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1.
Adv Exp Med Biol ; 1141: 407-466, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571171

RESUMO

Blood-brain interfaces comprise the cerebral microvessel endothelium forming the blood-brain barrier (BBB) and the epithelium of the choroid plexuses forming the blood-cerebrospinal fluid barrier (BCSFB). Their main functions are to impede free diffusion between brain fluids and blood; to provide transport processes for essential nutrients, ions, and metabolic waste products; and to regulate the homeostasis of central nervous system (CNS), all of which are attributed to absent fenestrations, high expression of tight junction proteins at cell-cell contacts, and expression of multiple transporters, receptors, and enzymes. Existence of BBB is an important reason that systemic drug administration is not suitable for the treatment of CNS diseases. Some diseases, such epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and diabetes, alter BBB function via affecting tight junction proteins or altering expression and function of these transporters. This chapter will illustrate function of BBB, expression of transporters, as well as their alterations under disease status.


Assuntos
Barreira Hematoencefálica , Proteínas de Membrana Transportadoras , Preparações Farmacêuticas , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo
2.
Adv Exp Med Biol ; 1141: 467-504, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571172

RESUMO

Blood-retinal barrier (BRB) includes inner BRB (iBRB) and outer BRB (oBRB), which are formed by retinal capillary endothelial (RCEC) cells and by retinal pigment epithelial (RPE) cells in collaboration with Bruch's membrane and the choriocapillaris, respectively. Functions of the BRB are to regulate fluids and molecular movement between the ocular vascular beds and retinal tissues and to prevent leakage of macromolecules and other potentially harmful agents into the retina, keeping the microenvironment of the retina and retinal neurons. These functions are mainly attributed to absent fenestrations of RCECs, tight junctions, expression of a great diversity of transporters, and coverage of pericytes and glial cells. BRB existence also becomes a reason that systemic administration for some drugs is not suitable for the treatment of retinal diseases. Some diseases (such as diabetes and ischemia-reperfusion) impair BRB function via altering tight junctions, RCEC death, and transporter expression. This chapter will illustrate function of BRB, expressions and functions of these transporters, and their clinical significances.


Assuntos
Barreira Hematorretiniana , Proteínas de Membrana Transportadoras , Expressão Gênica , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Retina/metabolismo , Doenças Retinianas/fisiopatologia , Junções Íntimas
3.
Adv Exp Med Biol ; 1141: 505-548, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571173

RESUMO

The placenta is the only organ linking two different individuals, mother and fetus, termed as blood-placental barrier. The functions of the blood-placental barrier are to regulate material transfer between the maternal and fetal circulation. The main functional units are the chorionic villi within which fetal blood is separated by only three or four cell layers (placental membrane) from maternal blood in the surrounding intervillous space. A series of drug transporters such as P-glycoprotein (P-GP), breast cancer resistance protein (BCRP), multidrug resistance-associated proteins (MRP1, MRP2, MRP3, MRP4, and MRP5), organic anion-transporting polypeptides (OATP4A1, OATP1A2, OATP1B3, and OATP3A1), organic anion transporter 4 (OAT4), organic cation transporter 3 (OCT3), organic cation/carnitine transporters (OCTN1 and OCTN2), multidrug and toxin extrusion 1 (MATE1), and equilibrative nucleoside transporters (ENT1 and ENT2) have been demonstrated on the apical membrane of syncytiotrophoblast, some of which also expressed on the basolateral membrane of syncytiotrophoblast or fetal capillary endothelium. These transporters are involved in transport of most drugs in the placenta, in turn, affecting drug distribution in fetus. Moreover, expressions of these transporters in the placenta often vary along with the gestational ages and are also affected by pathophysiological factor. This chapter will mainly illustrate function and expression of these transporters in placentas, their contribution to drug distribution in fetus, and their clinical significance.


Assuntos
Regulação da Expressão Gênica , Proteínas de Membrana Transportadoras , Placenta , Feminino , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Placenta/metabolismo , Gravidez , Distribuição Tecidual , Trofoblastos/metabolismo
4.
J Agric Food Chem ; 67(38): 10563-10576, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31487171

RESUMO

Sulfur (S) metabolism plays a vital role in Cd detoxification, but the collaboration between melatonin biosynthesis and S metabolism under Cd stress remains unaddressed. Using exogenous melatonin, melatonin-deficient tomato plants with a silenced caffeic acid O-methyltransferase (COMT) gene, and COMT-overexpressing plants with cosuppression of sulfate transporter (SUT)1 and SUT2 genes, we found that melatonin deficiency decreased S accumulation and aggravated Cd phytotoxicity, whereas exogenous melatonin or overexpression of COMT increased S uptake and assimilation, resulting in an improved plant growth and Cd tolerance. Melatonin deficiency promoted Cd translocation from root to shoot, but COMT overexpression caused the opposite effect. COMT overexpression failed to compensate the functional hierarchy of S when its uptake was inhibited by cosilencing of transporter SUT1 and SUT2. Our study provides genetic evidence that melatonin-mediated tolerance to Cd is closely associated with the efficient regulation of S metabolism, redox homeostasis, and Cd translocation in tomato plants.


Assuntos
Cádmio/metabolismo , Lycopersicon esculentum/metabolismo , Melatonina/metabolismo , Enxofre/metabolismo , Transporte Biológico , Regulação da Expressão Gênica de Plantas , Lycopersicon esculentum/genética , Lycopersicon esculentum/crescimento & desenvolvimento , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Oxirredução , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteína O-Metiltransferase/genética , Proteína O-Metiltransferase/metabolismo
5.
Adv Exp Med Biol ; 1155: 497-505, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468426

RESUMO

Taurine (2-aminoethanesulfonic acid) is a sulfur-containing organic acid possessing several important effects, including antioxidant and anti-inflammatory ones. Exposure to ionizing radiation generates free radicals and reactive oxygen species (ROS) in irradiated cells, and free radical generation leads to oxidative stress. It is known that radiation nephropathy includes an inflammation-based process in which ROS and cytokines are responsible. Different doses of explored radiation can cause apoptosis, inflammation and a profound oxidative stress in kidneys. Oxidative stress is involved in renal injury after exposure to both ionizing radiation and inflammation. In this review, we describe the protective effect of taurine against several kidney diseases and the potential effects of taurine in the mitigation of radiation nephropathy. We also report that X-irradiation decreased the expression of taurine and TauT in the kidney. Taurine administration suppressed the decrease in the expression of taurine and TauT in the kidney after radiation exposure. Taurine might contribute to the mitigation of kidney injury induced by radiation.


Assuntos
Nefropatias/tratamento farmacológico , Lesões por Radiação/tratamento farmacológico , Taurina/farmacologia , Humanos , Rim/efeitos dos fármacos , Rim/efeitos da radiação , Nefropatias/fisiopatologia , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Estresse Oxidativo , Radiação Ionizante , Espécies Reativas de Oxigênio
6.
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
7.
BMC Bioinformatics ; 20(Suppl 13): 382, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31337335

RESUMO

BACKGROUND: Pathogenic protist membrane transporter proteins play important roles not only in exchanging molecules into and out of cells but also in acquiring nutrients and biosynthetic compounds from their hosts. Currently, there is no centralized protist membrane transporter database published, which makes system-wide comparisons and studies of host-pathogen membranomes difficult to achieve. RESULTS: We analyzed over one million protein sequences from 139 protists with full or partial genome sequences. Putative transmembrane proteins were annotated by primary sequence alignments, conserved secondary structural elements, and functional domains. We have constructed the PPTdb (Pathogenic Protist Transmembranome database), a comprehensive membrane transporter protein portal for pathogenic protists and their human hosts. The PPTdb is a web-based database with a user-friendly searching and data querying interface, including hierarchical transporter classification (TC) numbers, protein sequences, functional annotations, conserved functional domains, batch sequence retrieving and downloads. The PPTdb also serves as an analytical platform to provide useful comparison/mining tools, including transmembrane ability evaluation, annotation of unknown proteins, informative visualization charts, and iterative functional mining of host-pathogen transporter proteins. CONCLUSIONS: The PPTdb collected putative protist transporter proteins and offers a user-friendly data retrieving interface. Moreover, a pairwise functional comparison ability can provide useful information for identifying functional uniqueness of each protist. Finally, the host and non-host protein similarity search can fulfill the needs of comprehensive studies of protists and their hosts. The PPTdb is freely accessible at http://pptdb.cgu.edu.tw .


Assuntos
Bases de Dados Factuais , Proteínas de Membrana Transportadoras/análise , Interface Usuário-Computador , Fungos/metabolismo , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Plantas/metabolismo
8.
World J Microbiol Biotechnol ; 35(7): 112, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286266

RESUMO

Microorganisms have evolved permeases to incorporate various essential nutrients and exclude harmful products, which assists in adaptation to different environmental conditions for survival. As permeases are directly involved in the utilization of and regulatory response to nutrient sources, metabolic engineering of microbial permeases can predictably influence nutrient metabolism and regulation. In this mini-review, we have summarized the mechanisms underlying the general regulation of permeases, and the current advancements and future prospects of metabolic engineering strategies targeting the permeases in Saccharomyces cerevisiae. The different types of permeases and their regulatory mechanisms have been discussed. Furthermore, methods for metabolic engineering of permeases have been highlighted. Understanding the mechanisms via which permeases are meticulously regulated and engineered will not only facilitate research on regulation of global nutrition and yeast metabolic engineering, but can also provide important insights for future studies on the synthesis of valuable products and elimination of harmful substances in S. cerevisiae.


Assuntos
Proteínas de Membrana Transportadoras/metabolismo , Engenharia Metabólica/métodos , Saccharomyces cerevisiae/metabolismo , Transporte Biológico , Carbono/metabolismo , Glucose/metabolismo , Proteínas de Membrana Transportadoras/genética , Nitrogênio/metabolismo , Saccharomyces cerevisiae/genética
9.
Plant Sci ; 286: 57-67, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31300142

RESUMO

Phosphorus in plant cells occurs in inorganic form as both ortho- and pyrophosphate or bound to organic compounds, like e.g., nucleotides, phosphorylated metabolites, phospholipids, phosphorylated proteins, or phytate as P storage in the vacuoles of seeds. Individual compartments of the cell are surrounded by membranes that are selective barriers to avoid uncontrolled solute exchange. A controlled exchange of phosphate or phosphorylated metabolites is accomplished by specific phosphate transporters (PHTs) and the plastidial phosphate translocator family (PTs) of the inner envelope membrane. Plastids, in particular chloroplasts, are the site of various anabolic sequences of enzyme-catalyzed reactions. Apart from their role in metabolism PHTs and PTs are presumed to be also involved in communication between organelles and plant organs. Here we will focus on the integration of phosphate transport and homeostasis in signaling processes. Recent developments in this field will be critically assessed and potential future developments discussed. In particular, the occurrence of various plastid types in one organ (i.e. the leaf) with different functions with respect to metabolism or sensing, as has been documented recently following a tissue-specific proteomics approach (Beltran et al., 2018), will shed new light on functional aspects of phosphate homeostasis.


Assuntos
Homeostase , Proteínas de Membrana Transportadoras/metabolismo , Fosfatos/metabolismo , Células Vegetais/fisiologia , Proteínas de Plantas/metabolismo , Citoplasma/fisiologia , Família Multigênica , Plastídeos/metabolismo , Transdução de Sinais
10.
Life Sci ; 232: 116638, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31288013

RESUMO

AIMS: High-fat diet (HFD)-induced obesity resulting in cholesterol accumulation is one of the common pathogenic factors for lipids metabolic disorders. However, the potential mechanisms about cholesterol accumulation during obesity are still not clearly identified. Bile acids (BAs) as the natural ligands of farnesoid x receptor (Fxr) are demonstrated that can regulate the relevant enzymes and transporters at transcriptional level to determine the cholesterol homeostasis. Here, we explored the underlying mechanisms of hepatic cholesterol accumulation in HFD-induced obesity rats via the BAs-Fxr-enzymes/transporters signaling pathways. MATERIALS AND METHODS: BAs and cholesterol levels as well as mRNA expressions of enzymes, transporters and nuclear receptors involving in cholesterol homeostasis in liver and ileum tissue were evaluated in 4-week HFD-induced obesity rats. KEY FINDINGS: HFD promoted BAs intestine passive absorption to increase the concentrations of BAs especially the chenodeoxycholic acids (CDCAs) in ileum of HFD-induced obesity rats. The increased CDCAs concentrations activated Fxr-Fgf15 pathway in ileum to result in the mRNA expression of Cyp7a1 in liver down-regulation, which inhibited cholesterol metabolizing into primary BAs to contribute to the cholesterol level increase in liver tissue in HFD-induced obesity rats. SIGNIFICANCE: The hepatic cholesterol accumulation should be ascribed to the activation of ileum Fxr-Fgf15 pathway by the increased BAs passive absorption into ileal enterocytes under the condition of rats fed with HFD, which inhibited hepatic Cyp7a1 gene transcription to reduce metabolic elimination of cholesterol. Moreover, these findings are expected to provide a cue for the treatment of cholesterol metabolism disorders in obesity patient.


Assuntos
Colesterol 7-alfa-Hidroxilase/antagonistas & inibidores , Dieta Hiperlipídica , Fatores de Crescimento de Fibroblastos/metabolismo , Íleo/metabolismo , Fígado/metabolismo , Obesidade/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Células CACO-2 , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilase/metabolismo , Humanos , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Obesidade/enzimologia , Ratos , Ratos Wistar , Transdução de Sinais
11.
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
12.
Nat Commun ; 10(1): 2635, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201302

RESUMO

Multidrug efflux pumps actively expel a wide range of toxic substrates from the cell and play a major role in intrinsic and acquired drug resistance. In Gram-negative bacteria, these pumps form tripartite assemblies that span the cell envelope. However, the in situ structure and assembly mechanism of multidrug efflux pumps remain unknown. Here we report the in situ structure of the Escherichia coli AcrAB-TolC multidrug efflux pump obtained by electron cryo-tomography and subtomogram averaging. The fully assembled efflux pump is observed in a closed state under conditions of antibiotic challenge and in an open state in the presence of AcrB inhibitor. We also observe intermediate AcrAB complexes without TolC and discover that AcrA contacts the peptidoglycan layer of the periplasm. Our data point to a sequential assembly process in living bacteria, beginning with formation of the AcrAB subcomplex and suggest domains to target with efflux pump inhibitors.


Assuntos
Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Transporte/fisiologia , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/fisiologia , Escherichia coli/fisiologia , Lipoproteínas/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Antibacterianos/farmacologia , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/ultraestrutura , Microscopia Crioeletrônica/métodos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Tomografia com Microscopia Eletrônica/métodos , Escherichia coli/efeitos dos fármacos , Escherichia coli/ultraestrutura , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/efeitos dos fármacos , Proteínas de Escherichia coli/ultraestrutura , Microscopia Intravital/métodos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Peptidoglicano/metabolismo , Periplasma/metabolismo , Ligação Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína/efeitos dos fármacos
13.
Subcell Biochem ; 92: 275-299, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214990

RESUMO

Transport of solutes across biological membranes is essential for cellular life. This process is mediated by membrane transport proteins which move nutrients, waste products, certain drugs and ions into and out of cells. Secondary active transporters couple the transport of substrates against their concentration gradients with the transport of other solutes down their concentration gradients. The alternating access model of membrane transporters and the coupling mechanism of secondary active transporters are introduced in this book chapter. Structural studies have identified typical protein folds for transporters that we exemplify by the major facilitator superfamily (MFS) and LeuT folds. Finally, substrate binding and substrate translocation of the transporters LacY of the MFS and AdiC of the amino acid-polyamine-organocation (APC) superfamily are described.


Assuntos
Proteínas de Membrana Transportadoras/metabolismo , Sistemas de Transporte de Aminoácidos/química , Sistemas de Transporte de Aminoácidos/metabolismo , Transporte Biológico , Proteínas de Membrana Transportadoras/química
14.
Subcell Biochem ; 92: 337-366, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214992

RESUMO

The inner membrane of Gram-negative bacteria is a ~6 nm thick phospholipid bilayer. It forms a semi-permeable barrier between the cytoplasm and periplasm allowing only regulated export and import of ions, sugar polymers, DNA and proteins. Inner membrane proteins, embedded via hydrophobic transmembrane α-helices, play an essential role in this regulated trafficking: they mediate insertion into the membrane (insertases) or complete crossing of the membrane (translocases) or both. The Gram-negative inner membrane is equipped with a variety of different insertases and translocases. Many of them are specialized, taking care of the export of only a few protein substrates, while others have more general roles. Here, we focus on the three general export/insertion pathways, the secretory (Sec) pathway, YidC and the twin-arginine translocation (TAT) pathway, focusing closely on the Escherichia coli (E. coli) paradigm. We only briefly mention dedicated export pathways found in different Gram-negative bacteria. The Sec system deals with the majority of exported proteins and functions both as a translocase for secretory proteins and an insertase for membrane proteins. The insertase YidC assists the Sec system or operates independently on membrane protein clients. Sec and YidC, in common with most export pathways, require their protein clients to be in soluble non-folded states to fit through the translocation channels and grooves. The TAT pathway is an exception, as it translocates folded proteins, some loaded with prosthetic groups.


Assuntos
Membrana Celular/enzimologia , Membrana Celular/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/enzimologia , Proteínas de Membrana Transportadoras/metabolismo , Canais de Translocação SEC/metabolismo , Sistema de Translocação de Argininas Geminadas/metabolismo , Escherichia coli/citologia , Escherichia coli/metabolismo , Transporte Proteico
15.
Plant Cell Physiol ; 60(8): 1722-1733, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31076773

RESUMO

Phytohormones of the strigolactone (SL) family have been characterized as negative regulators of lateral bud outgrowth and triggers of symbioses between plants and mycorrhizal fungi. SLs and their precursors are synthesized in root tips as well as along shoot and root vasculature; they either move shoot-wards and regulate plant architecture or are exuded from roots into the soil to establish mycorrhizal symbiosis. Owing to the difficulty in quantification of SL in shoot tissues because of low abundance, it is not yet clear how SL distribution in plants is regulated at short- and long-distances from SL biosynthetic and target tissues. To address this question, we grafted wild-type scions and rootstocks from different petunia mutants for SL biosynthesis/transport and investigated SL activity by quantifying lateral bud outgrowth in the main shoot. Based on these results, we show that (i) the previously reported petunia SL transporter PLEIOTROPIC DRUG RESISTANCE 1 (PDR1) directly accounts for short-distance SL transport and (ii) long-distance transport of SLs seems to be partially and not directly dependent on PDR1. These data suggest that the root-to-shoot transport of SLs occurs either via the vasculature bundle through transporters other than PDR1 or involves SL precursors that are not substrates of PDR1.


Assuntos
Lactonas/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Petunia/metabolismo , Proteínas de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas , Petunia/genética , Petunia/fisiologia
16.
Cell Mol Biol (Noisy-le-grand) ; 65(4): 53-62, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31078153

RESUMO

Thyroid hormones regulate the development and maturation of the brain by maintaining levels of neurotransmitters and their related metabolites. The present work emphasizes the neural dysfunction in the brain caused by hypothyroidism and the potential role of Hordeum vulgare (water soluble barley, (B)) in ameliorating these effects. The study was conducted on euothyroid and hypothyroid adult female rats. The induction of hypothyroidism was conducted by oral-administration of neo-mercazole (5.0 mg.kg-1) daily for thirty days prior the study and terminated at the end of the study. The groups were assigned as; euthyroid (EU) and hypothyroid (H) groups and other two groups were treated with 100 mg.kg-1 water soluble barley; daily for one month and assigned as (EU+B) and (H+B) groups. Compared with EU and EU+B groups, a reduction in fT4, and ERK1/2 levels and elevation in TSH in brain tissue, Moreover, a  significant elevation in 8-OH deoxyguanosine and caspase-3 levels, confirmed with increase percentage DNA-damage in the brain and thyroid tissues in hypothyroid control rats. Furthermore, a significant decrease in all monoamines levels in different brain areas and downregulation of dopamine and 5-hydroxytreptamin receptors transcription, with a significant increase in excitatory amino acids and no significant change in the levels inhibitory amino acids were recorded in control hypothyroid group. Treatment of hypothyroid group with Hordeum vulgare improved the above-mentioned adverse impact by ameliorating the thyroid hormone levels with depleting the DNA-degradation and elaborating the levels of neurotransmitters with related receptors and amino acids in brain areas.  Water soluble Hordeum vulgare as a phytonutrient, is safe and efficient agent in ameliorating the neural dysfunction resulting from hypothyroidism status in adult female rats.


Assuntos
Monoaminas Biogênicas/metabolismo , Hordeum/química , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/fisiopatologia , Sistema Nervoso/fisiopatologia , Extratos Vegetais/uso terapêutico , Glândula Tireoide/fisiopatologia , Aminoácidos/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Caspase 3/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Sistema Nervoso/efeitos dos fármacos , Neurotransmissores/metabolismo , Extratos Vegetais/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Glândula Tireoide/efeitos dos fármacos , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo
17.
J Agric Food Chem ; 67(20): 5820-5826, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31060357

RESUMO

This work aims to uncover how glucose affected the production of phenyllactic acid (PLA) and p-hydroxyphenyllactic acid ( p-OH-PLA). The highest yields of PLA (68.53 mg/L) and p-OH-PLA (50.39 mg/L) were observed after Lactobacillus plantarum strain YM-4-3 fermentation in media containing 30 and 10 g/L glucose, respectively. Additionally, the antimicrobial activity of YM-4-3 against food-borne pathogens and the NADH/NAD+ ratio were positively correlated with the production of PLA and p-OH-PLA, respectively. In addition, a 2-oxoglutarate/malate translocator coding gene ( Omt1) was selected based on the qPCR results, and its knockout mutant, compared with the wild-type strain YM-4-3, showed that the PLA and p-OH-PLA production was decreased by 1.37-6.99 and 1.53-1.59 times, respectively. This result indicated that OMT1 was involved in the biosynthesis of PLA and p-OH-PLA. To conclude, this study suggests that glucose, NADH/NAD+ ratio and/or the Omt1 gene, PLA, and p-OH-PLA production, and antimicrobial activity contribute to a cause-and-effect relationship.


Assuntos
Antibacterianos/metabolismo , Antifúngicos/metabolismo , Proteínas de Bactérias/metabolismo , Glucose/metabolismo , Ácidos Cetoglutáricos/metabolismo , Lactatos/metabolismo , Lactobacillus plantarum/metabolismo , Malatos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Fenilalanina/análogos & derivados , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Proteínas de Bactérias/genética , Fermentação , Microbiologia de Alimentos , Fungos/efeitos dos fármacos , Lactatos/farmacologia , Lactobacillus plantarum/genética , Proteínas de Membrana Transportadoras/genética , Fenilalanina/biossíntese
18.
MBio ; 10(2)2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31040245

RESUMO

Staphylococcus aureus has the ability to cause infections in multiple organ systems, suggesting an ability to rapidly adapt to changing carbon and nitrogen sources. Although there is little information about the nutrients available at specific sites of infection, a mature skin abscess has been characterized as glucose depleted, indicating that peptides and free amino acids are an important source of nutrients for the bacteria. Our studies have found that mutations in enzymes necessary for growth on amino acids, including pyruvate carboxykinase (ΔpckA) and glutamate dehydrogenase (ΔgudB), reduced the ability of the bacteria to proliferate within a skin abscess, suggesting that peptides and free amino acids are important for S. aureus growth. Furthermore, we found that collagen, an abundant host protein that is present throughout a skin abscess, serves as a reservoir of peptides. To liberate peptides from the collagen, we identified that the host protease, MMP-9, as well as the staphylococcal proteases aureolysin and staphopain B function to cleave collagen into peptide fragments that can support S. aureus growth under nutrient-limited conditions. Moreover, the oligopeptide transporter Opp3 is the primary staphylococcal transporter responsible for peptide acquisition. Lastly, we observed that the presence of peptides (3-mer to 7-mer) induces the expression of aureolysin, suggesting that S. aureus has the ability to detect peptides in the environment.IMPORTANCE Staphylococcus aureus has the ability to cause infections in a variety of niches, suggesting a robust metabolic capacity facilitating proliferation under various nutrient conditions. The mature skin abscess is glucose depleted, indicating that peptides and free amino acids are important sources of nutrients for S. aureus Our studies have found that mutations in both pyruvate carboxykinase and glutamate dehydrogenase, enzymes that function in essential gluconeogenesis reactions when amino acids serve as the major carbon source, reduce bacterial burden in a murine skin abscess model. Moreover, peptides liberated from collagen by host protease MMP-9 as well as the staphylococcal protease aureolysin support S. aureus growth in an Opp3-dependent manner under nutrient-limited conditions. Additionally, the presence of peptides induces aureolysin expression. Overall, these studies define one pathway by which S. aureus senses a nutrient-limiting environment and induces factors that function to acquire and utilize carbon from host-derived sources.


Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Peptídeo Hidrolases/metabolismo , Proteínas/metabolismo , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/metabolismo , Animais , Análise Mutacional de DNA , Elementos de DNA Transponíveis , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
19.
Cancer Sci ; 110(8): 2337-2347, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31120184

RESUMO

Cancer metastasis is the most frequent cause of death for patients with cancer. The main current treatment for cancer metastasis is chemotherapy targeting cancer cells' ability to proliferate. However, some types of cancer cells show resistance to chemotherapy. Recently, cancer cell migration has become the subject of interest as a novel target of cancer therapy. Cell migration requires many factors, such as the cytoskeleton, cell-matrix adhesion and cell volume regulation. Here, we focus on cell volume regulation and the role of ion/water transport systems in cell migration. Transport proteins, such as ion channels, ion carriers, and aquaporins, are indispensable for cell volume regulation under steady-state conditions and during exposure to osmotic stress. Studies from the last ~25 years have revealed that cell volume regulation also plays an important role in the process of cell migration. Water flow in accordance with localized osmotic gradients generated by ion transport contributes to the driving force for cell migration. Moreover, it has been reported that metastatic cancer cells have higher expression of these transport proteins than nonmetastatic cancer cells. Thus, ion/water transport proteins involved in cell volume regulation and cell migration could be novel therapeutic targets for cancer metastasis. In this review, after presenting the importance of ion/water transport systems in cell volume regulation, we discuss the roles of transport proteins in a pathophysiological context, especially in the context of cancer cell migration.


Assuntos
Movimento Celular/fisiologia , Transporte de Íons/fisiologia , Neoplasias/metabolismo , Neoplasias/patologia , Osmose/fisiologia , Água/metabolismo , Animais , Tamanho Celular , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Transporte Proteico/fisiologia
20.
Nat Commun ; 10(1): 2340, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138794

RESUMO

The human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. While the endosomal trafficking of many other receptor tyrosine kinases is known to regulate their oncogenic signalling, the prevailing view on HER2 is that this receptor is predominantly retained on the cell surface. Here, we find that sortilin-related receptor 1 (SORLA; SORL1) co-precipitates with HER2 in cancer cells and regulates HER2 subcellular distribution by promoting recycling of the endosomal receptor back to the plasma membrane. SORLA protein levels in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA triggers HER2 targeting to late endosomal/lysosomal compartments and impairs HER2-driven signalling and in vivo tumour growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.


Assuntos
Neoplasias da Mama/genética , Carcinoma Intraductal não Infiltrante/genética , Carcinoma de Células de Transição/genética , Membrana Celular/metabolismo , Endossomos/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Receptor ErbB-2/metabolismo , Neoplasias da Bexiga Urinária/genética , Animais , Neoplasias da Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma de Células de Transição/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Proteínas Relacionadas a Receptor de LDL/metabolismo , Lisossomos/metabolismo , Células MCF-7 , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Nus , Transplante de Neoplasias , Transporte Proteico , Neoplasias da Bexiga Urinária/metabolismo
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