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1.
Eur J Pharm Biopharm ; 145: 76-84, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639417

RESUMO

Oral drug delivery is a preferred administration route due to its low cost, high patient compliance and fewer adverse events compared to intravenous administration. However, many pharmaceuticals suffer from poor solubility and low oral bioavailability. One major factor that contributes to low bioavailability are efflux transporters which prevent drug absorption through intestinal epithelial cells. P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are two important efflux transporters in the intestine functioning to prevent toxic materials from entering systemic circulation. However, due to its broad substrate specificity, P-gp limits the absorption of many therapeutics, including chemotherapeutics and antibacterial agents. Methods to inhibit P-gp with competitive inhibitors have not been clinically successful. Here, we show that micron scale devices (microdevices) made from a commonly used biomaterial, polyethylene glycol (PEG), inhibit P-gp through a biosimilar mucus in Caco-2 cells and that transporter function is restored when the microdevices are removed. Microdevices were shown to inhibit P-gp mediated transport of calcein AM, doxorubicin, and rhodamine 123 (R123) and BCRP mediated transport of BODIPY-FL-prazosin. When in contact with Caco-2 cells, microdevices decrease the cell surface amount of P-gp without affecting the passive transport. Moreover, there was an increase in mucosal to serosal transport of R123 with microdevices in an ex-vivo mouse model and increased absorption in vivo. This biomaterial-based approach to inhibit efflux transporters can be applied to a range of drug delivery systems and allows for a nonpharmacologic method to increase intestinal drug absorption while limiting toxic effects.


Assuntos
Transporte Biológico/efeitos dos fármacos , Hidrogéis/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Disponibilidade Biológica , Compostos de Boro/metabolismo , Células CACO-2 , Linhagem Celular Tumoral , Humanos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polietilenoglicóis/química , Prazosina/análogos & derivados , Prazosina/metabolismo , Rodamina 123/metabolismo , Solubilidade/efeitos dos fármacos
2.
J Agric Food Chem ; 67(40): 11119-11128, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31525874

RESUMO

Xanthohumol (Xan) is a prenylated chalcone mainly found in hops; it has been demonstrated to function against hypercholesterolemia, hyperlipidemia, and atherosclerosis. In this study, we focused on the hypocholesterolemic effect of Xan on cholesterol uptake and the underlying molecular mechanisms of Xan in human intestinal Caco-2 cells. The microarray data showed that Niemann-Pick C1-like 1 (NPC1L1), an essential transporter for dietary cholesterol absorption, was significantly downregulated in Xan-treated Caco-2 cells. We demonstrated that Xan (10 and 20 µM) suppressed the mRNA and protein expression of NPC1L1 by 0.65 ± 0.12-fold and 0.54 ± 0.15-fold and 0.72 ± 0.04-fold and 0.44 ± 0.12-fold, respectively, compared to that of the vehicle-treated Caco-2 cells. Moreover, Xan (10 and 20 µM) significantly inhibited cholesterol uptake by approximately 12 and 32% in Caco-2 cells. NPC1L1 promoter activity was significantly suppressed by Xan, and a DNA element within the NPC1L1 promoter involved in Xan-mediated NPC1L1 reduction located between the -120 and -20 positions was identified. Moreover, Xan markedly decreased the mRNA and protein levels of hepatocyte nuclear factor 4α (HNF-4α), a critical activator of NPC1L1 transcription, and subsequently attenuated HNF-4α/NPC1L1 promoter complex formation, resulting in the suppression of NPC1L1 gene expression. Finally, we demonstrated that Xan markedly abolished lovastatin-induced NPC1L1 overexpression in Caco-2 cells. These findings reveal that Xan suppresses NPC1L1 expression via downregulation of HNF-4α and exerts inhibitory effects on cholesterol uptake in the intestinal Caco-2 cells. Our findings suggest Xan could serve as a potential cholesterol-lowering agent and supplement for statin therapy.


Assuntos
Colesterol/metabolismo , Flavonoides/farmacologia , Fator 4 Nuclear de Hepatócito/metabolismo , Proteínas de Membrana/genética , Propiofenonas/farmacologia , Anticolesterolemiantes/farmacologia , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Regulação para Baixo/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Fator 4 Nuclear de Hepatócito/genética , Humanos , Proteínas de Membrana/metabolismo , Regiões Promotoras Genéticas
3.
J Agric Food Chem ; 67(42): 11638-11649, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31532204

RESUMO

Naturally occurring cinnamon compounds such as cinnamaldehyde (CAL) and structurally related constituents have been associated with antiobesity activities, although studies regarding the impact on intestinal fatty acid uptake are scarce. Here, we demonstrate the effects of CAL and structural analogues cinnamyl alcohol (CALC), cinnamic acid (CAC), and cinnamyl isobutyrate on mechanisms regulating intestinal fatty acid uptake in differentiated Caco-2 cells. CAL, CALC, and CAC (3000 µM) were found to decrease fatty acid uptake by 58.0 ± 8.83, 19.4 ± 8.98, and 21.9 ± 6.55%, respectively. While CAL and CALC at a concentration of 300 µM increased serotonin release 14.9 ± 3.00- and 2.72 ± 0.69-fold, respectively, serotonin alone showed no effect on fatty acid uptake. However, CAL revealed transient receptor potential channel A1-dependency in the decrease of fatty acid uptake, as well as in CAL-induced serotonin release. Overall, CAL was identified as the most potent of the cinnamon constituents tested.


Assuntos
Acroleína/análogos & derivados , Cinamatos/farmacologia , Cinnamomum zeylanicum/química , Ácidos Graxos/metabolismo , Extratos Vegetais/farmacologia , Propanóis/farmacologia , Acroleína/química , Acroleína/farmacologia , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Diferenciação Celular , Cinamatos/química , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Extratos Vegetais/química , Propanóis/química
4.
Int J Nanomedicine ; 14: 6339-6356, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496690

RESUMO

Objective: The rational combination of immunotherapy with standard chemotherapy shows synergistic clinical activities in cancer treatment. In the present study, an oral powder formulation of pemetrexed (PMX) was developed to enhance intestinal membrane permeability and investigate its application in metronomic chemotherapy in combination with immunotherapy. Methods: PMX was ionically complexed with a bile acid derivative (Nα-deoxycholyl-l-lysyl-methylester; DCK) as a permeation enhancer and mixed with dispersing agents, such as poloxamer 188 (P188) and Labrasol, to form an amorphous oral powder formulation of PMX/DCK (PMX/DCK-OP). Results: The apparent permeability (Papp) of PMX/DCK-OP across a Caco-2 cell monolayer was 2.46- and 8.26-fold greater than that of PMX/DCK and free PMX, respectively, which may have been due to the specific interaction of DCK with bile acid transporters, as well as the alteration of membrane fluidity due to Labrasol and P188. Furthermore, inhibition of bile acid transporters by actinomycin D in Caco-2 cell monolayers decreased the Papp of PMX/DCK-OP by 75.4%, suggesting a predominant role of bile acid transporters in the intestinal absorption of PMX/DCK-OP. In addition, caveola/lipid raft-dependent endocytosis, macropinocytosis, passive diffusion, and paracellular transport mechanisms significantly influenced the permeation of PMX/DCK-OP through the intestinal membrane. Therefore, the oral bioavailability of PMX/DCK-OP in rats was 19.8%±6.93%, which was 294% higher than that of oral PMX. Moreover, an in vivo anticancer efficacy study in B16F10 cell-bearing mice treated with a combination of oral PMX/DCK-OP and intraperitoneal anti-PD1 exhibited significant suppression of tumor growth, and the tumor volume was maximally inhibited by 2.03- and 3.16-fold compared to the oral PMX/DCK-OP and control groups, respectively. Conclusion: These findings indicated the therapeutic potential of a combination of low-dose oral chemotherapy and immunotherapy for synergistic anticancer efficacy.


Assuntos
Ácido Desoxicólico/química , Composição de Medicamentos , Intestinos/efeitos dos fármacos , Pemetrexede/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/química , Humanos , Íons , Lisina/análogos & derivados , Lisina/química , Camundongos Endogâmicos BALB C , Pemetrexede/administração & dosagem , Pemetrexede/sangue , Pemetrexede/farmacocinética , Permeabilidade , Ratos Sprague-Dawley
5.
Eur J Pharm Biopharm ; 143: 98-105, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31425857

RESUMO

Oral delivery of peptides is challenging due to their low uptake through the small intestinal epithelium. Tight junctions, connecting the enterocytes, impede permeability, often necessitating the use of permeation enhancers in the formulation. Loading of peptide and permeation enhancer into micro-scale devices, such as microcontainers, can potentially confine the effective absorptive area through unidirectional release and thereby enhance absorption. This concept is investigated by in vitro permeation studies of insulin across Caco-2 cell and Caco-2/HT29-MTX-E12 co-culture monolayers mimicking the intestinal absorption barrier. The importance of proximity between the microcontainers and the barrier is assessed, by keeping the amounts of insulin and sodium caprate fixed throughout all experiments, while collectively orienting the unidirectional release towards the cell monolayers. Increasing the distance is observed to have a negative effect on insulin permeation matching a one-phase exponential decay function, while no difference in insulin transport is observed between Caco-2 and co-culture monolayers. Although there are no signs of cytotoxicity caused by the microcontainer material, reversible cell deterioration, as a consequence of high local concentrations of sodium caprate, becomes evident upon qualitative assessment of the cell monolayers. These results both suggest a potential of increasing oral bioavailability of peptides by the use of microcontainers, while simultaneously visualising the ability of regaining monolayer integrity upon local permeation enhancer induced toxicity.


Assuntos
Insulina/administração & dosagem , Insulina/química , Permeabilidade/efeitos dos fármacos , Administração Oral , Disponibilidade Biológica , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Linhagem Celular Tumoral , Técnicas de Cocultura/métodos , Humanos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Peptídeos/administração & dosagem , Peptídeos/química , Junções Íntimas/metabolismo
6.
Curr Protein Pept Sci ; 20(10): 1004-1011, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31453783

RESUMO

Cardiovascular disease (CVD) is the biggest killer globally and atherosclerosis (AS) is the major trigger to this pathology. Abnormal cholesterol homeostasis is the starting point of AS, especially the aggregation of macrophage foam cells in the intra-arterial subcutaneous region. Reverse cholesterol transport (RCT) can remove excess cholesterol from macrophages and transport it to the liver for excretion, making this process vital to alleviate AS. MicroRNAs (miRNAs) are small, noncoding RNAs that play critical roles in various diseases including AS, by regulating post-transcriptional gene expression. Many natural compounds can exert anti-atherosclerotic effects by regulating different miRNAs that are implicated in RCT. Hence, targeting these miRNAs using natural functional compounds may be a safe, novel, and promising strategy to prevent and treat AS. This review describes the miRNAs involved in RCT and the potential uses of natural compounds to target RCT-related miRNAs to modulate AS.


Assuntos
Aterosclerose/tratamento farmacológico , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Colesterol/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , MicroRNAs/metabolismo
7.
J Agric Food Chem ; 67(36): 10126-10136, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31433635

RESUMO

Soil microbes have recently been utilized to improve cadmium (Cd) tolerance and lower its accumulation in plants. Nevertheless, whether rhizobacteria can prevent Cd uptake by graminaceous plants and the underlying mechanisms remain elusive. In this study, inoculation with Enterobacter asburiae NC16 reduced transpiration rates and the expression of some iron (Fe) uptake-related genes including ZmFer, ZmYS1, ZmZIP, and ZmNAS2 in maize (Zea mays) plants, which contributed to mitigation of Cd toxicity. However, the inoculation with NC16 failed to suppress the transpiration rates and transcription of these Fe uptake-related genes in plants treated with fluridone, an abscisic acid (ABA) biosynthetic inhibitor, indicating that the impacts of NC16-inoculation observed were dependent on the actions of ABA. We found that NC16 increased the host ABA levels by mediating the metabolism of ABA rather than its synthesis. Moreover, the capacity of NC16 to inhibit plant uptake of Cd was greatly weakened in plants overexpressing ZmZIP, encoding a zinc/iron transporter. Collectively, our findings indicated that E. asburiae NC16 reduced Cd toxicity in maize plants at least partially by hampering the Fe uptake-associated pathways.


Assuntos
Cádmio/metabolismo , Enterobacter/metabolismo , Ferro/metabolismo , Zea mays/metabolismo , Inoculantes Agrícolas/metabolismo , Transporte Biológico/efeitos dos fármacos , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raízes de Plantas/metabolismo , Raízes de Plantas/microbiologia , Piridonas/farmacologia , Zea mays/efeitos dos fármacos , Zea mays/genética , Zea mays/microbiologia
8.
An Acad Bras Cienc ; 91(3): e20180654, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365653

RESUMO

Candida albicans is the most frequent fungal species that causes infections in humans. Fluconazole is the main antifungal used to treat Candida infections, and its prolonged and indiscriminate use for the last decades are the most established causes which originated resistant strains. Fungal drug resistance is associated to alterations in ERG11 gene and overexpression of multidrug resistance (MDR) transporters belonging to two families: ATP-binding cassette (ABC) and Major Facilitator Superfamily (MFS). To evaluate the role of MFS transporters in azoles resistance of C. albicans clinical strains, this study aimed to analyze four Candida albicans clinical isolates from the University Hospital in Juiz de Fora (Minas Gerais/Brazil), selected in our previous study as they were unaffected by FK506, an ABC pumps inhibitor. In a primary investigation on MFS proteins overexpression, the extrusion of fluorescent substrates (rhodamine 6G and nile red) was analyzed by fluorescence microscopy and flow cytometry. Results suggest participation of MFS transporters in azole resistance of C. albicans isolates and indicate the existence of secondary resistance mechanisms. Therefore, this study contributes to the information about Candida albicans infections in Brazil and reinforces the importance of epidemiological studies focusing on an improved understanding of the disease and further resistance reversion.


Assuntos
Antifúngicos/farmacologia , Azóis/farmacologia , Candida albicans/efeitos dos fármacos , Proteínas de Membrana Transportadoras/metabolismo , Azóis/classificação , Transporte Biológico/efeitos dos fármacos , Citometria de Fluxo , Humanos , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Microscopia de Fluorescência , Centros de Atenção Terciária
9.
J Agric Food Chem ; 67(32): 8839-8846, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31334651

RESUMO

Natural products are one of the main sources for discovering new lead compounds. We previously reported that cinnamon extract has a promising effect in regulating lipid tissue volume and insulin sensitivity in vivo. However, its effective component and the underlying mechanism are not known. In the present study, we analyzed the effect of different components of cinnamon on regulating insulin sensitivity in 3T3-L1 adipocytes. Functional assay revealed that, of the six major components of cinnamon extracts, the B-type procyanidin, procyanidin C1, improves the differentiation of 3T3-L1 cells (TG content: 1.10 ± 0.09 mM at a dosage of 25 µM vs 0.67 ± 0.02 mM in vehicle group, p < 0.001) and promotes insulin-induced glucose uptake (8.58 ± 1.43 at a dosage of 25 µM vs 3.05 ± 1.24 in vehicle group, p < 0.001). Mechanism studies further suggested that procyanidin C1 activates the AKT-eNOS pathway, thus up-regulating glucose uptake and enhancing insulin sensitivity in mature adipocytes. Taken together, our study identified B-type procyanidin C1, a component of cinnamon extract, that stimulates preadipocyte differentiation and acts as a potential insulin action enhancer through the AKT-eNOS pathway in mature adipocytes.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Biflavonoides/farmacologia , Catequina/farmacologia , Cinnamomum zeylanicum/química , Insulina/metabolismo , Extratos Vegetais/farmacologia , Proantocianidinas/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Animais , Transporte Biológico/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Glucose/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo
10.
Environ Pollut ; 253: 959-965, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351304

RESUMO

Application of Zinc (Zn) is considered an effective measure to reduce Cadmium (Cd) uptake and toxicity in Cd-contaminated soils for many plant species. However, interaction between Zn and Cd in rice plant is complex and uncertain. In this study, four indica rice cultivars were selected to evaluate the effect of Zn exposure in an EGTA-buffered nutrient solution under varying Zn activities and a field level of Cd activity to characterize the interaction between Zn and Cd in rice. Severe depression in shoots' biomass, tiller number, and SPAD (Soil and Plant Analyzer Development) value were found at both Zn deficiency and Zn phytotoxicity levels among four tested rice cultivars. There existed a strong antagonism interaction between Zn and Cd in both shoot and root from Zn deficiency to Zn phytotoxicity. The reduction of Cd accumulation in roots and shoots could be explained by the competition between Zn and Cd as well as the dilution effect of increasing biomass. The conflicting effect of Zn supply on Cd uptake may be attributed to the increasing transfer ratio of Cd from root to shoot with the increasing Zn2+ activities and the strong depression of Fe and Mn in shoots with the increasing Zn2+ activities as well as the variation of genotypes. Balance between Zn and Cd should be considered in field application.


Assuntos
Cádmio/metabolismo , Oryza/fisiologia , Poluentes do Solo/metabolismo , Zinco/metabolismo , Transporte Biológico/efeitos dos fármacos , Biomassa , Cádmio/análise , Poluição Ambiental , Oryza/efeitos dos fármacos , Raízes de Plantas/efeitos dos fármacos , Solo , Poluentes do Solo/análise , Poluentes do Solo/toxicidade
11.
J Cancer Res Clin Oncol ; 145(8): 1949-1976, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31292714

RESUMO

PURPOSE: Efflux transporters of the adenosine triphosphate-binding cassette (ABC)-superfamily play an important role in the development of multidrug resistance (multidrug resistant; MDR) in cancer. The overexpression of these transporters can directly contribute to the failure of chemotherapeutic drugs. Several in vitro and in vivo models exist to screen for the efficacy of chemotherapeutic drugs against MDR cancer, specifically facilitated by efflux transporters. RESULTS: This article reviews a range of efflux transporter-based MDR models used to test the efficacy of compounds to overcome MDR in cancer. These models are classified as either in vitro or in vivo and are further categorised as the most basic, conventional models or more complex and advanced systems. Each model's origin, advantages and limitations, as well as specific efflux transporter-based MDR applications are discussed. Accordingly, future modifications to existing models or new research approaches are suggested to develop prototypes that closely resemble the true nature of multidrug resistant cancer in the human body. CONCLUSIONS: It is evident from this review that a combination of both in vitro and in vivo preclinical models can provide a better understanding of cancer itself, than using a single model only. However, there is still a clear lack of progression of these models from basic research to high-throughput clinical practice.


Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Antineoplásicos/isolamento & purificação , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Modelos Biológicos , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/genética , Técnicas de Cultura/métodos , Técnicas de Apoio para a Decisão , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Especificidade de Órgãos , Seleção de Pacientes
12.
Eur J Pharm Biopharm ; 142: 70-82, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31176723

RESUMO

Nanoparticles may provide a viable way for neuroprotective drugs to cross the blood-brain barrier (BBB), which limits the passage of most drugs from the peripheral circulation to the brain. Heterotelechelic polymer prodrugs comprising a neuroprotective model drug (adenosine) and a maleimide functionality were synthesized by the "drug-initiated" approach and subsequent nitroxide exchange reaction. Nanoparticles were obtained by nanoprecipitation and exhibited high colloidal stability with diameters in the 162-185 nm range and narrow size distributions. Nanoparticles were then covalently surface-conjugated to different proteins (albumin, α2-macroglobulin and fetuin A) to test their capability of enhancing BBB translocation. Their performances in terms of endothelial permeability and cellular uptake in an in vitro BBB model were compared to that of similar nanoparticles with surface-adsorbed proteins, functionalized or not with the drug. It was shown that bare NPs (i.e., NPs not surface-functionalized with proteins) without the drug exhibited significant permeability and cellular uptake, which were further enhanced by NP surface functionalization with α2-macroglobulin. However, the presence of the drug at the polymer chain-end prevented efficient passage of all types of NPs through the BBB model, likely due to adecrease in the hydrophobicity of the nanoparticle surface and alteration of the protein binding/coupling, respectively. These results established a new and facile synthetic approach for the surface-functionalization of polymer nanoparticles for brain delivery purposes.


Assuntos
Barreira Hematoencefálica/metabolismo , Nanopartículas/metabolismo , Polímeros/metabolismo , Pró-Fármacos/metabolismo , Proteínas/metabolismo , Adsorção/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Portadores de Fármacos/metabolismo , Humanos , Permeabilidade/efeitos dos fármacos
13.
Bull Environ Contam Toxicol ; 103(3): 461-467, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31222423

RESUMO

The study aimed to determine the impact of treated domestic wastewater on seed germination, seedling growth and reserve mobilization from Fenugreek (Trigonellafoenum graecum L.). Seeds were germinated by soaking in distilled water (H2O) or wastewater treated with various methods: activated sludge processes (T1), facultative lagoons treatment (T2) and dilution. Results show high levels of organic matter (OM), suspended solids (TSS) and nutrients in TWW (T2) than that of TWW (T1). The embryo length and biomass of fenugreek imbibed by TWW were higher in TWW (T2) compared with TWW (T1). There was more reduction in free amino acids and soluble sugar contents in fenugreek treated with TWW (T1) than treated by TWW (T2). Important solutes leakage is recorded by measuring electric conductivity during seed imbibition with TWW. Improving the quality of wastewater by dilution (50%) stimulated germination of seeds and the growth of the tested plant. Moreover, it significantly reduces the solutes leakage and enhanced seed metabolites accumulation.


Assuntos
Sementes/efeitos dos fármacos , Trigonella/efeitos dos fármacos , Trigonella/metabolismo , Águas Residuárias/toxicidade , Agricultura , Transporte Biológico/efeitos dos fármacos , Biomassa , Monitoramento Ambiental , Germinação/efeitos dos fármacos , Plântula/química , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento , Plântula/metabolismo , Esgotos/efeitos adversos , Esgotos/química , Trigonella/química , Trigonella/crescimento & desenvolvimento , Eliminação de Resíduos Líquidos , Águas Residuárias/química
14.
BMC Plant Biol ; 19(1): 283, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31248369

RESUMO

BACKGROUND: Metal homeostasis is critical for plant growth, development and adaptation to environmental stresses and largely governed by a variety of metal transporters. The plant ZIP (Zn-regulated transporter, Iron-regulated transporter-like Protein) family proteins belong to the integral membrane transporters responsible for uptake and allocation of essential and non-essential metals. However, whether the ZIP family members mediate metal efflux and its regulatory mechanism remains unknown. RESULTS: In this report, we provided evidence that OsZIP1 is a metal-detoxified transporter through preventing excess Zn, Cu and Cd accumulation in rice. OsZIP1 is abundantly expressed in roots throughout the life span and sufficiently induced by excess Zn, Cu and Cd but not by Mn and Fe at transcriptional and translational levels. Expression of OsZIP-GFP fusion in rice protoplasts and tobacco leaves shows that OsZIP1 resides in the endoplasmic reticulum (ER) and plasma membrane (PM). The yeast (Saccharomyces cerevisiae) complementation test shows that expression of OsZIP1 reduced Zn accumulation. Transgenic rice overexpressing OsZIP1 grew better under excess metal stress but accumulated less of the metals in plants. In contrast, both oszip1 mutant and RNA interference (RNAi) lines accumulated more metal in roots and contributed to metal sensitive phenotypes. These results suggest OsZIP1 is able to function as a metal exporter in rice when Zn, Cu and Cd are excess in environment. We further identified the DNA methylation of histone H3K9me2 of OsZIP1 and found that OsZIP1 locus, whose transcribed regions imbed a 242 bp sequence, is demethylated, suggesting that epigenetic modification is likely associated with OsZIP1 function under Cd stress. CONCLUSION: OsZIP1 is a transporter that is required for detoxification of excess Zn, Cu and Cd in rice.


Assuntos
Cádmio/metabolismo , Proteínas de Transporte de Cátions/genética , Cobre/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Oryza/genética , Proteínas de Plantas/genética , Zinco/metabolismo , Transporte Biológico/efeitos dos fármacos , Proteínas de Transporte de Cátions/química , Proteínas de Transporte de Cátions/metabolismo , Oryza/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Estresse Fisiológico
15.
J Microbiol Biotechnol ; 29(6): 973-983, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31216793

RESUMO

It is well known that iron is critical for bacterial growth and pathogenic virulence. Due to chemical similarity, Ga3+ competes with Fe3+ for binding to compounds that usually bind Fe3+, thereby interfering with various essential biological reactions. In our present study, gallium(III) nitrate [Ga(NO3)3] could repress the growth of V. splendidus Vs without complete inhibition. In the presence of Ga(NO3)3, the secretion of homogentisic acid-melanin (HGAmelanin) in V. splendidus Vs cells could be increased by 4.8-fold, compared to that in the absence of Ga(NO3)3. HGA-melanin possessed the ability to reduce Fe3+ to Fe2+. In addition, HGA-melanin increased the mRNA levels of feoA and feoB, genes coding Fe2+ transport system proteins to 1.86- and 6.1-fold, respectively, and promoted bacterial growth to 139.2%. Similarly, the mRNA expression of feoA and feoB was upregulated 4.11-fold and 2.71-fold in the presence of 640 µM Ga(NO3)3, respectively. In conclusion, our study suggested that although Ga(NO3)3 could interfere with the growth of V. splendidus Vs, it could also stimulate both the production of Fe3+-reducing HGA-melanin and the expression of feoA and feoB , which facilitate Fe2+ transport in V. splendidus Vs.


Assuntos
Gálio/farmacologia , Ferro/metabolismo , Vibrio/efeitos dos fármacos , Proteínas de Bactérias/genética , Transporte Biológico/efeitos dos fármacos , Proteínas de Transporte de Cátions/genética , Relação Dose-Resposta a Droga , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Ácido Homogentísico/química , Ácido Homogentísico/metabolismo , Ácido Homogentísico/farmacologia , Melaninas/química , Melaninas/metabolismo , Melaninas/farmacologia , Oxirredução , Sideróforos/metabolismo , Vibrio/crescimento & desenvolvimento , Vibrio/metabolismo
16.
Bull Environ Contam Toxicol ; 103(3): 453-460, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31183504

RESUMO

The accumulation of strontium (Sr) in lettuce and radish under 0 (control), 0.5, 1, 2.5, 5, and 10 mM Sr treatments in hydroponic solution at 16, 23 and 30 days and the effects of Sr stress on six nutrient elements in plants were investigated. The results showed that Sr concentrations in plant aerial and underground parts increased in low-Sr treatments (0.5, 1 and 2.5 mM) and fluctuated in high-Sr treatments (5 and 10 mM) throughout the three sampling periods. Sr concentrations were higher in roots than in leaves, reaching 108.8 ± 14.7 and 134.1 ± 1.2 mg/g in lettuce and radish roots, respectively, after 10 mM Sr treatment. Translocation factor (TF) values (ratio of the Sr concentrations in aerial parts to that in roots) were inversely related to the Sr content in the hydroponic solution, and reached 1.45 ± 0.17 to 0.15 ± 0.03 and 1.06 ± 0.20 to 0.12 ± 0.004 for lettuce and radish. The variation in chlorophyll content was consistent with that in plant biomass.


Assuntos
Hidroponia , Alface/metabolismo , Raphanus/metabolismo , Estrôncio/metabolismo , Poluentes Químicos da Água/metabolismo , Transporte Biológico/efeitos dos fármacos , Biomassa , Clorofila/metabolismo , Alface/efeitos dos fármacos , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Raphanus/efeitos dos fármacos , Estrôncio/toxicidade , Poluentes Químicos da Água/toxicidade
17.
J Agric Food Chem ; 67(26): 7232-7242, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31184888

RESUMO

In the present study, the effect of imidacloprid uptake from contaminated soils on the growth of leaf vegetable Shanghaiqing was investigated. The result showed that during 35-day exposure, the concentration of imidacloprid (IMI) was in the order of vegetable shoots > vegetable roots > soil, indicating that IMI was more readily concentrated in vegetable shoots than in roots. Moreover, the biomass of IMI-treated vegetable shoots was comparable to that of the controls with early exposure, but was higher than that of the controls after 7-day exposure, showing that the test concentration of IMI could stimulate vegetable growth. The plant metabolic analysis of vegetable shoots using LC-QTOF/MS revealed that IMI may cause oxidative stress to the plant shoots with early exposure; however, the stressful situation of IMI seems to be relieved with the increase of some substances (such as spermidine and phenylalanine) with late exposure. Moreover, the upregulation of N-rich amino acids (glutamine, aspartate, and arginine) suggested that the process of fixing inorganic nitrogen in the plant should be enhanced, possibly contributing to enhanced growth rates. Additionally, four IMI's metabolites were identified by using MS-FINDER software, and the distribution of three metabolites in vegetable tissues was compared.


Assuntos
Inseticidas/farmacologia , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Poluentes do Solo/farmacologia , Verduras/efeitos dos fármacos , Aminoácidos/metabolismo , Transporte Biológico/efeitos dos fármacos , Inseticidas/análise , Espectrometria de Massas , Neonicotinoides/análise , Nitrocompostos/análise , Estresse Oxidativo/efeitos dos fármacos , Folhas de Planta/química , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo , Raízes de Plantas/química , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Brotos de Planta/química , Brotos de Planta/efeitos dos fármacos , Brotos de Planta/crescimento & desenvolvimento , Brotos de Planta/metabolismo , Solo/química , Poluentes do Solo/análise , Verduras/química , Verduras/crescimento & desenvolvimento , Verduras/metabolismo
18.
Molecules ; 24(11)2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185615

RESUMO

The aim of the current study was to examine the preventive effect of green tea catechins on the transport of Benzo[a]pyrene (B[α]P) into the brain using an in vitro bio-mimic system coupled with sequential co-cultures. When 72 µM of catechins was pre-treated, cellular cytotoxicity induced by IC50 of B[α]P in human liver hepatocellular carcinoma (HepG2) and human brain microvascular endothelial cells (HBMECs) was reduced by 27% and 26%, respectively. The cellular integrity measured in HBMECs, which was exposed to IC50 of B[α]P, slowly decreased. However, the pre-treatment of catechins retained cellular integrity that was 1.14 times higher than with the absence of catechins. Co-consumption of catechins reduced not only the bio-accessibility of B[α]P in digestive fluid, but it also decreased absorption of B[α]P in human intestinal epithelial cells (Caco-2) with a HepG2 co-culture system. It was found that approximately a two times lower amount of B[α]P was transported via the blood-brain barrier (BBB) compared to only the B[α]P intake. These results are taken in conjunction with each other support that catechins could be able to prevent brain toxicity induced by B[α]P in the human body by limiting the bio-availability of B[α]P.


Assuntos
Benzo(a)pireno/metabolismo , Benzo(a)pireno/toxicidade , Encéfalo/metabolismo , Catequina/farmacologia , Trato Gastrointestinal/metabolismo , Disponibilidade Biológica , Transporte Biológico/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Células CACO-2 , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Hep G2 , Humanos , Substâncias Protetoras/farmacologia
19.
J Agric Food Chem ; 67(26): 7348-7364, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31180673

RESUMO

A chemical study on the peels of the cultivated edible mushroom Wolfiporia cocos led to the isolation and identification of 47 lanostane triterpenoids including 16 new compounds (1-16). The structures of the new compounds were determined by analysis of the NMR, MS, and electronic circular dichroism (ECD) data. Compounds 1 and 2 represent new members of the family of 4,5-secolanostane triterpenes. Compound 3 is a new aromatic lanostane triterpene with an unusual methyl rearrangement from C-10 to C-6. The absolute configurations of 1 and 8 were assigned by ECD spectra calculation. All compounds were evaluated for cytotoxicity (K562, SW480, and HepG2) and glucose-uptake-stimulating effects. Compounds 23, 25, 29, and 31 showed weak inhibition on the K562 cells with IC50 in the range of 25.7 to 68.2 µM, respectively. Compounds 21, 28, and 30 increased the glucose uptake in 3T3-L1 cells by 25%, 14%, and 50% at 5 µM, respectively. In addition, compounds 14, 23, 29, 35, and 43 showed insulin-sensitizing activity by increasing the insulin-stimulated glucose uptake at 2.5 µM in 3T3-L1 adipocytes. A preliminary structure-activity relationship analysis indicates that the 6/6/6/5 ring skeleton and the double bond between C-8 and C-9 are beneficial for the glucose-uptake-stimulating and insulin-sensitizing activities. Furthermore, the alkaline-insoluble fraction mainly containing compounds 22, 24, 28, and 31 were confirmed to have hypoglycemic and hypolipidemic activity on high-fat-diet-induced obese mice. This work confirms the potential of the peels' extracts of W. cocos as a functional food or dietary supplements.


Assuntos
Glucose/metabolismo , Extratos Vegetais/farmacologia , Triterpenos/farmacologia , Wolfiporia/química , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Camundongos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Triterpenos/química , Triterpenos/isolamento & purificação
20.
Life Sci ; 231: 116557, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31194994

RESUMO

AIMS: Vinegar-baked Radix Bupleuri (VBRB) potentiates the activity of anticancer drugs in the liver by increasing their hepatic distribution. However, this phenomenon may be associated with drug transporters. We investigated the effect of saikosaponin b2 (SSb2; the main component of VBRB) on the activity and expression of different drug transporters in both normal cells and those that overexpress the transporter. MAIN METHODS: The activities of transporters were analyzed by concentration of their cellular substrates. Concentrations of colchicine (substrate of Pgp and MRP1) and cisplatin (substrate of OCT2 and MRP2) were determined by high-performance liquid chromatography (HPLC). The concentration of rhodamine B was determined by flow cytometry. The expression of transporter gene and protein were determined by qRT-PCR and Western blotting analysis. KEY FINDINGS: SSb2 increased colchicine efflux in HEK293 cells by primarily increasing Mrp1 activity, independent of gene and protein expression. SSb2 enhanced Mrp2 function and increased cisplatin efflux in BRL3A cells by upregulating Mrp2 gene expression, with a marginal effect on Pgp in normal cells. SSb2 increased OCT2 activity in OCT2-HEK293 cells by increasing the expression of OCT2 protein and mRNA; however, SSb2 inhibited MRP2 activity in MRP2-HEK293 cells by decreasing MRP2 protein expression, and decreased Pgp and MRP1 activity in Pgp- and MRP1-HEK293 cells. SIGNIFICANCE: SSb2 might potentially be the key active component of VBRB that enhances the hepatotargeting of anticancer drugs through the inhibition of multidrug resistance-associated drug transporters (Pgp, MRP1, and MRP2) in an environment-dependent manner.


Assuntos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Saponinas/metabolismo , Saponinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Cisplatino/análise , Cisplatino/metabolismo , Cisplatino/farmacologia , Colchicina/análise , Colchicina/metabolismo , Colchicina/farmacologia , Resistência a Múltiplos Medicamentos/fisiologia , Células HEK293 , Humanos , Medicina Tradicional Chinesa , Proteínas de Membrana Transportadoras/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacologia , RNA Mensageiro/metabolismo , Rodaminas/análise , Rodaminas/metabolismo , Regulação para Cima/efeitos dos fármacos
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