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1.
J Agric Food Chem ; 67(31): 8485-8492, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31304752

RESUMO

How short-chain fatty acids (FAs) affect cell membrane morphology and milk fat biosynthesis in mammary epithelial cells (MECs) is yet unclear. This study investigated the primary bovine MEC response to different FAs. We observed that the cell surface ultrastructures were influenced by chain length and degree of saturability of FAs. The CD36, FATP1, and FABP3 gene expression was affected independent of the type of FA. FASN, LPIN1, PPARα, and PPARγ transcripts were more sensitive to the short-chain FAs (acetic and ß-hydroxybutyric acids). Furthermore, short-chain FAs inclined to regulate FA degradation-, elongation-, and metabolism-associated pathways, while long-chain FAs (stearic and trans-10,cis-12 conjugated linolenic acids) modulated extracellular matrix-receptor interaction-, transcriptional misregulation-, microRNA-, and ribosome biogenesis-related pathways. However, triacylglycerol accumulation in the cytoplasm was not changed by all of the FAs. Overall, FAs with different chain lengths and degrees of saturability could differentially alter primary bovine MEC cell morphology and influence protein profiles involved in milk fat synthesis pathways.


Assuntos
Bovinos/metabolismo , Células Epiteliais/metabolismo , Gorduras/metabolismo , Ácidos Graxos não Esterificados/química , Ácidos Graxos não Esterificados/metabolismo , Glândulas Mamárias Animais/metabolismo , Leite/metabolismo , Animais , Antígenos CD36/genética , Antígenos CD36/metabolismo , Bovinos/genética , Gorduras/química , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Feminino , Glândulas Mamárias Animais/citologia , Leite/química , PPAR alfa/genética , PPAR alfa/metabolismo , Triglicerídeos/metabolismo
2.
Food Chem ; 300: 125232, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31352286

RESUMO

The mechanisms of main tomato carotenes (phytoene, phytofluene, lycopene and ß-carotene) intestinal absorption are still only partly understood. We thus compared carotene bioavailability in mice after gavage with carotene-rich oil-in-water emulsions. We also determined each carotene absorption profile along the duodenal-ileal axis of the intestine to identify their respective absorption sites and compared these profiles with the gene expression sites of their identified transporters, i.e. SR-BI and CD36. Our data show that phytofluene presented a significantly higher bioavailability compared to lycopene and ß-carotene (areas under the curve of 0.76 ±â€¯0.09 vs. 0.30 ±â€¯0.05, 0.09 ±â€¯0.05 and 0.08 ±â€¯0.01 µmol/L·h for phytofluene, phytoene, lycopene and ß-carotene, respectively). ß-Carotene was mostly converted in the proximal and median intestine. Phytoene and phytofluene accumulation tended to be more important in the distal intestine, which did not correlate with the proximal expression of both Scarb1 and CD36. Overall, these results highlight the high bioavailability of phytofluene.


Assuntos
Carotenoides/farmacocinética , Absorção Intestinal , Licopeno/farmacocinética , beta Caroteno/farmacocinética , Animais , Disponibilidade Biológica , Antígenos CD36/genética , Intestinos/efeitos dos fármacos , Lycopersicon esculentum/química , Masculino , Camundongos Endogâmicos C57BL , Período Pós-Prandial , Receptores Depuradores Classe B/genética
3.
J Agric Food Chem ; 67(25): 7060-7072, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31240928

RESUMO

As one of the main metabolites of anthocyanin, protocatechuic acid (PCA) possesses strong antioxidant activity. In the present study, we explored the capacity of PCA on the alleviation of endothelial oxidative stress and investigated the underlying mechanisms using RNA sequencing (RNA-Seq). In comparison with palmitic acid (PA)-treated cells, PCA (100 µM) significantly decreased the generations of 3-nitrotyrosine (3-NT) and 8-hydroxydeoxyguanosine (8-OHdG) (0.82 ± 0.01 vs 1.16 ± 0.05 and 0.80 ± 0.01 vs 1.48 ± 0.15, respectively, p < 0.01), two biomarkers of oxidative damage, and restored the levels of nitric oxide (NO) (0.97 ± 0.04 vs 0.54 ± 0.02, p < 0.01) and mitochondrial membrane potential (MMP) (0.96 ± 0.03 vs 0.86 ± 0.02, p < 0.01) in human umbilical vein endothelial cells (HUVECs). PCA also obviously reduced the level of reactive oxygen species (ROS) (0.86 ± 0.15 vs 2.67 ± 0.09, p < 0.01) in aorta from high-fat diet (HFD)-fed mice. RNA-Seq and Western blot analysis indicated that PCA markedly reduced the expression of cluster of differentiation 36 (CD36), a membrane fatty acid transporter, and reduced the generations of adenosine triphosphate (ATP) and acetyl coenzyme A (Ac-CoA). These effects of PCA were associated with decreased level of acetylated-lysine and restored the activity of manganese-dependent superoxide dismutase (MnSOD) through reducing the generation of Ac-CoA or activating Sirt1 and Sirt3 via a CD36/AMP-kinase (AMPK) dependent pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antígenos CD36/metabolismo , Hidroxibenzoatos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/genética , Acetilação/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Antígenos CD36/genética , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
4.
Dis Markers ; 2019: 5702026, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089396

RESUMO

The increased requirement of fatty acids forces cancer cells to enhance uptake of fatty acids from the extracellular milieu, in addition to de novo lipogenesis. Coexpression of cluster of differentiation 36 (CD36) with fatty acid transport protein 4 (FATP4) or long-chain acyl CoA synthetase 1 (ACSL1) synergistically activated fatty acid uptake in experimental models. In this study, we investigated the immunohistochemical expression of CD36, FATP4, and ACSL1 in 180 cases of clear cell renal cell carcinoma (RCC) in comparison with 80 specimens of the normal kidney. We also examined the clinical implication of these three fatty acid transporters in RCC, which was validated by an open-access The Cancer Genome Atlas data analysis. Both CD36 and FATP4 revealed higher membranous expressions in RCC tumor cells than in normal cells. In contrast, ACSL1 expression was remarkably reduced in RCC tumor cells compared to normal cells. CD36, FATP4, and ACSL1 showed high expressions in 74 (41.1%), 85 (47.2%), and 72 (40.0%) out of 180 RCC cases, respectively. Clinically, high FATP4 in tumor cells was associated with female gender (p = 0.05), high TNM stage (p = 0.039), tumor necrosis (p = 0.009), and tumor recurrence (p = 0.037), while high ACSL1 was only related to female gender (p = 0.023). CD36 expression revealed no correlation with the clinicopathologic parameters of RCC. Increased FATP4 expression displayed an association with short recurrence-free survival (p = 0.003). In conclusion, the high FATP4 expression was clinically associated with poor prognostic factors of RCC. Overexpression of membranous FATP4 and CD36 combined with reduced cytoplasmic expression of ACSL1 might be a tumor-specific feature of RCC, contributing to the tumorigenesis and tumor progression.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinogênese/genética , Carcinoma de Células Renais/metabolismo , Coenzima A Ligases/metabolismo , Proteínas de Transporte de Ácido Graxo/metabolismo , Neoplasias Renais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Antígenos CD36/genética , Antígenos CD36/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Membrana Celular/metabolismo , Coenzima A Ligases/genética , Proteínas de Transporte de Ácido Graxo/genética , Feminino , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade
5.
Infect Immun ; 87(7)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31010815

RESUMO

Using an affinity column retention assay, we showed that the purified Tet38 membrane transporter of Staphylococcus aureus bound specifically to host cell CD36 and to the complex CD36-Toll-like receptor 2 (TLR-2), but not to TLR-2 alone or TLR-2 and S. aureus lipoteichoic acid (LTA). We tested the effect of LTA on the internalization of S. aureus tet38 mutant QT7 versus RN6390 by A549 epithelial cells. Addition of anti-LTA antibody to the bacteria prior to adding to A549 cells reduced internalization of QT7 2-fold compared to that with nonspecific antibody treatment. QT7 internalized 4- to 6-fold less than RN6390 with or without anti-LTA antibody. These data suggested that Tet38 and LTA were independently involved in the invasion process. The wall teichoic acid (WTA) inhibitor tunicamycin had an 8-fold decrease in activity with overexpression of tet38 and a 2-fold increase in activity in QT7 (tet38). Reserpine (an inhibitor of efflux pumps) reduced the effect of tet38 overexpression on tunicamycin resistance 4-fold. In addition, tet38 affected growth in the presence of LTA inhibitor Congo red, with overexpression increasing growth and deletion of tet38 reducing growth. In conclusion, Tet38 contributes to S. aureus invasion of A549 via direct binding to CD36 of the complex CD36-TLR-2, and LTA independently bound to TLR-2. The reduction of tunicamycin resistance in the presence of reserpine and the survival ability of the tet38 overexpressor in the presence of Congo red suggest that Tet38 can also protect the synthesis of LTA and WTA in S. aureus against their inhibitors, possibly functioning as an efflux pump.


Assuntos
Proteínas de Bactérias/metabolismo , Antígenos CD36/metabolismo , Vermelho Congo/farmacologia , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus/metabolismo , Ácidos Teicoicos/biossíntese , Receptor 2 Toll-Like/metabolismo , Tunicamicina/farmacologia , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Antígenos CD36/genética , Humanos , Lipopolissacarídeos/metabolismo , Ligação Proteica , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/crescimento & desenvolvimento , Ácidos Teicoicos/metabolismo , Receptor 2 Toll-Like/genética
6.
MBio ; 10(2)2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992359

RESUMO

Mast cells (MCs) are critical mediators of inflammation; however, their microbicidal activity against invading pathogens remains largely unknown. Here, we describe a nonpreviously reported antibacterial mechanism used by MCs against Coxiella burnetii, the agent of Q fever. We show that C. burnetii interaction with MCs does not result in bacterial uptake but rather induces the formation of extracellular actin filaments named cytonemes. MC cytonemes express cathelicidin and neutrophil elastase and mediate the capture and destruction of entrapped bacteria. We provide evidence that MC cytoneme formation and microbicidal activity are dependent on the cooperation of the scavenger receptor CD36 and Toll-like receptor 4. Taken together, our results suggest that MCs use an extracellular sophisticated mechanism of defense to eliminate intracellular pathogens, such as C. burnetii, before their entry into host cells.IMPORTANCE Mast cells (MCs) are found in tissues that are in close contact with external environment, such as skin, lungs, or intestinal mucosa but also in the placenta during pregnancy. If their role in mediating allergic conditions is established, several studies now highlight their importance during infection with extracellular pathogens. This study showed a new and effective antimicrobial mechanism of MCs against Coxiella burnetii, an intracellular bacterium whose infection during pregnancy is associated with abortion, preterm labor, and stillbirth. The data reveal that in response to C. burnetii, MCs release extracellular actin filaments that contain antimicrobial agents and are capable to trap and kill bacteria. We show that this mechanism is dependent on the cooperation of two membrane receptors, CD36 and Toll-like receptor 4, and may occur in the placenta during pregnancy by using ex vivo placental MCs. Overall, this study reports an unexpected role for MCs during infection with intracellular bacteria and suggests that MC response to C. burnetii infection is a protective defense mechanism during pregnancy.


Assuntos
Citoesqueleto de Actina/imunologia , Coxiella burnetii/imunologia , Mastócitos/imunologia , Animais , Anti-Infecciosos , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/imunologia , Antígenos CD36/genética , Antígenos CD36/imunologia , Linhagem Celular , Humanos , Elastase de Leucócito/genética , Elastase de Leucócito/imunologia , Mastócitos/citologia , Camundongos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia
7.
Fish Shellfish Immunol ; 89: 614-622, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30991152

RESUMO

Scavenger receptor class B type 1 (SRB1) is a transmembrane protein belonging to the scavenger receptors (SRs) family and it plays an important role in viral entry. Not much is known on SRB1 in teleost fish. Grass carp reovirus (GCRV) cause huge economic losses in grass carp industry. In this study, rare minnow (Gobiocypris rarus) was used as a model fish to investigate the mechanism of GCRV infection, which is sensitive to GCRV. The structure of SRB1 gene in G. rarus (GrSRB1) was cloned and elucidated. GrSRB1 is composed of 13 exons and 12 introns, and its full-length cDNA is 2296 bp in length, with 1521 bp open reading frame (ORF) that encodes a 506 amino acid protein. The GrSRB1 protein is predicted to contain a typical CD36 domain and two transmembrane regions. In G. rarus, GrSRB1 is expressed strongly in the liver (L), intestines (I), brain (B) and muscle (M), while it is expressed poorly in the heart (H), middle kidney (MK), head kidney (HK) and gills (G). After infection with GCRV, GrSRB1 expression was up-regulated in main immune tissues during the early infection period. Moreover, co-immunoprecipitation assays revealed that GrSRB1 could interact with the outer capsid protein of GCRV (VP5 and VP7). These results suggest that GrSRB1 could be a receptor for GCRV. We have managed to characterize the GrSRB1 gene and provide evidence for its potential functions for GCRV entry into host cells.


Assuntos
Antígenos CD36/genética , Antígenos CD36/imunologia , Cyprinidae/genética , Cyprinidae/imunologia , Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Antígenos CD36/química , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Filogenia , Reoviridae/fisiologia , Infecções por Reoviridae/imunologia , Infecções por Reoviridae/veterinária , Alinhamento de Sequência/veterinária
8.
Int J Mol Med ; 43(5): 1927-1938, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896855

RESUMO

The farnesoid X receptor (FXR) is known to regulate the gene expression of SR­BI, which mediates plasma high­density lipoprotein (HDL)­cholesterol uptake. Our previous study demonstrated that the activation of FXR by obeticholic acid (OCA) lowered plasma HDL­cholesterol levels and increased the hepatic mRNA and protein expression levels of SR­BI in hypercholesterolemic hamsters, but not in normolipidemic hamsters, suggesting that dietary cholesterol may be involved in the OCA­induced transcription of SR­BI. In the present study, a functional 90­base­pair regulatory region was identified in the first intron of the SR­BI gene of hamster and mouse that contains a FXR response element (IR­1) and an adjacent liver X receptor (LXR) response element (LXRE). By in vitro DNA binding and luciferase reporter gene assays, it was demonstrated that FXR and LXR bind to their recognition sequences within this intronic region and transactivate the SR­BI reporter gene in a synergistic manner. It was also shown that mutations at either the IR­1 site or the LXRE site eliminated OCA­mediated gene transcription. Utilizing chow­fed hamsters as an in vivo model, it was demonstrated that treating normolipidemic hamsters with OCA or GW3965 alone did not effectively induce levels of SR­BI, whereas their combined treatment significantly increased the mRNA and protein levels of SR­BI in the liver. The study further investigated effects of FXR and LXR coactivation on the gene expression of SR­BI in human liver cells. The intronic FXRE and LXRE regulatory region was not conserved in the human SR­BI genomic sequence, however, higher mRNA expression levels of SR­BI were observed in human primary hepatocytes and HepG2 cells exposed to combined treatments of FXR and LXR agonists, compared with those in cells exposed to individual ligand treatment. Therefore, these results suggest that human SR­BI gene transcription may also be subject to concerted activation by FXR and LXR, mediated via currently unidentified regulatory sequences.


Assuntos
Antígenos CD36/genética , Ácido Quenodesoxicólico/análogos & derivados , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transcrição Genética/efeitos dos fármacos , Animais , Sequência de Bases , Benzoatos/farmacologia , Benzilaminas/farmacologia , Antígenos CD36/metabolismo , Ácido Quenodesoxicólico/farmacologia , Genes Reporter , Células Hep G2 , Humanos , Íntrons/genética , Fígado/efeitos dos fármacos , Masculino , Mesocricetus , Motivos de Nucleotídeos/genética , Elementos de Resposta/genética
10.
Nat Commun ; 10(1): 1135, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850595

RESUMO

Tumor-immune cell interactions shape the immune cell phenotype, with microRNAs (miRs) being crucial components of this crosstalk. How they are transferred and how they affect their target landscape, especially in tumor-associated macrophages (TAMs), is largely unknown. Here we report that breast cancer cells have a high constitutive expression of miR-375, which is released as a non-exosome entity during apoptosis. Deep sequencing of the miRome pointed to enhanced accumulation of miR-375 in TAMs, facilitated by the uptake of tumor-derived miR-375 via CD36. In macrophages, miR-375 directly targets TNS3 and PXN to enhance macrophage migration and infiltration into tumor spheroids and in tumors of a xenograft mouse model. In tumor cells, miR-375 regulates CCL2 expression to increase recruitment of macrophages. Our study provides evidence for miR transfer from tumor cells to TAMs and identifies miR-375 as a crucial regulator of phagocyte infiltration and the subsequent development of a tumor-promoting microenvironment.


Assuntos
Neoplasias da Mama/genética , Antígenos CD36/genética , Regulação Neoplásica da Expressão Gênica , Macrófagos/imunologia , MicroRNAs/genética , Animais , Apoptose , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Antígenos CD36/imunologia , Movimento Celular , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Técnicas de Cocultura , Feminino , Perfilação da Expressão Gênica , Humanos , Células MCF-7 , Macrófagos/patologia , Camundongos , Camundongos Nus , MicroRNAs/imunologia , Paxilina/genética , Paxilina/imunologia , Fenótipo , Transdução de Sinais , Esferoides Celulares/imunologia , Esferoides Celulares/patologia , Tensinas/genética , Tensinas/imunologia , Carga Tumoral , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cell Physiol Biochem ; 52(3): 532-552, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30897320

RESUMO

BACKGROUND/AIMS: Thrombospondins (TSPs) are large multi-modular proteins, identified as natural angiogenesis inhibitors that exert their activity by binding to CD36 and CD47 receptors. The anti-angiogenic effect of TSPs in luteal regression of water buffalo has not been addressed. The present study characterized the expression pattern and localization of TSPs and their receptors in ovarian corpus luteum during different stages of development in buffalo. This study also elucidated the effect of exogenous Thrombospondin1 (TSP1) or the knocking out of the endogenous protein on luteal cell viability and function. Further, the in vitro transcriptional interaction of TSP1 with hormones, LH, PGF2α and angiogenic growth factors, VEGF and FGF2 were also evaluated. METHODS: First, the CLs were classified into four groups based on macroscopic observation and progesterone concentration. mRNA expression of examined factors was measured by qPCR, localization by immunoblotting and immunohistochemistry. TSP1 was knocked out (KO) in cultured luteal cells isolated from late luteal stage CLs (day 1116) by CRISPR/Cas9 mediated gene editing technology in order to functionally validate the TSP1 gene. Isolated cells from late stage CLs were also stimulated with different doses of TSP1, LH, PGF2α, VEGF and FGF2 for various time intervals to determine transcriptional regulation of thrombospondins. RESULTS: mRNA expression of TSPs and their receptors were found to be significantly higher in late and regressed stage of CL as compared to other groups which was consistent with the findings of immunoblotting and immunolocalization experiments. It was observed that TSP1 induced apoptosis, down regulated angiogenic growth factors, VEGF and FGF2 and attenuated progesterone production in cultured luteal cells. However, knocking out of endogenous TSP1 with CRISPR/Cas9 system improved the viability of luteal cells, progesterone synthesis and upregulated the expression of VEGF and FGF2 in the KO luteal cells. PGF2α induced the upregulation of TSPs and Caspase 3 transcripts, whereas treatment with LH and angiogenic growth factors (VEGF and FGF2) down regulated the TSP system in luteal cells. CONCLUSION: Collectively, these data provide evidence that thrombospondins along with their receptors are expressed at varying levels in different stages of CL progression with maximum expression during the late and regressing stages. These results are consistent with the hypothesis that thrombospondins stimulated by PGF2α plays an essential modulatory role in bringing about structural and functional luteolysis in buffalo.


Assuntos
Sistemas CRISPR-Cas/genética , Corpo Lúteo/metabolismo , Edição de Genes , Trombospondina 1/genética , Animais , Apoptose , Búfalos/metabolismo , Antígenos CD36/genética , Antígenos CD36/metabolismo , Antígeno CD47/genética , Antígeno CD47/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Sobrevivência Celular , Corpo Lúteo/citologia , Corpo Lúteo/patologia , Dinoprosta/metabolismo , Regulação para Baixo , Feminino , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Trombospondina 1/metabolismo , Trombospondinas/genética , Trombospondinas/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
Clin Chim Acta ; 494: 143-150, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30905589

RESUMO

Although atypical hemolytic uremic syndrome (aHUS) is a genetic disorder, molecular defects are detected in only 60% of patients. We aim to dissect the genetic background by whole exome sequence and the clinical characteristics of pediatric patients with aHUS. Ten patients (6 male and 4 female) with mean age 5.2 ±â€¯5.0 years were enrolled. The age at onset ranged from 2 days to 11 years. Eighteen different mutations (17 missense, 2 nonsense, and 11 novel) on 7 complement and 3 coagulation genes were detected in all patients. The majority of mutation was heterozygous and S1191L on CFH were the recurrent mutation. Sixty percent of patients had multiple genetic mutations. Nine mutations were associated with genes known to be implicated in aHUS (CFH, CFI, CD46, CFHR5, and DGKE), while 4 and 5 mutations were detected on complement- (C8B, C9, and MASP1) and coagulation-associated (VWF and CD36) genes, respectively. CD36 may be a candidate gene act as disease modifier for aHUS through the contribution of thrombosis by impairing the interaction with TSP-1 and ADAMTS 13 shown in simulation model. Genetic defects on both complement and coagulation pathways play pathogenic roles on aHUS. CD36 may be a novel candidate gene act as disease modifier of aHUS.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Mutação , Sequenciamento Completo do Exoma , Adolescente , Antígenos CD36/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Taiwan
13.
Pharmacol Rep ; 71(2): 319-329, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826573

RESUMO

BACKGROUND: The increased influx of free fatty acids (FFAs) into the kidney is a risk factor for diabetes nephropathy (DN). In the present study we investigated the effects of astragaloside IV (AS-IV) on FFA-induced lipid accumulation, oxidative stress, and activation of TGF-ß1 signaling in human glomerular mesangial cells (HMCs). METHODS: A DN model was induced in Sprague Dawley rats by the administration of a high-fat diet and streptozocin, and HMCs were stimulated with palmitate. Lipid accumulation and FFA uptake were detected using Oil Red O and BODIPY™ FL C16 staining, respectively. The expression levels of TGF-ß1, p-Smad2/3, FN, Col4 A1, NOX4, p22phox, and CD36 were evaluated by western blotting or immunofluorescence/immunohistochemistry. The level of reactive oxygen species (ROS) was detected using 2',7'-dichlorofluorescein diacetate and dihydroethidium. RESULTS: Exposure to palmitate induced marked lipid accumulation in HMCs, whereas co-treatment with AS-IV significantly attenuated this phenomenon. Moreover, AS-IV suppressed palmitate-induced expression of TGF-ß1, p-Smad2/3, FN, Col4 A1, NOX4, and p22phox, in addition to ROS production. Notably, AS-IV reduced the palmitate-induced expression of CD36 in HMCs and DN rats. Treatment of HMCs with the CD36 inhibitor, sulfo-N-succinimidyl oleate (SSO), significantly attenuated FFA uptake, oxidative stress, and fibrosis. Nevertheless, the combined use of SSO and AS-IV did not enhance the efficacy. CONCLUSION: AS-IV inhibited palmitate-induced HMCs oxidative stress and fibrosis via the downregulation of CD36 expression, mediating FFA uptake and lipid accumulation.


Assuntos
Antígenos CD36/genética , Nefropatias Diabéticas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Nefropatias Diabéticas/patologia , Dieta Hiperlipídica/efeitos adversos , Regulação para Baixo/efeitos dos fármacos , Ácidos Graxos não Esterificados/metabolismo , Fibrose/patologia , Humanos , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/patologia , Palmitatos/toxicidade , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
14.
Nutrients ; 11(2)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717278

RESUMO

The perception of fat varies among individuals and has also been associated with CD36 rs1761667 polymorphism and genetic ability to perceive oral marker 6-n-propylthiouracil (PROP). Nevertheless, data in the literature are controversial. We present direct measures for the activation of the peripheral taste system in response to oleic acid by electrophysiological recordings from the tongue of 35 volunteers classified for PROP taster status and genotyped for CD36. The waveform of biopotentials was analyzed and values of amplitude and rate of potential variation were measured. Oleic acid stimulations evoked positive monophasic potentials, which represent the summated voltage change consequent to the response of the stimulated taste cells. Bio-electrical measurements were fully consistent with the perceived intensity during stimulation, which was verbally reported by the volunteers. ANOVA revealed that the amplitude of signals was directly associated, mostly in the last part of the response, with the CD36 genotypes and PROP taster status (which was directly associated with the density of papillae). The rate of potential variation was associated only with CD36, primarily in the first part of the response. In conclusion, our results provide direct evidence of the relationship between fat perception and rs1761667 polymorphism of the CD36 gene and PROP phenotype.


Assuntos
Antígenos CD36/genética , Ácido Oleico/farmacologia , Propiltiouracila/farmacologia , Língua/efeitos dos fármacos , Língua/fisiologia , Adulto , Antígenos CD36/metabolismo , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Paladar/efeitos dos fármacos , Paladar/fisiologia , Língua/metabolismo
15.
Food Funct ; 10(2): 1049-1061, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30706921

RESUMO

The present study was designed to explore the neuroprotective effects of docosahexaenoic acid (DHA) and/or vitamin E (VE) in vitro. The PC12 cells were pretreated with DHA and/or VE for 4 h, followed by 50 µmol L-1 Aß25-35 treatments for another 48 h. The cells were then collected and used for the measurements of oxidative stress parameters. Real time-PCR and western blot were applied to measure fatty acid transporters, Nrf2 and its downstream antioxidant targets' gene and protein expression. Our results indicated that the Aß25-35 treatment inhibited cellular growth, increased intracellular ROS generation and decreased the mitochondrial membrane potential. The Aß25-35 treatment decreased the total antioxidant capacity (T-AOC), whereas it increased the MDA levels in neuron cells. Pretreatment of cells with VE or DHA could antagonize the Aß25-35-mediated cell growth inhibition and mitochondrial membrane potential decline. Activation of the Nrf2 signaling pathway and regulation of CD36, SRB1 and FABP5 expression were observed in DHA- and DHA + VE-pretreated cells. Our results indicated a synergistic effect of DHA and VE in antagonizing the oxidative damage caused by Aß25-35 in the PC12 cells. The results of the present study will shed light on the application of nutritional intervention for DHA and VE in preventing neuronal damage-related diseases.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Ácidos Docosa-Hexaenoicos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Vitamina E/farmacologia , Animais , Antígenos CD36/genética , Antígenos CD36/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/administração & dosagem , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Células PC12 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Espécies Reativas de Oxigênio , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Vitamina E/administração & dosagem
16.
J Assist Reprod Genet ; 36(4): 777-786, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30659447

RESUMO

OBJECTIVE: To study the location and expression of receptors (SR-BI/CLA-1, SR-BII, and LDLr) and transporter (ABCA1) involved in uptake and efflux of cholesterol in human spermatozoa and assess whether obesity alters its location/expression and whether this could be related to infertility. DESIGN: Observational study. SETTING: None PATIENT(S): Ten controls and 20 obese patients. INTERVENTION(S): Anthropometric parameters. Serum and semen samples were collected. MAIN OUTCOME MEASURE(S): Spermatozoon concentration, immunolocalization, and protein expression in semen. RESULTS: Spermatozoon concentration and motility was decreased in morbidly obese patients. SR-BI/CLA-1, SR-BII, LDLr, and ABCA1 are located in the spermatozoon cell membrane and the localization does not change between obese patients and controls. Control spermatozoa showed high SR-BI expression, and less expression for the rest of the receptors analyzed, indicating that SR-BI/CLA-1 is relevant in human spermatozoon cholesterol uptake/efflux. On the contrary, spermatozoa of obese patients showed less SR-BI/CLA-1 expression than controls, and more intense positive staining for SR-BII, LDLr, and ABCA1. Finally, human sperm expresses the 130- and 82-kDa hormone-sensitive lipase (HSL) isoforms. The 130-kDa isoform is expressed in the control sperm, and the expression disappears in the obese patients. CONCLUSION(S): The presence of lipid receptors/transporters and HSL in human spermatozoa suggests their role in the process of maturation/capacitation. The changes in the expression of lipid receptors/transporters and the lack of the 130-kDa HSL isoform in obese patients prevent the hydrolysis of cholesterol esters internalized by these receptors, and favor their accumulation in the cytoplasm of the spermatozoa that could contribute to lipotoxicity and infertility.


Assuntos
Infertilidade Masculina/genética , Obesidade Mórbida/genética , Sêmen/metabolismo , Espermatozoides/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Adulto , Antígenos CD36/genética , Membrana Celular/genética , Colesterol/genética , Colesterol/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Infertilidade Masculina/complicações , Infertilidade Masculina/patologia , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Masculino , Obesidade Mórbida/complicações , Obesidade Mórbida/patologia , Isoformas de Proteínas/genética , Receptores de LDL/genética , Receptores Depuradores/genética , Capacitação Espermática/genética , Espermatozoides/patologia , Esterol Esterase/genética
17.
Nat Commun ; 10(1): 425, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683852

RESUMO

Atherosclerosis-related cardiovascular diseases are the leading cause of mortality worldwide. Macrophages uptake modified lipoproteins and transform into foam cells, triggering an inflammatory response and thereby promoting plaque formation. Here we show that casein kinase 2-interacting protein-1 (CKIP-1) is a suppressor of foam cell formation and atherosclerosis. Ckip-1 deficiency in mice leads to increased lipoprotein uptake and foam cell formation, indicating a protective role of CKIP-1 in this process. Ablation of Ckip-1 specifically upregulates the transcription of scavenger receptor LOX-1, but not that of CD36 and SR-A. Mechanistically, CKIP-1 interacts with the proteasome activator REGγ and targets the transcriptional factor Oct-1 for degradation, thereby suppressing the transcription of LOX-1 by Oct-1. Moreover, Ckip-1-deficient mice undergo accelerated atherosclerosis, and bone marrow transplantation reveals that Ckip-1 deficiency in hematopoietic cells is sufficient to increase atherosclerotic plaque formation. Therefore, CKIP-1 plays an essential anti-atherosclerotic role through regulation of foam cell formation and cholesterol metabolism.


Assuntos
Aterosclerose/genética , Autoantígenos/genética , Proteínas de Transporte/genética , Células Espumosas/metabolismo , Fator 1 de Transcrição de Octâmero/genética , Placa Aterosclerótica/genética , Complexo de Endopeptidases do Proteassoma/genética , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Autoantígenos/metabolismo , Transplante de Medula Óssea , Antígenos CD36/genética , Antígenos CD36/metabolismo , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Dieta Ocidental , Modelos Animais de Doenças , Células Espumosas/patologia , Regulação da Expressão Gênica , Células HEK293 , Humanos , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 1 de Transcrição de Octâmero/metabolismo , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe A/metabolismo , Receptores Depuradores Classe E/genética , Receptores Depuradores Classe E/metabolismo , Transdução de Sinais , Irradiação Corporal Total
18.
J Oleo Sci ; 67(10): 1355-1360, 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30210081

RESUMO

Abdominal aortic aneurysm (AAA) is a common disease among the elderly. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been indicated as useful therapeutic tools for the treatment of cardiovascular diseases. The aim of this study was to elucidate the role of PCSK9 in the pathogenesis of AAA. We used fluorescence immunohistochemistry to assess the expression of PCSK9 in aortic tissues resected from 24 patients with AAA. Histological examination showed that PCSK9 expression in the adventitia region of the aneurysms was decreased in AAA samples. In the same region, the expression of CD36 increased. We hypothesized that CD36 expression might upregulate the transport of fatty acids into cells such as the adipocytes, and subsequently cause degradation of the adventitia in the aortic wall, contributing to AAA development.


Assuntos
Adipócitos/patologia , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/patologia , Estudos de Associação Genética , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Adipócitos/metabolismo , Idoso , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Antígenos CD36/genética , Antígenos CD36/metabolismo , Ácidos Graxos/metabolismo , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pró-Proteína Convertase 9/fisiologia , Regulação para Cima/genética
19.
J Exp Clin Cancer Res ; 37(1): 231, 2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30231922

RESUMO

BACKGROUND: Cartilage oligomeric matrix protein (COMP) is known to promote fibrosis in skin, lung and liver. Emerging evidence shows that COMP plays critical roles in tumor development, including breast cancer, colon cancer and hepatocellular carcinoma (HCC). Nevertheless, the role of COMP in HCC proliferation and metastasis and its underlying mechanisms remain fully unclear. METHODS: Serum COMP was determined by ELISA. Cell Counting Kit-8 and plate colony formation were performed to evaluate cell proliferation. Wound healing and transwell assays were used to determine migration and invasion of HCC cells. Western blotting and immunofluorescence were carried out for detection of epithelial-to-mesenchymal transition (EMT) markers and MMPs in HCC cells. The in vivo role of COMP was evaluated using mouse models. We also measured effects of hepatic stellate cells (HSCs)-conditioned medium (CM) on HCC progression using transwell coculture system. RESULTS: Here, we found that serum COMP levels in HCC patients were significantly higher than those in healthy controls. Accordingly, high serum COMP levels in HCC patients significantly correlated with malignant clinical characteristics and poor clinical outcomes. Next, we investigated that recombinant human COMP protein (rCOMP) treatment resulted in increased abilities of proliferation, invasion and migration of HCC cells. Furthermore, rCOMP treatment enhanced proliferative and metastatic colonization of HCC cells in vivo. Mechanistically, CD36 receptor played an essential role in COMP-mediated HCC cell proliferation and metastasis. Functionally, COMP/CD36 signaling caused phosphorylation of ERK and AKT, resulting in the upregulation of tumor-progressive genes such as EMT markers, MMP-2/9, Slug and Twist in HCC cells. Interestingly, we revealed that COMP was secreted by HSCs. CM of LX2 cells with COMP knockdown showed weaker effects on the activation of MEK/ERK and PI3K/AKT signaling pathways in HCC cells compared to control CM. CONCLUSIONS: Our findings indicated that HSCs-derived COMP collaborated with CD36 and subsequently played an essential role in MEK/ERK and PI3K/AKT-mediated HCC progression. COMP might act as a promising target for the diagnosis and treatment of aggressive HCC.


Assuntos
Antígenos CD36/genética , Carcinoma Hepatocelular/genética , Proteína de Matriz Oligomérica de Cartilagem/genética , Neoplasias Hepáticas/genética , Fígado/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Proliferação de Células/genética , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Medicine (Baltimore) ; 97(38): e12470, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30235742

RESUMO

This research was aimed to explore correlation of gene polymorphisms of CD36 and ApoE with susceptibility of Alzheimer disease (AD).This study was a case-control study. Two hundred eleven AD hospitalized patients were selected as the AD group and 241 subjects were selected as the control group. PCR-RFLP was used to detect three loci (rs7755, rs3211956, and rs10499859) of CD36 gene and ApoE genotype. Chi-square test and univariate nonconditional logistic regression analysis were used to calculate the odds ratio (OR) and 95% confidence interval (95% CI). The haplotypes were constructed using SHEsis online software and the correlation between haplotypes and AD was analyzed. Meanwhile, differences of 3 alleles of ApoE and 6 genotypes (E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, E4/E4) were compared between AD and control groups.The frequencies of rs7755 genotype (χ = 10.780, P = .005) and allele (χ = 10.549, P = .001) were statistically different between 2 groups. The genotype frequency of rs3211956 was statistically different between AD and control groups (χ = 10.119, P = .006). For the rs7755 locus, GG genotype (OR: 2.013, 95% CI: 1.098-3.699) was an independent risk factor for AD compared with AA genotype. In the dominant model, the risk to develop AD in AG/GG genotype was 1.686 times higher than AA genotype. For the rs3211956 locus, compared with TT genotype, GT genotype (OR: 0.536, 95% CI: 0.340-0.846) was a protective factor for AD after adjusting various physiological and biochemical factors. In the dominant model, the risk of GT/GG genotype to develop AD was reduced by 41.6%. For ApoE gene, the distribution differences of E2/E3 (χ = 9.216, P = .002), E3/E4 (χ = 7.728, P = .005), and E4/E4 had statistical significance between the 2 groups. The frequencies of allele E2 (χ = 9.359, P = .002) and E4 (χ = 13.995, P < .001) were statistically significant between AD and control groups.The rs7755 and rs3211956 loci polymorphisms of CD36 gene and genotype E2/E3, E3/E4, E4/E4 of ApoE gene, and E2 and E4 alleles were statistically related with AD.


Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Antígenos CD36/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
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