD. El açai mostró efectos atenuantes en algunos marcadores de esteatosis hepática y de inflamación


Assuntos
Animais , Ratos , Fígado Gorduroso/dietoterapia , Euterpe , Extratos Vegetais/farmacocinética , Modelos Animais de Doenças , Substâncias Protetoras/farmacocinética , Suplementos Nutricionais , Resultado do Tratamento , Estudos de Casos e Controles , Inflamação/fisiopatologia
20.
Nutr. hosp ; 35(2): 428-433, mar.-abr. 2018. tab
Artigo em Inglês | IBECS | ID: ibc-172757

RESUMO

Objectives: to evaluate the efficacy of glutamine in the prevention of the incidence of oral mucositis secondary to cancer therapies in patients with head and neck cancer (HNC). Secondary objectives were to know the incidence of odynophagia, interruptions of treatment and the requirements of analgesia and nasogastric tube. Material and methods: prospective cohort study of patients with squamous cell carcinoma of HNC treated with radiotherapy ± concomitant chemotherapy. We compared 131 patients receiving glutamine orally at a dose of 10 g/8 hours with 131 patients who did not receive it. Results: patients not taking glutamine had a hazard ratio 1.78 times higher of mucositis (95% CI [1.01-3.16], p = 0.047). Regarding odynophagia, patients not taking glutamine had a hazard ratio 2.87 times higher (95% CI [1.62-5.18], p = 0.0003). The 19.8% of patients who did not take glutamine discontinued treatment versus 6.9% of patients who took (p = 0.002). Regarding support requirements, 87.8% of patients without glutamine required analgesia versus 77.9% of patients with glutamine (p = 0.03) and nasogastric tube was indicated in 9.9% and 3.1% respectively (p = 0.02). Conclusion: oral glutamine in patients receiving cancer treatments for HNC prevents the incidence of oral mucositis and odynophagia, and decreases treatment interruptions and the use of analgesia and nasogastric tube


Objetivos: evaluar la eficacia de la glutamina en la prevención de la incidencia de mucositis secundaria a las terapias oncológicas en pacientes con carcinoma de cabeza y cuello. Los objetivos secundarios fueron conocer la incidencia de odinofagia e interrupciones de los tratamientos y los requerimientos de analgesia y sonda nasogástrica. Material y métodos: estudio prospectivo de cohortes de pacientes con carcinoma epidermoide de cabeza y cuello tratados con radioterapia ± quimioterapia concomitante. Se compararon 131 pacientes que recibieron glutamina oral a una dosis de 10 g/8 horas con 131 pacientes que no la recibieron. Resultados: los pacientes que no tomaron glutamina tuvieron una hazard ratio 1,78 veces mayor de mucositis (IC 95% [1,01-3,16], p = 0,047). Respecto a la odinofagia, los pacientes que no tomaron glutamina tuvieron una hazard ratio 2,87 veces mayor (IC 95% [1,62-5,18], p = 0,0003]. El 19,8% de los pacientes que no tomaron glutamina interrumpieron el tratamiento versus 6,9% de los pacientes que la tomaron (p = 0,002). En cuanto a los tratamientos de soporte, el 87,8% de los pacientes sin glutamina requirieron analgesia versus 77,9% de los pacientes con glutamina (p = 0,03) y la sonda nasogástrica fue indicada en un 9,9% y 3,1% respectivamente (p = 0,02). Conclusión: la glutamina oral en pacientes que reciben tratamiento por carcinoma de cabeza y cuello, previene la incidencia de mucositis oral y odinofagia y disminuye las interrupciones de tratamientos y el uso de analgesia y sonda nasogástrica


Assuntos
Humanos , Mucosite/prevenção & controle , Neoplasias de Cabeça e Pescoço/complicações , Glutamina/farmacocinética , Quimiorradioterapia/efeitos adversos , Neoplasias de Cabeça e Pescoço/terapia , Estudos Prospectivos , Substâncias Protetoras/farmacocinética , Transtornos de Deglutição/etiologia , Lesões por Radiação/prevenção & controle
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