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1.
Adv Exp Med Biol ; 1141: 293-340, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571168

RESUMO

Hepatic drug transporters are mainly distributed in parenchymal liver cells (hepatocytes), contributing to drug's liver disposition and elimination. According to their functions, hepatic transporters can be roughly divided into influx and efflux transporters, translocating specific molecules from blood into hepatic cytosol and mediating the excretion of drugs and metabolites from hepatic cytosol to blood or bile, respectively. The function of hepatic transport systems can be affected by interspecies differences and inter-individual variability (polymorphism). In addition, some drugs and disease can redistribute transporters from the cell surface to the intracellular compartments, leading to the changes in the expression and function of transporters. Hepatic drug transporters have been associated with the hepatic toxicity of drugs. Gene polymorphism of transporters and altered transporter expressions and functions due to diseases are found to be susceptible factors for drug-induced liver injury (DILI). In this chapter, the localization of hepatic drug transporters, their regulatory factors, physiological roles, and their roles in drug's liver disposition and DILI are reviewed.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Proteínas de Membrana Transportadoras , Preparações Farmacêuticas , Transporte Biológico , Variação Genética , Hepatócitos , Humanos , Proteínas de Membrana Transportadoras/genética , 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.
Brain Nerve ; 71(10): 1071-1079, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31588051

RESUMO

Next generation sequencing (NGS) technology has dramatically influenced the field of omics studies, such as genomics and transcriptomics. It is now possible to access a significant number of previously known and novel genomic variants through NGS. Although the effective manipulation and accurate interpretation of the inordinate amount of data may pose a considerable challenge, it enables us to identify specific genes responsible for causing or influencing the susceptibility to a plethora of diseases. Alzheimer's disease (AD) is the most common etiology of dementia in the elderly (approximately 60-70%). The current research trend of AD genetics focuses on the analysis of rare variants (allelic frequency <1%) instead of common variants (allelic frequency >1%) to identify AD-associated genes/variants. A number of genes (such as TREM2, ABCA7, SORL1) that carry rare pathogenic variants have reportedly conferred susceptibility to AD with stronger genetic risk effects (odds ratio >2.0). Here, we are going to introduce a small part of the latest many attractive findings about AD genetic researches.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Transportadores de Cassetes de Ligação de ATP/genética , Alelos , Frequência do Gene , Testes Genéticos , Genômica , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Receptores Imunológicos/genética
5.
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
6.
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
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.
Microbiol Res ; 226: 48-54, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31284944

RESUMO

The Burkholderia pseudomallei complex consists of six phylogenetically related Gram-negative bacterial species that include environmental saprophytes and mammalian pathogens. These microbes possess multiple type VI secretion systems (T6SS) that provide a fitness advantage in diverse niches by translocating effector molecules into prokaryotic and eukaryotic cells in a contact-dependent manner. Several recent studies have elucidated the regulation and function of T6SS-2, a novel contact-independent member of the T6SS family. Expression of the T6SS-2 gene cluster is repressed by OxyR, Zur and TctR and is activated by GvmR and reactive oxygen species (ROS). The last two genes of the T6SS-2 gene cluster encode a zincophore (TseZ) and a manganeseophore (TseM) that are exported into the extracellular milieu in a contact-independent fashion when microbes encounter oxidative stress. TseZ and TseM bind Zn2+ and Mn2+, respectively, and deliver them to bacteria where they provide protection against the lethal effects of ROS. The TonB-dependent transporters that interact with TseZ and TseM, and actively transport Zn2+ and Mn2+ across the outer membrane, have also been identified. Finally, T6SS-2 provides a contact-independent growth advantage in nutrient limited environments and is critical for virulence in Galleria mellonella larvae, but is dispensable for virulence in rodent models of infection.


Assuntos
Proteínas de Bactérias/genética , Burkholderia pseudomallei/genética , Burkholderia pseudomallei/metabolismo , Manganês/metabolismo , Sistemas de Secreção Tipo VI/genética , Sistemas de Secreção Tipo VI/metabolismo , Zinco/metabolismo , Animais , Proteínas de Bactérias/metabolismo , Burkholderia pseudomallei/classificação , Regulação Bacteriana da Expressão Gênica , Genes Reguladores/genética , Homeostase , Larva , Proteínas de Membrana Transportadoras/genética , Metiltransferases , Família Multigênica , Oxirredução , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Virulência/genética
9.
BMC Med Genet ; 20(1): 106, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196117

RESUMO

BACKGROUND: Oculocutaneous albinism (OCA) is a human autosomal-recessive hypopigmentation disorder with hypopigmentation in the skin, hair, and eyes. OCA1 and OCA2 are caused by mutations of the TYR and OCA2 genes, respectively, which are responsible for most oculocutaneous albinism. However, the incidence of oculocutaneous albinism patients in Guangxi remains unclear. METHODS: To evaluate the molecular basis of oculocutaneous albinism in thirty-six patients in Guangxi, China. Peripheral venous blood samples were collected from these unrelated patients. The TYR and OCA2 genes of all individuals were analyzed by direct DNA sequencing and the sequences compared with are reference database and bioinformatics analysis. RESULTS: Among the 36 OCA patients, 8(22.2%) were found mutations on TYR gene, 28 (77.8%) on OCA2. And we identified Twenty-seven different TYR and OCA2 mutations in these patients, including one novel TYR framshift mutation c.561_562insTTATTATGTGTCAAATTATCCCCCA, three novel OCA2 mutations: one nonsense mutation c.2195C > G(p.S732X), one deletation mutation(c.1139-1141delTGG), one missense mutations c.2495A > C(p.H832P). The population screening and the bioinformatic analysis to determined the effects of the mutations, which revealed these four novel mutations were pathogenic. CONCLUSIONS: This study expands the mutation spectrum of oculocutaneous albinism. Four novel mutational alleles c.1139-1141delTGG, c.1832 T > C and c.2195C > G and of the OCA2 gene and c.561_562insTTATTATGTGTCAAATTATCCCCCA of TYR were associated with OCA. The genotype-phenotype correlations suggest that molecular diagnosis is more accurate and important in OCA.


Assuntos
Albinismo Oculocutâneo/genética , Análise Mutacional de DNA/métodos , Predisposição Genética para Doença/genética , Mutação , Adolescente , Adulto , Albinismo Oculocutâneo/diagnóstico , Albinismo Oculocutâneo/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Criança , Pré-Escolar , China , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/etnologia , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana Transportadoras/genética , Monofenol Mono-Oxigenase/genética
10.
Zhonghua Yi Xue Za Zhi ; 99(22): 1712-1716, 2019 Jun 11.
Artigo em Chinês | MEDLINE | ID: mdl-31216817

RESUMO

Objective: To evaluate the correlation between single nucleotide polymorphisms (SNPs) of rs4778137 located in OCA2 gene and clinical response of breast cancer patients receiving neoadjuvant chemotherapy. Methods: A total of 140 breast cancer patients receiving neoadjuvant chemotherapy were enrolled to detect DNA in blood sample by DNA extraction kit and the rs4778137 polymorphism by sequenom. The relationship between SNPs of rs4778137 and pathologic complete response (pCR) were analyzed. Results: The frequency of CC, GC and GG genetype of rs4778137 was 48.6%, 31.4% and 20.0%,respectively. Thirty cases (21.4%) achieved pCR with CC allele in 9 cases(13.2%),GC allele in 10 cases (22.7%) and GG allele in 11 cases (39.3%),respectively,with a statistically significant difference(P<0.05). When conducting stratified analysis in accordance with the estrogen receptor (ER) status,only in ER negative group pCR was significantly associated with SNPs of rs4778137 (P<0.05). SNPs of Rs4778137, targeted therapy,subtypes,tumor stage were independent predictors of pCR in multivariate logistic regression analysis (P<0.05),and SNPs of rs4778137 was an independent predictors of pCR in ER negative group (P<0.05), but not in ER positive group group (P>0.05). Conclusion: SNPs of rs4778137 was associated with pCR only in ER negative patients receiving neoadjuvant therapy, and breast cancer patients with the GG allele were more likely to achieve pCR.


Assuntos
Neoplasias da Mama , Proteínas de Membrana Transportadoras/genética , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Humanos , Terapia Neoadjuvante , Polimorfismo de Nucleotídeo Único , Receptor ErbB-2 , Resultado do Tratamento
11.
Vet Microbiol ; 233: 154-158, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31176402

RESUMO

Increasing resistance to fluoroquinolones (FQs), such as norfloxacin and enrofloxacin, supports the need for the discovery of novel molecules and alternative approaches in antimicrobial therapy. Quorum sensing (QS) is a promising target for next-generation anti-infective agents designed to address the evolving drug resistance in bacterial pathogens. Given that the LuxS/autoinducer-2 (AI-2) quorum-sensing system regulates microbial group behaviors, we hypothesized that this system influences the FQ susceptibility in Streptococcus suis. It was found that a luxS mutant (ΔluxS) of S. suis possesses an increased susceptibility to FQs compared to the wild type strain. When grown in the presence of sub-MIC of antibiotics, the ΔluxS strain showed a significant decrease in growth rate and biofilm formation. These results suggest that the FQ resistance in S. suis could involve a signaling mechanism associated with the LuxS/AI-2 quorum-sensing system. HPLC (High Performance Liquid Chromatography) analyses showed a significant increase in the intracellular accumulation of enrofloxacin in the ΔluxS strain compared to the wild type strain. This increase was less pronounced in the presence of exogenous AI-2. Moreover, the expression of satA and satB genes was decreased in the ΔluxS strain. Exogenous AI-2 reversed the down-regulated gene expression observed in the ΔluxS strain. Our study brought strong evidence that the LuxS/AI-2 system in S. suis is involved in FQ susceptibility by regulating the efflux pump SatAB. LuxS is highly conserved among Gram-positive bacteria and may therefore represent a novel antimicrobial target for an alternative approach in antimicrobial therapy.


Assuntos
Proteínas de Bactérias/genética , Liases de Carbono-Enxofre/genética , Fluoroquinolonas/farmacologia , Homosserina/análogos & derivados , Proteínas de Membrana Transportadoras/genética , Streptococcus suis/efeitos dos fármacos , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Regulação Bacteriana da Expressão Gênica , Homosserina/genética , Lactonas , Streptococcus suis/genética
12.
Sci Data ; 6(1): 94, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209217

RESUMO

Transcript levels powerfully influence cell behavior and phenotype and are carefully regulated at several steps. Recently developed single cell approaches such as RNA single molecule fluorescence in-situ hybridization (smFISH) have produced advances in our understanding of how these steps work within the cell. In comparison to single-cell sequencing, smFISH provides more accurate quantification of RNA levels. Additionally, transcript subcellular localization is directly visualized, enabling the analysis of transcription (initiation and elongation), RNA export and degradation. As part of our efforts to investigate how this type of analysis can generate improved models of gene expression, we used smFISH to quantify the kinetic expression of STL1 and CTT1 mRNAs in single Saccharomyces cerevisiae cells upon 0.2 and 0.4 M NaCl osmotic stress. In this Data Descriptor, we outline our procedure along with our data in the form of raw images and processed mRNA counts. We discuss how these data can be used to develop single cell modelling approaches, to study fundamental processes in transcription regulation and develop single cell image processing approaches.


Assuntos
Hibridização in Situ Fluorescente , RNA Fúngico , RNA Mensageiro , Saccharomyces cerevisiae/genética , Análise de Célula Única , Proteínas de Membrana Transportadoras/análise , Proteínas de Membrana Transportadoras/genética , RNA Fúngico/análise , RNA Fúngico/genética , RNA Mensageiro/análise , RNA Mensageiro/genética , Proteínas de Saccharomyces cerevisiae/análise , Proteínas de Saccharomyces cerevisiae/genética , Análise de Célula Única/métodos , Análise de Célula Única/normas
13.
J Microbiol Immunol Infect ; 52(4): 638-647, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31239204

RESUMO

BACKGROUND: The emergence of multiple-antibiotic-resistant (MAR) Salmonella has been a serious threat worldwide. Salmonella can invade into host cells and evade the attacks of host humoral defenses and antibiotics. Thus, a new antibacterial agent capable of inhibiting intracellular Salmonella is highly needed. METHODS: The anti-intracellular activity and cytotoxicity of drugs on intracellular bacteria and macrophages were assayed using intracellular CFU assay and MTT cell viability assay, respectively. The uptake of gentamicin into macrophage and the effect of autophagy inhibitor on loxapine's anti-intracellular Salmonella activity were assessed by using image-based high-content system. The expression of bacterial genes was measured by real-time PCR. The efflux pump activity of bacteria was measured by Hoechst accumulation assays. RESULTS: With our efforts, an antipsychotic drug, loxapine, was identified to exhibit high potency in suppressing intracellular MAR S. Typhimurium, Staphylococcus aureus, Shigella flexneri or Yersinia enterocolitica. Subsequent investigations indicated that loxapine's anti-intracellular bacteria activity was not associated with increased penetration of gentamicin into bacteria and macrophages. Loxapine didn't inhibit bacterial growth in broth at concentration up to 500 µM and has no effect on Salmonella's type III secretion system genes' expression. Blockage of autophagy also didn't reverse loxapine's anti-intracellular activity. Lastly, loxapine suppressed bacterial efflux pump activity in all bacteria tested. CONCLUSION: Altogether, our data suggested that loxapine might suppress intracellular bacteria through inhibiting of bacterial efflux pumps. In light of its unique activity, loxapine represents a promising lead compound with translational potential for the development of a new antibacterial agent against intracellular bacteria.


Assuntos
Antibacterianos/farmacologia , Antipsicóticos/farmacologia , Loxapina/farmacologia , Macrófagos/microbiologia , Salmonella typhimurium/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Proteínas de Bactérias/genética , Sobrevivência Celular/efeitos dos fármacos , Contagem de Colônia Microbiana , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Gentamicinas/farmacologia , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Proteínas de Membrana Transportadoras/genética , Camundongos , Testes de Sensibilidade Microbiana , Fenotiazinas/farmacologia , Células RAW 264.7 , Salmonella typhimurium/genética , Salmonella typhimurium/crescimento & desenvolvimento , Sorogrupo , Shigella flexneri/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Sistemas de Secreção Tipo III/efeitos dos fármacos , Sistemas de Secreção Tipo III/genética , Yersinia enterocolitica/efeitos dos fármacos
14.
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
15.
J Med Microbiol ; 68(6): 957-960, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31050633

RESUMO

The qacA/B gene is one of the major determinants of resistance to antiseptics in methicillin-resistant Staphylococcus aureus (MRSA). Here, we compared the fast-acting bactericidal activity of skin antiseptics, including olanexidine gluconate (OLG), a new biguanide antiseptic agent introduced in Japan, against clinical qacA/B-positive MRSA strains by determination of minimum bactericidal concentration and time-kill assay. Our findings provide, for the first time, data indicating that the fast-acting bactericidal activity of OLG against qacA/B-positive MRSA is higher than that of chlorhexidine gluconate, even though both are biguanide antiseptics.


Assuntos
Anti-Infecciosos Locais/farmacologia , Proteínas de Bactérias/genética , Biguanidas/farmacologia , Glucuronatos/farmacologia , Proteínas de Membrana Transportadoras/genética , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções Estafilocócicas/microbiologia , Clorexidina/análogos & derivados , Clorexidina/farmacologia , Meticilina/farmacologia , Staphylococcus aureus Resistente à Meticilina/enzimologia , Staphylococcus aureus Resistente à Meticilina/genética , Infecções Estafilocócicas/tratamento farmacológico
16.
MBio ; 10(2)2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31040246

RESUMO

The global spread of Plasmodium falciparum chloroquine resistance transporter (PfCRT) variant haplotypes earlier caused the widespread loss of chloroquine (CQ) efficacy. In Asia, novel PfCRT mutations that emerged on the Dd2 allelic background have recently been implicated in high-level resistance to piperaquine, and N326S and I356T have been associated with genetic backgrounds in which resistance emerged to artemisinin derivatives. By analyzing large-scale genome sequencing data, we report that the predominant Asian CQ-resistant Dd2 haplotype is undetectable in Africa. Instead, the GB4 and previously unexplored Cam783 haplotypes predominate, along with wild-type, drug-sensitive PfCRT that has reemerged as the major haplotype. To interrogate how these alleles impact drug susceptibility, we generated pfcrt-modified isogenic parasite lines spanning the mutational interval between GB4 and Dd2, which includes Cam783 and involves amino acid substitutions at residues 326 and 356. Relative to Dd2, the GB4 and Cam783 alleles were observed to mediate lower degrees of resistance to CQ and the first-line drug amodiaquine, while resulting in higher growth rates. These findings suggest that differences in growth rates, a surrogate of parasite fitness, influence selection in the context of African infections that are frequently characterized by high transmission rates, mixed infections, increased immunity, and less recourse to treatment. We also observe that the Asian Dd2 allele affords partial protection against piperaquine yet does not directly impact artemisinin efficacy. Our results can help inform the regional recommendations of antimalarials, whose activity is influenced by and, in certain cases, enhanced against select PfCRT variant haplotypes.IMPORTANCE Our study defines the allelic distribution of pfcrt, an important mediator of multidrug resistance in Plasmodium falciparum, in Africa and Asia. We leveraged whole-genome sequence analysis and gene editing to demonstrate how current drug combinations can select different allelic variants of this gene and shape region-specific parasite population structures. We document the ability of PfCRT mutations to modulate parasite susceptibility to current antimalarials in dissimilar, pfcrt allele-specific ways. This study underscores the importance of actively monitoring pfcrt genotypes to identify emerging patterns of multidrug resistance and help guide region-specific treatment options.


Assuntos
Resistência a Múltiplos Medicamentos , Aptidão Genética , Genótipo , Malária Falciparum/parasitologia , Proteínas de Membrana Transportadoras/genética , Plasmodium falciparum/crescimento & desenvolvimento , Proteínas de Protozoários/genética , África/epidemiologia , Ásia/epidemiologia , Frequência do Gene , Genética Populacional , Malária Falciparum/epidemiologia , Proteínas Mutantes/genética , Plasmodium falciparum/classificação , Plasmodium falciparum/genética , Plasmodium falciparum/isolamento & purificação
17.
BMC Neurol ; 19(1): 97, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092209

RESUMO

BACKGROUND: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare clinical entity, characterized by headaches, seizures, rapidly progressive cognitive decline, behavioral changes and magnetic resonance imaging (MRI) findings underlying the autoimmune and inflammatory reaction at the level of CAA-affected vessel. CAA-ri is likely responsive to corticosteroid. MRI shows asymmetric and multifocal white matter hyperintensity (WMH) lesions and multiple cerebral microbleeds. Apolipoprotein E (ApoE) ε4 homozygosity is associated with CAA-ri strongly [Neurology 68(17):1411-1416, 2007, Ann Neurol 73(4):449-458, 2013, J Alzheimers Dis 44(4):1069-1074, 2015]. SORL1 processes a causal involvement in Alzheimer's disease (AD) as a proposed modulator of the amyloid precursor protein (APP). It is unclear whether SORL1 is involved with CAA-ri or not. CASE PRESENTATION: A 48-year-old woman suffered from a one-day history of a headache, nausea, and vomiting. Neurological examination revealed normal. We diagnosed this case as probable CAA-ri according to the clinic manifestations and MRI. Gene detection indicated a rare variant in SORL1 and ApoE ε4 homozygosity. When treated with corticosteroid, the patient's clinical symptoms and MRI manifestations were almost relieved. However, when keeping the corticosteroid withdrawal for three months, the patient relapsed with a headache and typical images on MRI emerged. Corticosteroid therapy was effective again. Unfortunately, susceptibility weighted imaging (SWI) showed increased microbleeds. With tapering corticosteroid slowly, no recurrence was found on this patient with four-month follow-up. CONCLUSION: A variant of SORL1 may be associated with CAA-ri, recurrence of disease could be detected with MRI by an increased microbleeds. Our case report suggests that corticosteroid therapy might be effective for CAA-ri.


Assuntos
Angiopatia Amiloide Cerebral/genética , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/patologia , Feminino , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade
18.
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
19.
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
20.
BMC Med Genet ; 20(1): 70, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053099

RESUMO

BACKGROUND: X-linked spondyloepiphyseal dysplasia tarda (SEDT-XL) is a skeletal disorder characterized by defective structures of vertebral bodies and/or of epiphyses of the long bones, resulting in moderately short stature and early joint degeneration. TRAPPC2 gene, which is important for collagen secretion, has been reported as causative for SEDT-XL. CASE PRESENTATION: Here, we report two variants of TRAPPC2 gene of SEDT-XL patients, a missense variant of start codon, c.1A > T, and a deletion variant, c.40delG. To understand molecular consequence of the variants, we establish an in vitro gene expression assay system and demonstrate that both mutated genes are transcribed, but are not properly translated, indicative of the pathogenic nature of those TRAPPC2 variants. CONCLUSIONS: In the current study, we provide additional experimental data showing that loss-of-function TRAPPC2 variants are probably causative for SEDT-XL phenotype. These findings further contribute to the understanding the clinical picture related to TRAPPC2 gene.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas de Membrana Transportadoras/genética , Osteocondrodisplasias/genética , Fatores de Transcrição/genética , Adolescente , Humanos , Masculino , Pessoa de Meia-Idade
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