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1.
Adv Mater ; : e2006532, 2020 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-33283355

RESUMO

Precise manipulation of optical properties through the structure-evolution of plasmonic nanoparticles is of great interest in biomedical fields including bioimaging and phototherapy. However, previous success has been limited to fixed assembled structures or visible-NIR-I absorption. Here, an activatable NIR-II plasmonic theranostics system based on silica-encapsulated self-assembled gold nanochains (AuNCs@SiO2 ) for accurate tumor diagnosis and effective treatment is reported. This transformable chain structure breaks through the traditional molecular imaging window, whose absorption can be redshifted from the visible to the NIR-II region owing to the fusion between adjacent gold nanoparticles in the restricted local space of AuNCs@SiO2 triggered by the high H2 O2 level in the tumor microenvironment (TME), leading to the generation of a new string-like structure with strong NIR-II absorption, which is further confirmed by finite-difference-time-domain (FDTD) simulation. With the TME-activated characteristics, AuNCs@SiO2 exhibits excellent properties for photoacoustic imaging and a high photothermal conversion efficiency of 82.2% at 1064 nm leading to severe cell death and remarkable tumor growth inhibition in vivo. These prominent intelligent TME-responsive features of AuNCs@SiO2 may open up a new avenue to explore optical regulated nano-platform for intelligent, accurate, and noninvasive theranostics in NIR-II window.

2.
Int Immunopharmacol ; 86: 106698, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32559567

RESUMO

Acute lung injury is the main causative factor in paraquat dichloride (PQ)-induced mortality. The innate immune system-triggered detrimental inflammatory cascade plays a vital role in PQ-induced acute lung injury. However, the role of natural killer (NK) cells, which are essential for innate response, in PQ-induced acute lung injury remains largely unknown. Here, we found that in an acute PQ poisoning model, depletion of NK cells attenuated PQ-induced lung injury by inhibiting macrophage polarization towards the M1 type. Specifically, the percentages of NK cells were reduced in the lung, spleen, and peripheral blood in a murine model of acute PQ poisoning. NK cells were aberrantly activated, evidenced by upregulation of the activating markers CD69, CD107a, and NKG2D and downregulation of the inhibitive marker KLRG1. Further, NK-specific depletion in mice greatly prolonged the survival time and ameliorated reactive oxygen species-induced damage following PQ treatment compared with the control group. Importantly, NK cell depletion alleviated macrophage and neutrophil infiltration in the lung and reversed PQ induced-macrophage polarization towards the pro-inflammatory M1 type. Our study demonstrates a crucial role of NK cells and NK cell-to-macrophage interaction in PQ-induced acute lung injury.

3.
Ultrason Sonochem ; 67: 105107, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32276174

RESUMO

With the rapid development of oil hydrogenation industry, the development of oil hydrogenation catalyst has also become a research hotspot. In this paper, ultrasound-assisted precipitation technique is used to prepare Ni/Al2O3 catalyst. The effect of ultrasonic output power on catalyst performance is investigated. The prepared catalyst is applied to the hydrogenation reaction of castor oil. It is found that the prepared catalyst shows the best hydrogenation performance when ultrasonic output power, frequency and ultrasonic treatment time are 80 W, 40 kHz and 600 min respectively. It also indicates that ultrasound-assisted precipitation technique can reduce the particle size and increase the specific surface area of Ni/Al2O3 catalyst so that its activity is improved. In addition, six important elements that should be considered in the development of industrial oil refining catalysts are discussed, and the effects of these factors on the catalyst performance are discussed. Finally, new way for improving catalyst performance is given, and the application of some new materials and methods in oil refining is introduced.

4.
J Cell Mol Med ; 24(11): 6233-6241, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32343488

RESUMO

The pathogenesis of cardiac hypertrophy is tightly associated with activation of intracellular hypertrophic signalling pathways, which leads to the synthesis of various proteins. Tripartite motif 10 (TRIM10) is an E3 ligase with important functions in protein quality control. However, its role in cardiac hypertrophy was unclear. In this study, neonatal rat cardiomyocytes (NRCMs) and TRIM10-knockout mice were subjected to phenylephrine (PE) stimulation or transverse aortic constriction (TAC) to induce cardiac hypertrophy in vitro and in vivo, respectively. Trim10 expression was significantly increased in hypertrophied murine hearts and PE-stimulated NRCMs. Knockdown of TRIM10 in NRCMs alleviated PE-induced changes in the size of cardiomyocytes and hypertrophy gene expression, whereas TRIM10 overexpression aggravated these changes. These results were further verified in TRIM10-knockout mice. Mechanistically, we found that TRIM10 knockout or knockdown decreased AKT phosphorylation. Furthermore, we found that TRIM10 knockout or knockdown increased ubiquitination of phosphatase and tensin homolog (PTEN), which negatively regulated AKT activation. The results of this study reveal the involvement of TRIM10 in pathological cardiac hypertrophy, which may occur by prompting of PTEN ubiquitination and subsequent activation of AKT signalling. Therefore, TRIM10 may be a promising target for treatment of cardiac hypertrophy.

5.
Molecules ; 25(4)2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32098126

RESUMO

Benzoxazole derivative K313 has previously been reported to possess anti-inflammatory effects in lipopolysaccharide-induced RAW264.7 macrophages. To date, there have been no related reports on the anticancer effects of K313. In this study, we found that K313 reduced the viability of human B-cell leukemia (Nalm-6) and lymphoma (Daudi) cells in a dose-dependent manner without affecting healthy peripheral blood mononuclear cells (PBMCs) and induced moderate cell cycle arrest at the G0/G1 phase. Meanwhile, K313 mediated cell apoptosis, which was accompanied by the activation of caspase-9, caspase-3, and poly ADP-ribose polymerase (PARP). Furthermore, cells treated with K313 showed a significant decrease in mitochondrial membrane potential (MMP), which may have been caused by the caspase-8-mediated cleavage of Bid, as detected by Western blot analysis. We also found that K313 led to the downregulation of p-p70S6K protein, which plays an important role in cell survival and cell cycle progression. In addition, treatment of these cells with K313 blocked autophagic flux, as reflected in the accumulation of LC3-II and p62 protein levels in a dose- and time-dependent manner. In conclusion, K313 decreases cell viability without affecting normal healthy PBMCs, induces cell cycle arrest and apoptosis, reduces p-p70S6K protein levels, and mediates strong autophagy inhibition. Therefore, K313 and its derivatives could be developed as potential anticancer drugs or autophagy blockers in the future.


Assuntos
Benzoxazóis/farmacologia , Linfoma/tratamento farmacológico , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Serina-Treonina Quinases TOR/genética , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzoxazóis/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Leucócitos Mononucleares , Linfoma/genética , Linfoma/patologia , Camundongos , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
6.
J Alzheimers Dis ; 74(1): 245-259, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31985470

RESUMO

Lactoferrin (LF) is present in senile plaques and neurofibrillary tangles in the brains of Alzheimer's disease (AD) patients and amyloid-ß protein precursor transgenic (AßPP-Tg) mice. LF has anti-inflammatory and antioxidant functions, which exert neuroprotective effects against AD. However, its effects on memory impairment and AD pathogenesis have not been fully examined. In this study, we examined the effects of LF on memory impairment and AD pathogenesis in AßPP-Tg mice (J20 mice). Nine-month-old J20 mice were fed with control, 2% lactoferrin-containing (LF), and 0.5% pepsin-hydrolyzed lactoferrin-containing (LF-hyd) diets for 3 months. We found that both the LF and LF-hyd diets attenuated memory impairment in J20 mice and decreased brain Aß40 and Aß42 levels through the inhibition of amyloidogenic processing of AßPP, as it decreased ß-site amyloid protein precursor cleaving enzyme 1 (BACE1) levels. Furthermore, we found for the first time that LF and LF-hyd treatments increased both ApoE secretion and ATP-binding cassette A1 (ABCA1) protein levels in the brains of J20 mice and in primary astrocyte cultures. Moreover, LF and LF-hyd promoted extracellular degradation of Aß in primary astrocyte cultures. These findings indicate that the reduction in Aß levels in the brains of mice fed with both the LF and LF-hyd diets may also be mediated by increased ApoE secretion and ABCA1 protein levels, which in turn leads to the enhanced degradation of Aß in the brains of J20 mice. Our findings suggest that LF and LF-hyd can be used for the treatment and/or prevention of the development of AD.

7.
Mol Neurobiol ; 57(2): 1099-1114, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31686372

RESUMO

Mitochondrial dysfunctions and oxidative stress play important roles in the early pathogenesis of Alzheimer's disease (AD), which also involves the aberrant expression levels of mitochondrial proteins. However, the molecular mechanisms underlying the aberrant expression levels of these proteins in the pathogenesis of AD are still not completely understood. Tid1 (DnaJA3/mtHsp40), a mammalian homolog of the Drosophila tumor suppressor Tid56, is reported to induce mitochondrial fragmentation associated with an increase in reactive oxygen species (ROS) levels, resulting in cell death in some cancer cells. However, the involvement of Tid1 in AD pathogenesis is as yet unknown. In this study, we found that the Tid1 protein levels were upregulated in the hippocampus of AD patients and Tg2576 mice. Our in vitro studies showed that Aß42 increased the expression levels of Tid1 in primary rat cortical neurons. The knockdown of Tid1 protected against neuronal cell death induced by Aß42, and Tid1-mediated neuronal cell death, was dependent on the increased ROS generation and caspase-3 activity. The overexpression of Tid1 in HEK293-APP cells increased the BACE1 levels, resulting in increased Aß production. Conversely, Tid1 knockdown in HEK293-APP cells and primary cultured neurons decreased Aß production through the reduction in the BACE1 levels. We also found that the overexpression of Tid1 activated c-Jun N-terminal kinase (JNK) leading to increased Aß production. Taken together, our results suggest that upregulated Tid1 levels in the hippocampus of patients with AD and Tg2576 mice induce apoptosis and increase Aß production, and Tid1 may therefore be a suitable target in therapeutic interventions for AD.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Hipocampo/metabolismo , Humanos , Neurônios/metabolismo
8.
Int J Nanomedicine ; 14: 8499-8507, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695377

RESUMO

Background: Beyond magnetic resonance imaging (MRI), which has been widely used clinically, molecular MRI (mMRI) can further provide qualitative and quantitative information at the cellular and molecular levels. However, the diagnostic accuracy may not be satisfactory via single-contrast mMRI due to some interferences in vivo. T1/T2 dual-contrast MRI using the same contrast agent (CA) could significantly improve the detection accuracy. Therefore, in this study, we fabricated poly(ethylene glycol) (PEG)-coated, manganese-doped iron oxide nanocomposites (Mn-IONPs@PEG) as T1/T2 dual-contrast CA, and evaluated its feasibility of T1/T2 dual-contrast MRI in vitro and in vivo. Methods: Mn-IONPs were prepared by the thermal decomposition of iron-eruciate and manganese-oleate complexes and were coated with 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-(methoxy[polyethylene glycol]-2000) (DSPE-PEG 2000). The physicochemical properties and cytotoxicity of the Mn-IONPs were fully characterized, followed by MRI in vitro and in vivo. Results: Ultrasmall 3 nm-sized nanoparticles were successfully prepared and were identified using transmission electron microscopy (TEM), high-resolution TEM, and X-ray diffraction. After coating with DSPE-PEG, the Mn-IONPs@PEG displayed excellent hydrophilicity and good biocompatibility. Due to the manganese-doping and PEG coating, the Mn-IONPs@PEG showed good relaxivity in vitro. Especially, the Mn-IONPs@PEG coated with DSPE-PEG following a mass ratio to Mn-IONPs of 1:20 showed harmonious longitudinal relaxivity (r 1 = 7.1 mM-1s-1) and transversal relaxivity (r 2 = 120.9 mM-1s-1), making it a better candidate for T1/T2 dual-contrast mMRI. After administrated via a caudal vein, the Mn-IONPs@PEG can induce significant enhancement in both T1-weighted and T2-weighted MR images and the time at 10 mins after injection was regarded as a suitable time for imaging because both the T1 and T2 enhancement were optimum at that time. Conclusion: The obtained Mn-IONPs@PEG exhibited good r 1 and r 2 and was a reasonable candidate for T1/T2 dual-contrast mMRI.


Assuntos
Compostos Férricos/química , Imagem por Ressonância Magnética , Compostos de Manganês/química , Nanopartículas/química , Óxidos/química , Tamanho da Partícula , Polietilenoglicóis/química , Animais , Sobrevivência Celular , Meios de Contraste/química , Células Hep G2 , Humanos , Fígado/patologia , Camundongos Endogâmicos C57BL , Nanopartículas/ultraestrutura
9.
Clin Exp Nephrol ; 23(9): 1100-1108, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31214872

RESUMO

BACKGROUND: Patients with uremia have an excessive mortality from cardiovascular disease (CVD). Arterial remodeling is mainly responsible for uremia-induced CVD and has been well studied, yet venous remodeling is poorly understood. Here we investigate the histopathology and proteomic profiles of venous remodeling in uremic patients. METHODS: Forearm cephalic veins were isolated from nine uremic patients during surgeries for arteriovenous fistula, and from nine healthy controls when applying surgical debridement. Hematoxylin-eosin, Masson's trichrome, von Kossa, and immunohistochemistry (IHC) against proliferating cell nuclear antigen were stained for histopathology. Isobaric tags for relative and absolute quantitation (iTRAQ) proteomic analysis was executed to explore the proteome of the veins. The core regulatory protein was validated by western blot, IHC, and immunofluorescence. RESULTS: Phlebosclerosis, characterized by intimal rarefaction and medial thickening with disordered proliferation of vascular smooth muscle cells (VSMCs), was the prominent pathological manifestation of peripheral veins in uremic patients, while inflammatory cell infiltration, atherosclerosis or calcification were not obviously detected. iTRAQ analysis showed that 350 proteins were significantly changed in phlebosclerosis of uremic patients compared with healthy controls, of which integrin-ß1 (ITGß1) exhibited the strongest regulatory ability by intermolecular interaction network analysis. The enhanced ITGß1 expression was mainly co-expressed with the disordered proliferation of VSMCs while a little with vascular endothelial cells in the forearm cephalic veins of uremic patients. CONCLUSIONS: Phlebosclerosis is the prominent pathological manifestation in peripheral veins of uremic patients. This pathological alteration mainly attributes to the disordered proliferation of VSMCs, which is potentially mediated by ITGß1.


Assuntos
Antebraço/irrigação sanguínea , Integrina beta1/análise , Doenças Vasculares Periféricas/etiologia , Proteômica/métodos , Uremia/complicações , Remodelação Vascular , Veias/química , Veias/patologia , Estudos de Casos e Controles , Proliferação de Células , Células Endoteliais/química , Células Endoteliais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/química , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/química , Miócitos de Músculo Liso/patologia , Doenças Vasculares Periféricas/metabolismo , Doenças Vasculares Periféricas/patologia , Esclerose , Uremia/diagnóstico
10.
Cell Rep ; 27(5): 1567-1578.e5, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31042481

RESUMO

In vertebrates, hematopoiesis occurring in different niches is orchestrated by intrinsic and extrinsic regulators. Previous studies have revealed numerous linear and planar regulatory mechanisms. However, a multi-dimensional transcriptomic atlas of any given hematopoietic organ has not yet been established. Here, we use multiple RNA sequencing (RNA-seq) approaches, including cell type-specific, temporal bulk RNA-seq, in vivo GEO-seq, and single-cell RNA-seq (scRNA-seq), to characterize the detailed spatiotemporal transcriptome during hematopoietic stem and progenitor cell (HSPC) expansion in the caudal hematopoietic tissue (CHT) of zebrafish. Combinatorial expression profiling reveals that, in the CHT niche, HSPCs and their neighboring supporting cells are co-regulated by shared signaling pathways and intrinsic factors, such as integrin signaling and Smchd1. Moreover, scRNA-seq analysis unveils the strong association between cell cycle status and HSPC differentiation. Taken together, we report a global transcriptome landscape that provides valuable insights and a rich resource to understand HSPC expansion in an intact vertebrate hematopoietic organ.


Assuntos
Hematopoese , Células-Tronco Hematopoéticas/citologia , Transcriptoma , Animais , Células-Tronco Hematopoéticas/classificação , Células-Tronco Hematopoéticas/metabolismo , RNA-Seq , Transdução de Sinais , Análise de Célula Única , Nicho de Células-Tronco , Peixe-Zebra
11.
Genomics Proteomics Bioinformatics ; 17(1): 76-90, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31026580

RESUMO

Agricultural activities, including stock-farming, planting industry, and fish aquaculture, can affect the physicochemical and biological characters of freshwater lakes. However, the effects of pollution producing by agricultural activities on microbial ecosystem of lakes remain unclear. Hence, in this work, we selected Honghu Lake as a typical lake that is influenced by agriculture activities. We collected water and sediment samples from 18 sites, which span a wide range of areas from impacted and less-impacted areas. We performed a geospatial analysis on the composition of microbial communities associated with physicochemical properties and antibiotic pollution of samples. The co-occurrence networks of water and sediment were also built and analyzed. Our results showed that the microbial communities of impacted and less-impacted samples of water were largely driven by the concentrations of TN, TP, NO3--N, and NO2--N, while those of sediment were affected by the concentrations of Sed-OM and Sed-TN. Antibiotics have also played important roles in shaping these microbial communities: the concentrations of oxytetracycline and tetracycline clearly reflected the variance in taxonomic diversity and predicted functional diversity between impacted and less-impacted sites in water and sediment samples, respectively. Furthermore, for samples from both water and sediment, large differences of network topology structures between impacted and less-impacted were also observed. Our results provide compelling evidence that the microbial community can be used as a sentinel of eutrophication and antibiotics pollution risk associated with agricultural activity; and that proper monitoring of this environment is vital to maintain a sustainable environment in Honghu Lake.


Assuntos
Agricultura , Antibacterianos/análise , Lagos/microbiologia , Microbiota , Poluentes Químicos da Água/análise , Animais , China , Eutrofização , Sedimentos Geológicos/química , Sedimentos Geológicos/microbiologia , Lagos/química , Fatores de Risco
12.
Clin Exp Nephrol ; 23(4): 474-483, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30859350

RESUMO

BACKGROUND: The herbicide paraquat (1, 1'-dimethyl-4, 4'-bipyridylium dichloride; PQ) is a poison well-known to cause delayed mortality due to acute kidney injuries (AKI). This study examines the changes in serum amino acids (AAs) metabolite profiles as surrogate markers of renal cell metabolism and function after paraquat poisoning. METHODS: To identify the metabolic profiling of free serum AAs and its metabolites, serum from 40 paraquat-poisoned patients with or without AKI is collected. LC-MS/GC-MS is performed to analyze AA molecules. A Cox proportional hazard model was used to assess for incidence of AKI. Receiver operating characteristic (ROC) curve is applied to evaluate AKI occurrence and prognosis. RESULTS: A total of 102 serum AAs and its metabolites were identified. Compared with non-AKI patients, 37 varied significantly in AKI patients. The univariate Cox proportional hazard model analysis revealed that the estimated PQ amount, plasma PQ concentration, urine PQ concentration, APACHE, SOFA scores and 16 amino acids correlated with the incidence of AKI. Further analyses revealed that 3-methylglutarylcarnitine, 1-methylimidazoleacetate, and urea showed higher cumulative hazard ratios for the occurrence of AKI during follow-up (P < 0.05). The area under the curve (AUC) of 3-methylglutarylcarnitine, 1-methylimidazoleacetate and urea were 0.917, 0.857, 0.872, respectively. CONCLUSION: 3-methylglutarylcarnitine, 1-methylimidazoleacetate and urea were associated with AKI in patients with paraquat intoxication.


Assuntos
Lesão Renal Aguda/sangue , Aminoácidos/sangue , Carnitina/análogos & derivados , Glutaratos/sangue , Herbicidas/envenenamento , Imidazóis/sangue , Paraquat/envenenamento , Ureia/sangue , Lesão Renal Aguda/induzido quimicamente , Adulto , Área Sob a Curva , Biomarcadores/sangue , Carnitina/sangue , Estudos de Casos e Controles , Feminino , Herbicidas/sangue , Herbicidas/urina , Humanos , Masculino , Metaboloma , Pessoa de Meia-Idade , Paraquat/sangue , Paraquat/urina , Envenenamento/sangue , Envenenamento/urina , Modelos de Riscos Proporcionais , Curva ROC , Adulto Jovem
13.
Proc Natl Acad Sci U S A ; 116(11): 5154-5159, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30804206

RESUMO

A high-fat diet (HFD) causes obesity-associated morbidities involved in macroautophagy and chaperone-mediated autophagy (CMA). AMPK, the mediator of macroautophage, has been reported to be inactivated in HFD-caused renal injury. However, PAX2, the mediator for CMA, has not been reported in HFD-caused renal injury. Here we report that HFD-caused renal injury involved the inactivation of Pax2 and Ampk, and the activation of soluble epoxide hydrolase (sEH), in a murine model. Specifically, mice fed on an HFD for 2, 4, and 8 wk showed time-dependent renal injury, the significant decrease in renal Pax2 and Ampk at both mRNA and protein levels, and a significant increase in renal sEH at mRNA, protein, and molecular levels. Also, administration of an sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea, significantly attenuated the HFD-caused renal injury, decreased renal sEH consistently at mRNA and protein levels, modified the renal levels of sEH-mediated epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) as expected, and increased renal Pax2 and Ampk at mRNA and/or protein levels. Furthermore, palmitic acid (PA) treatment caused significant increase in Mcp-1, and decrease in both Pax2 and Ampk in murine renal mesangial cells (mRMCs) time- and dose-dependently. Also, 14(15)-EET (a major substrate of sEH), but not its sEH-mediated metabolite 14,15-DHET, significantly reversed PA-induced increase in Mcp-1, and PA-induced decrease in Pax2 and Ampk. In addition, plasmid construction revealed that Pax2 may positively regulate Ampk transcriptionally in mRMCs. This study provides insights into and therapeutic target for the HFD-mediated renal injury.


Assuntos
Adenilato Quinase/metabolismo , Dieta Hiperlipídica , Epóxido Hidrolases/antagonistas & inibidores , Rim/lesões , Fator de Transcrição PAX2/metabolismo , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Eicosanoides/metabolismo , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/metabolismo , Hipertrofia , Rim/patologia , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Células Mesangiais/patologia , Camundongos , Ácido Palmítico , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Solubilidade , Fatores de Tempo , Ganho de Peso
14.
Biochem Biophys Res Commun ; 505(1): 81-86, 2018 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-30241938

RESUMO

Reelin is a secreted protein essential for the development and function of the mammalian brain. The receptors for Reelin, apolipoprotein E receptor 2 and very low-density lipoprotein receptor, belong to the low-density lipoprotein receptor family, but it is not known whether Reelin is involved in the brain lipid metabolism. In the present study, we performed lipidomic analysis of the cerebral cortex of wild-type and Reelin-deficient (reeler) mice, and found that reeler mice exhibited several compositional changes in phospholipids. First, the ratio of phospholipids containing one saturated fatty acid (FA) and one docosahexaenoic acid (DHA) or arachidonic acid (ARA) decreased. Secondly, the ratio of phospholipids containing one monounsaturated FA (MUFA) and one DHA or ARA increased. Thirdly, the ratio of phospholipids containing 5,8,11-eicosatrienoic acid, or Mead acid (MA), increased. Finally, the expression of stearoyl-CoA desaturase-1 (SCD-1) increased. As the increase of MA is seen as an index of polyunsaturated FA (PUFA) deficiency, and the expression of SCD-1 is suppressed by PUFA, these results strongly suggest that the loss of Reelin leads to PUFA deficiency. Hence, MUFA and MA are synthesized in response to this deficiency, in part by inducing SCD-1 expression. This is the first report of changes of FA composition in the reeler mouse brain and provides a basis for further investigating the new role of Reelin in the development and function of the brain.


Assuntos
Encéfalo/metabolismo , Moléculas de Adesão Celular Neuronais/deficiência , Proteínas da Matriz Extracelular/deficiência , Lipídeos/química , Proteínas do Tecido Nervoso/deficiência , Serina Endopeptidases/deficiência , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/metabolismo , Animais , Ácido Araquidônico/metabolismo , Encéfalo/embriologia , Moléculas de Adesão Celular Neuronais/genética , Ácidos Docosa-Hexaenoicos/metabolismo , Proteínas da Matriz Extracelular/genética , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Metabolismo dos Lipídeos , Camundongos Endogâmicos ICR , Camundongos Mutantes Neurológicos , Proteínas do Tecido Nervoso/genética , Fosfolipídeos/metabolismo , Serina Endopeptidases/genética , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo
15.
Med Sci Monit ; 24: 1397-1407, 2018 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-29513648

RESUMO

BACKGROUND Paraquat is a major cause of fatal poisoning after ingestion in many parts of Asia and the Pacific nations. However, optimal prognostic indicators to evaluate patient mortality have not been unequivocally established. Following acute paraquat poisoning, a number of amino acids (AA), are abnormally expressed in metabolic pathways. However, the alterations in AA metabolite levels after paraquat poisoning remain unknown in humans. MATERIAL AND METHODS In the present study, 40 patients were enrolled, of whom 16 survived and 24 died. A metabolomics approach was used to assess changes in AA metabolites in plasma and its potential prognostic value following paraquat poisoning. Mass spectrometry (MS) based on metabolite identification was conducted. RESULTS Twenty-five AA levels in plasma were abnormally expressed in non-survivor patients. Among them, creatinine, indolelactate, and 3-(4-hydroxyphenyl)lactate were found to be highly correlated with paraquat death prediction. It was noted that the intensity levels of these 3 AA metabolites in the non-survivor group were substantially higher than in the survivor group. Furthermore, we examined receiver operating characteristic (ROC) curves for clinical validation. ROC results showed that 3-(4-hydroxyphenyl)lactate had the highest AUC of 0.84, while indolelactate and creatinine had AUCs of 0.75 and 0.83, respectively, suggesting that they can be used to predict the clinical outcome (although this methodology is expensive to implement). CONCLUSIONS Metabolic profiling of AA levels could be a reliable tool to identify effective indicators for the early high precision prognosis of paraquat poisoning.


Assuntos
Aminoácidos/metabolismo , Metabolômica/métodos , Paraquat/envenenamento , Envenenamento/metabolismo , Envenenamento/mortalidade , Doença Aguda , Adulto , Creatinina/metabolismo , Demografia , Feminino , Humanos , Ácidos Indolacéticos/metabolismo , Ácido Láctico/metabolismo , Masculino , Metaboloma , Análise de Componente Principal , Sobreviventes , Adulto Jovem
16.
Digestion ; 97(3): 205-211, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29393230

RESUMO

This study was conducted to investigate whether chronic kidney disease (CKD) affects intestinal inflammation and intestinal motility and the underlying mechanisms. Rats were randomized into control group and uremic group. Uremia rats were induced by the 5/6 kidney resection, while the control went through the same procedures but without any kidney resection. Intestinal motility was assessed by charcoal transport assay; intestinal inflammation was assessed by analyses of levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 in the ileum tissue. The inducible nitric oxide synthesis (iNOS) activity was assessed in the ileum tissue. The results showed that the intestinal motility in uremic group was significantly decreased compared with that in the control group on postoperative weeks 8 and 10. Meanwhile, the uremic group presented significantly higher concentrations of TNF-α, IL-6, and IL-10 than control group on postoperative weeks 8 and/or 10, and higher gene expression on postoperative weeks 6, 8, and 10. Furthermore, the intestinal iNOS activity in the uremic group was significantly increased compared with that in control group on postoperative weeks 8 and 10. These results suggest that CKD could induce intestinal inflammation and lead to intestinal dysmotility, which may be associated with iNOS activation in the intestine.


Assuntos
Motilidade Gastrointestinal , Ileíte/fisiopatologia , Íleo/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Insuficiência Renal Crônica/complicações , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Ileíte/patologia , Íleo/fisiopatologia , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/sangue , Fator de Necrose Tumoral alfa , Uremia/sangue , Uremia/complicações
17.
Metabolomics ; 14(8): 104, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30830362

RESUMO

INTRODUCTION: Nearly all the enzymes that mediate the metabolism of polyunsaturated fatty acids (PUFAs) are present in the kidney. However, the correlation of renal dysfunction with PUFAs metabolism in uremic patients remains unknown. OBJECTIVES: To test whether the alterations in the metabolism of PUFAs reflect the renal dysfunction in uremic patients. METHODS: LC-MS/MS-based oxylipin profiling was conducted for the plasma samples from the uremic patients and controls. The data were analyzed by principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA). The receiver operating characteristic (ROC) curves and the correlation of the estimated glomerular filtration rate (eGFR) with the key markers were evaluated. Furthermore, qPCR analysis of the whole blood cells was conducted to investigate the possible mechanisms. In addition, a 2nd cohort was used to validate the findings from the 1st cohort. RESULTS: The plasma oxylipin profile distinguished the uremic patients from the controls successfully by using both PCA and OPLS-DA models. 5,6-Dihydroxyeicosatrienoic acid (5,6-DHET), 5-hydroxyeicosatetraenoic acid (5-HETE), 9(10)-epoxyoctadecamonoenoic acid [9(10)-EpOME] and 12(13)-EpOME were identified as the key markers to discriminate the patients from controls. The excellent predictive performance of these four markers was validated by ROC analysis. The eGFR significantly correlated with plasma levels of 5,6-DHET and 5-HETE positively but with plasma 9(10)-EpOME and 12(13)-EpOME negatively. The changes of these markers may account for the inactivation of cytochrome P450 2C18, 2C19, microsome epoxide hydrolase (EPHX1), and 5-lipoxygenase in the patients. CONCLUSION: The alterations in plasma metabolic profile reflect the renal dysfunction in the uremic patients.


Assuntos
Biomarcadores/sangue , Ácidos Graxos Insaturados/sangue , Nefropatias/diagnóstico , Metaboloma , Oxilipinas/sangue , Uremia/complicações , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Taxa de Filtração Glomerular , Humanos , Nefropatias/sangue , Nefropatias/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico
18.
Bioanalysis ; 9(22): 1751-1760, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28967800

RESUMO

AIM: To establish a method to simultaneously measure uric acid (UA) and creatinine (Cr) in human saliva. MATERIALS & METHODS: By using HPLC-MS/MS, we developed and validated a fast, sensitive and accurate method to simultaneously determine UA and Cr in human saliva. The determination range for Cr and UA is of 10-5000 ng/ml with the R2 for both calibration curves over 0.999. The accuracy, precision and recovery of Cr and UA were all acceptable. By using the established method, the Cr and UA levels in saliva from 28 healthy volunteers were measured as 2.9 ± 0.8 µM and 46.8 ± 18.2 µM, respectively. CONCLUSION: This method can simultaneously determine Cr and UA in saliva for clinical and translational study.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Creatinina/análise , Saliva/química , Espectrometria de Massas em Tandem/métodos , Ácido Úrico/análise , Adulto , Feminino , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Saliva/metabolismo , Adulto Jovem
19.
Toxicol Lett ; 273: 97-105, 2017 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-28366735

RESUMO

Insulin or insulin like signaling (IIS) pathway is a crucial pathway in Caenorhabditis elegans associated with mediating longevity, and stress resistance. Regulators of G protein signaling (RGS) also modulate stress resistance and longevity in multiple in vitro and in vivo models. However, the mechanism underlying RGS mediating stress resistance and longevity remains largely unclear. Here we report that rgs-1, an important member of rgs family, is a novel modulator of IIS pathway in C. elegans. We found that the loss of rgs-1 dramatically promoted paraquat resistance in C. elegans. Further genetic analyses demonstrated that rgs-1 acted downstream of daf-2 and upstream of age-1, pdk-1, daf-16. Instead of affecting those IIS-associated genes in transcriptional process, loss of rgs-1 promoted DAF-16's nucleus translocation and subset genes' expression in paraquat-induced oxidative status. By this way, rgs-1 mutant worms exhibited lower ROS damage and longer survival time than wild type worms when both exposed to paraquat. Other than paraquat exposure, rgs-1 mutant also promoted lifespan and cadmium resistance relying on daf-16. As rgs is evolutionarily conserved, our findings open a new insight into rgs family and its role in paraquat-induced oxidative stress and longevity in C. elegans or even mammals.


Assuntos
Animais Geneticamente Modificados , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Longevidade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Paraquat/toxicidade , Somatomedinas/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Estimativa de Kaplan-Meier , Longevidade/genética , Mutação , Estresse Oxidativo/genética , Transdução de Sinais
20.
ACS Appl Mater Interfaces ; 8(39): 25933-25940, 2016 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-27611174

RESUMO

We have developed a Pd-graphene nanocomposite for hydrogen storage. The spherically shaped Pd nanoparticles of 5-45 nm in size are homogeneously distributed over the graphene matrix. This new hydrogen storage system has favorable features like desirable hydrogen storage capacity, ambient conditions of hydrogen uptake, and low temperature of hydrogen release. At a hydrogen charging pressure of 50 bar, the material could yield a gravimetric density of 6.7 wt % in the 1% Pd/graphene nanocomposite. As we increased the applied pressure to 60 bar, the hydrogen uptake capacity reached 8.67 wt % in the 1% Pd/graphene nanocomposite and 7.16 wt % in the 5% Pd/graphene nanocomposite. This system allows storage of hydrogen in amounts that exceed the capacity of the gravimetric target announced by the U.S. Department of Energy (DOE).

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