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1.
Nanoscale Horiz ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34542134

RESUMO

Treating cancer with high efficacy while eliminating side effects has been the holy grail of cancer research. The challenge, however, arises from the similarity in molecular traits of cancer cells and normal cells because truly specific cancer biomarkers are extremely scarce if not entirely unavailable. Often, biomarkers serving as the therapeutic targets are present on both healthy cells and cancers, but at different levels, causing not only off-target side effects but also on-target side effects. This work has reported a new concept of cancer treatment, spatial confinement of cells to inhibit cell migration and invasion, which directly addresses the defining trait of cancer on the cellular level, unchecked division. Using large sized graphene oxide (LS-GO), cell surfaces can be patched. Unlike conventional chemotherapy, this spatial confinement does not affect the viability of non-dividing cells but significantly inhibits tumor cell migration and invasion in vitro and in vivo. This new concept has the potential to become a general therapeutic for many cancer types with reduced side effects.

2.
ACS Appl Mater Interfaces ; 13(33): 39719-39729, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34392680

RESUMO

In this work, cucurbiturils (CBs), a class of macrocyclic supramolecules, were observed to have an interesting peroxidase-like activity, which is metal-free, substrate-specific, thermophilic, acidophilic, and insensitive to ionic strength. By coating CBs on enzyme-encapsulated zeolitic imidazolate framework-8 (ZIF-8), a composite nanozyme was constructed, which retains the catalytic ability of CBs and enzymes and makes them cascade. On addition of the substrate, i.e., the detection target, a highly efficient cascade catalysis can be launched in all the spatial directions to generate sensitive and visible signals. Convenient detection of glucose and cholesterol as models is thereby achieved. More importantly, we have also successfully constructed a composite nanozyme-based sensor array (6 × 8 wells) and thereby achieved simultaneous colorimetric analysis of multiple samples. The concept and successful practice of the construction of the unique core-shell supramolecule/biomolecule@nanomaterial architecture provide the possibility to fabricate next-generation multifunctional materials and create new applications by integrating their unique functions.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Imidazóis/química , Nanocompostos/química , Peroxidases/química , Zeolitas/química , Técnicas Biossensoriais , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Catálise , Colorimetria , Corantes Fluorescentes/química , Glucose Oxidase/química , Glucose Oxidase/metabolismo , Peróxido de Hidrogênio/química , Imidazóis/metabolismo , Simulação de Acoplamento Molecular , Oxirredução , Peroxidases/metabolismo , Impressão Tridimensional
3.
Biomed Pharmacother ; 140: 111542, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34088571

RESUMO

Recent studies report that the gut microbiome can enhance systemic and antitumor immunity by modulating responses to antibody immunotherapy in melanoma patients. In this study, we found that icariside I, a novel anti-cancer agent isolated from Epimedium, significantly inhibited B16F10 melanoma growth in vivo through regulation of gut microbiota and host immunity. Oral administration of icariside I improved the microbiota community structure with marked restoration of Lactobacillus spp. and Bifidobacterium spp. abundance in the cecal contents of tumor-bearing mice. We also found that icariside I improves the levels of microbiota-derived metabolites such as short-chain fatty acids (SCFAs) and indole derivatives, consequently promoting repair of the intestinal barrier and reducing systemic inflammation of tumor-bearing mice. Icariside I exhibited strong immunological anti-tumor activity, directly manifested by up-regulation of multiple lymphocyte subsets including CD4+ and CD8+ T cells or NK and NKT cells in peripheral blood of tumor-bearing mice. Collectively, these results suggest that icariside I, via its microbiome remodeling and host immune regulation properties, may be developed as an anticancer drug.


Assuntos
Antineoplásicos/farmacologia , Flavonas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Melanoma/imunologia , Melanoma/terapia , Microbiota/efeitos dos fármacos , Umbeliferonas/farmacologia , Animais , Ceco/microbiologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Ácidos Graxos Voláteis/imunologia , Fezes/microbiologia , Feminino , Imunoterapia/métodos , Indóis/farmacologia , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
4.
Small ; 17(29): e2101224, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34145748

RESUMO

The delivery of mRNA to manipulate protein expression has attracted widespread attention, since that mRNA overcomes the problem of infection and mutation risks in transgenes and can work as drugs for the treatment of diseases. Although there are currently some vehicles that deliver mRNA into cells, they have not yet reached a good balance in terms of expression efficiency and biocompatibility. Here, a DNA nano-hydrogel system for mRNA delivery is developed. The nano-hydrogel is all composed of DNA except the target mRNA, so it has superior biocompatibility compared with those chemical vehicles. In parallel, the nano-hydrogel can be compacted into a nanosphere under the crosslinking by well-designed "X"-shaped DNA scaffolds and DNA linkers, facilitating the delivery into cells through endocytosis. In addition, smart intracellular release of the mRNA is achieved by incorporating a pH-responsive i-motif structure into the nano-hydrogel. Thus, taking the efficient delivery and release together, mRNA can be translated into the corresponding protein with a high efficiency, which is comparable to that of the commercial liposome but with a much better biocompatibility. Due to the excellent biocompatibility and efficiency, this nano-hydrogel system is expected to become a competitive alternative for delivering functional mRNA in vivo.


Assuntos
DNA , Hidrogéis , Sistemas de Liberação de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , RNA Mensageiro/genética
5.
Accid Anal Prev ; 158: 106192, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34029919

RESUMO

Crash severity model is a classical topic in road safety research. The multinomial logit (MNL) model, as a basic discrete outcome method, is widely applied to measure the association between crash severity and possible risk factors. However, the MNL model has several assumptions and properties that are possibly not consistent with the actual crash mechanism, and therefore with the association measure for crash severity. One significant attribute is the variation in drivers' safety perception. Risk-taking drivers tends to drive at a higher speed, which increases the likelihood of severe crashes. However, the variations in speed and other driving performance lead to the error in the utility function more profound. This violates the assumption of identical error distributions between different crash severity outcomes. In this paper, we propose a multinomial multiplicative (MNM) model, as an alternative for crash severity model. There are two possible formulations for the proposed MNM model: (1) Weibull and (2) Fréchet, according to the distributions of random propensities and subject to the signs of the systematic parts of the regression equation. The two heavy-tailed distributions can capture the effect of unobserved contributory factors on crash injury severity. Additionally, the MNM model can incorporate the effects of the non-identical, heavy-tailed, and asymmetric properties of the distribution, whereas the conventional MNL model cannot. Several operational considerations are also attempted in this study, including the specifications of the systematic parts and the interpretations of the parameters. The MNM model is further extended to the mixed MNM (MMNM) model by considering unobserved heterogeneities using random coefficients, while the mixed MNL (MMNL) model is used as the benchmark model. The proposed MMNM model is calibrated using the crash dataset obtained from the Guangdong Province, China. Results indicated that the proposed MMNM model outperformed the MMNL model in this case. Also, the results of parameter estimates are indicative to impact factors on crash severity as well as the design and implementation of policies. This justified the use of MMNM model as an alternative for crash severity model in practice. This is the first application of MMNM model in the traffic safety literature, it is worth exploring the application of other advanced multiplicative models for safety analysis in the future.


Assuntos
Acidentes de Trânsito , Ferimentos e Lesões , China , Humanos , Modelos Logísticos , Fatores de Risco
6.
J Agric Food Chem ; 69(13): 3982-3991, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33755449

RESUMO

As important signal metabolites within enterohepatic circulation, bile acids (BAs) play a pivotal role during the occurrence and development of diet-induced nonalcoholic fatty liver disease (NAFLD). Here, we evaluated the functional effects of BAs and gut microbiota contributing to sucralose consumption-induced NAFLD of mice. The results showed that sucralose consumption significantly upregulated the abundance of intestinal genera Bacteroides and Clostridium, which produced deoxycholic acid (DCA) accumulating in multiple biological matrixes including feces, serum, and liver of mice. Subsequently, elevated hepatic DCA, one of the endogenous antagonists of the farnesol X receptor (Fxr), inhibited hepatic gene expression including a small heterodimer partner (Shp) and Fxr leading to sucralose-induced NAFLD in mice. Dietary supplements with fructo-oligosaccharide or metformin markedly restored genera Bacteroides and Clostridium abundance and the DCA level of sucralose-consuming mice, which eventually ameliorated NAFLD. These findings highlighted the effects of gut microbiota and its metabolite DCA on sucralose-induced NAFLD of mice.


Assuntos
Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Animais , Ácidos e Sais Biliares , Ácido Desoxicólico , Fígado , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Sacarose/análogos & derivados
7.
Ecotoxicol Environ Saf ; 212: 111989, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524913

RESUMO

Drinking water exposure to microcystin-leucine-arginine (MC-LR), the most widely occurring cyanotoxins, poses a highly potential risk for human health. However, the health risk of MC-LR exposure at current guideline value in drinking water has not yet entirely evaluated. In the current study, we used 1H NMR-based metabolomics combined with targeted metabolic profiling by GC/LC-MS to explore the toxic effects of MC-LR exposure at environmentally relevant concentrations via drinking water in rats. The results revealed that multiple biological consequences of MC-LR exposure on host metabolism in rats. Both relatively low and high doses of MC-LR used here induced hepatic lipogenesis and inflammation. While only relatively high dose MC-LR (10 µg/L) in drinking water caused more metabolic disorders including inhibition of gluconeogenesis and promotion of ß-oxidation of fatty acid. Although the dose of 1.0 µg/L MC-LR is extremely low for rats, alterations of metabolic profiles were unexpectedly found in rat liver and serum, alarming potential health risk of MC-LR at the WHO guideline level.


Assuntos
Água Potável/química , Microcistinas/toxicidade , Animais , Cromatografia Líquida , Água Potável/análise , Fígado/efeitos dos fármacos , Masculino , Metaboloma , Metabolômica , Ratos
8.
Sci Rep ; 11(1): 2689, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514843

RESUMO

In order to study the influence of distance weight on ore-grade estimation, the inverse distance weighted (IDW) is used to estimate the Ni grade and MgO grade of serpentinite ore based on a three-dimensional ore body model and related block models. Manhattan distance, Euclidean distance, Chebyshev distance, and multiple forms of the Minkowski distance are used to calculate distance weight of IDW. Results show that using the Minkowski distance for the distance weight calculation is feasible. The law of the estimated results along with the distance weight is given. The study expands the distance weight calculation method in the IDW method, and a new method for improving estimation accuracy is given. Researchers can choose different weight calculation methods according to their needs. In this study, the estimated effect is best when the power of the Minkowski distance is 3 for a 10 m × 10 m × 10 m block model. For a 20 m × 20 m × 20 m block model, the estimated effect is best when the power of the Minkowski distance is 9.

9.
J Agric Food Chem ; 69(5): 1478-1486, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33351610

RESUMO

Hesperetin-7-O-glucoside (Hes-7-G) is a typical flavonoid monoglucoside isolated from Citri Reticulatae Pericarpium (CRP), which is commonly used as a food adjuvant and exhibits potential biological activities. To explore the interaction between Hes-7-G ingestion and microbiome and host metabolism, here, 16S rRNA gene sequencing was first used to analyze the alteration of fecal microbiome in mice after Hes-7-G intake. Metabolic homeostasis in mice was subsequently investigated using untargeted 1H NMR-based metabolomics and targeted metabolite profiling. We found that dietary Hes-7-G significantly regulated fecal microbiota and its derived metabolites, including short-chain fatty acids (SCFAs) and tryptophan metabolites (indole and its derivatives), in feces of mice. Regulation of microbiota was further confirmed by the significantly changed urinary hippurate and trimethylamine N-oxide (TMAO), co-metabolites of the microbe and host. We also found that dietary Hes-7-G modulated the host tricarboxylic acid cycle (TCA) involved in energy metabolism. These findings suggested that Hes-7-G exhibits potential beneficial effects for human health.


Assuntos
Bactérias/efeitos dos fármacos , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Hesperidina/farmacologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/metabolismo , Ciclo do Ácido Cítrico/efeitos dos fármacos , Ácidos Graxos Voláteis/química , Ácidos Graxos Voláteis/metabolismo , Feminino , Homeostase/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Metaboloma/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL
10.
Biomed Opt Express ; 11(11): 6634-6648, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33282513

RESUMO

Two-photon microscopy (TPM) has been widely used in biological imaging owing to its intrinsic optical sectioning and deep penetration abilities. However, the conventional TPM suffers from poor axial resolution, which makes it difficult to recognize some three-dimensional fine features. We present multi-frame reconstruction two-photon microscopy (MR-TPM) using a liquid lens as a fast axial scanning engine. A sensorless adaptive optics (AO) approach is adopted to correct the aberrations caused by both the liquid lens and the optical system. By overcoming the effect of optical aberrations, inadequate sampling, and poor focusing capability of a conventional TPM, the axial resolution can be improved by a factor of 3 with a high signal-to-noise ratio. The proposed technology is compatible with the conventional TPM and requires no optical post-processing. We demonstrate the proposed method by imaging fluorescent beads, in vitro imaging of the neural circuit of mouse brain slice, and in vivo time-lapse imaging of the morphological changes of microglial cells in septic mice model. The results suggest that the axon of the neural circuit and the process of microglia along the axial direction, which cannot be resolved using conventional TPM, become distinguishable using the proposed AO MR-TPM.

11.
ACS Nano ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33054177

RESUMO

Microtubules gliding on surfaces coated with kinesin motors are minimalist experimental systems for studying collective behavior. Collective behavior in these systems arises from interactions between filaments, for example, from steric interactions, depletion forces, or cross-links. To maximize the utilization of system components and the production of work, it is desirable to achieve mutualistic interactions leading to the congregations of both types of agents, that is, cytoskeletal filaments and molecular motors. To this end, we used a microtubule-kinesin system, where motors reversibly bind to the surface via an interaction between a hexahistidine (His6) tag on the motor and a Ni(II)-nitrilotriacetic acid (Ni-NTA) moiety on the surface. The surface density of binding sites for kinesin motors was increased relative to our earlier work, driving the motors from the solution to the surface. Characterization of the motor-surface interactions in the absence of microtubules yielded kinetic parameters consistent with previous data and revealed the capacity of the surface to support two-dimensional motor diffusion. The motor density gradually fell over 2 h, presumably due to the stripping of Ni(II) from the NTA moieties on the surface. Microtubules gliding on these reversibly bound motors were unable to cross each other and at high enough densities began to align and form long, dense bundles. The kinesin motors accumulated in trails surrounding the microtubule bundles and participated in microtubule transport.

13.
Exp Ther Med ; 20(2): 714-726, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32742317

RESUMO

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental and behavioral disorder with a serious negative impact on the quality of life from childhood until adulthood, which may cause academic failure, family disharmony and even social unrest. The pathogenesis of ADHD has remained to be fully elucidated, leading to difficulties in the treatment of this disease. Genetic and environmental factors contribute to the risk of ADHD development. Certain studies indicated that ADHD has high comorbidity with allergic and autoimmune diseases, with various patients with ADHD having a high inflammatory status. Increasing evidence indicated that mast cells (MCs) are involved in the pathogenesis of brain inflammation and neuropsychiatric disorders. MCs may cause or aggravate neuroinflammation via the selective release of inflammatory factors, interaction with glial cells and neurons, activation of the hypothalamic-pituitary adrenal axis or disruption of the blood-brain barrier integrity. In the present review, the notion that MC activation may be involved in the occurrence and development of ADHD through a number of ways is discussed based on previously published studies. The association between MCs and ADHD appears to lack sufficient evidence at present and this hypothesis is considered to be worthy of further study, providing a novel perspective for the treatment of ADHD.

14.
J Hazard Mater ; 399: 122829, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32531671

RESUMO

Triclocarban (TCC), a widely used antibacterial agent, has aroused considerable public concern due to its potential toxicity. In the current study, we applied targeted metabolite profiling (LC/GC-MS) and untargeted 1H NMR-based metabolomics in combination with biological assays to unveil TCC exposure-induced cellular metabolic responses in murine preadipocyte and human normal hepatocytes. We found that TCC promoted adipocyte differentiation in 3T3L1 preadipocytes, manifested by marked triglyceride (TG) and fatty acids accumulation, which were consistent with significant up-regulation of mRNA levels in the key adipogenic markers Fasn, Srebp1 and Ap2. In human hepatocytes (L02), TCC exposure dose-dependently interfered with the cellular redox state with down-regulated levels of antioxidant reduced-GSH and XBP1 and further induced the accumulation of TG, ceramides and saturated fatty acid (16:0). We also found that TCC exposure triggered unfold protein response (UPR) and endoplasmic reticulum (ER) stress in both cells through activation of ATF4 and ATF6, resulting in toxic lipid accumulation. These findings about lipid metabolism and metabolic responses to TCC exposure in both preadipocytes and hepatocytes provide novel perspectives for revealing the mechanisms of TCC toxicity.


Assuntos
Adipogenia , Carbanilidas , Animais , Carbanilidas/toxicidade , Hepatócitos , Humanos , Metabolismo dos Lipídeos , Camundongos
15.
Chem Commun (Camb) ; 56(51): 6961-6964, 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32436536

RESUMO

We have designed a DNA logic gate that can integrate the recognition of multiple biomarkers with signal amplification to perform the accurate and sensitive analysis of circulating tumor cells (CTCs). It also has the potential to analyze rare cells that exist in small amounts but are of great significance (such as stem cells) in the fields of clinical diagnosis and biomedicine.


Assuntos
Aptâmeros de Nucleotídeos/química , DNA/química , Células Neoplásicas Circulantes/patologia , Biomarcadores Tumorais/análise , Técnicas Biossensoriais , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Imagem Óptica
16.
Theranostics ; 10(10): 4410-4421, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32292504

RESUMO

Non-destructive analysis of cells at the molecular level is of critical importance for cell research. At present, immunoassay-based and aptamer-based methods can achieve non-structural destructive cell analysis, but still lead to changes in cells at the molecular level. Here, we have proposed a dual-terminal amplification (DTA) strategy, which enables nondestructive analysis of membrane protein MUC1 without the effect on protein expression and cell viability in living cells. Methods: A fluorophore (Cy5)-labeled DNA ternary complex consisting of three oligonucleotides is designed. It can recognize MUC1 through its aptamer region, and thus make the MUC1 of cells visible under a fluorescence microscope. When DNA polymerase is added, dual-terminal amplification is performed. One direction dissociates aptamer from MUC1, and the other direction, also known as rolling circle amplification (RCA), produces long linear DNA strands, which can be further adopted for quantitative analysis of MUC1. In this way, all reagents are removed from the surface of the cells after the analysis, which allows nondestructive analysis. We named this strategy dual-terminal amplification (DTA) analysis. Results: By using the DTA analysis, both in situ fluorescence imaging analysis and ex situ fluorescence quantitative analysis of MUC1 were achieved. In addition, the aptamer-containing DNA ternary complex stays on cell surface only during the analysis and leaves the cell after the analysis is complete. The cells can be maintained in a non-interfering state for the rest of the time. So after the analysis, it is found that there are no effect on the physiological activity of cells and the expression of target protein even after two rounds of repeatable imaging and quantitative analysis. Conclusion: In summary, we have successfully constructed a strategy for nondestructive analysis of membrane protein in living cells. We believe that this method provides a promising way for the analysis of the key membrane proteins of cells and the versatile utilization of precious cell samples.


Assuntos
Aptâmeros de Nucleotídeos/química , Mucina-1/metabolismo , Neoplasias , Imagem Óptica/métodos , Análise de Célula Única/métodos , Linhagem Celular Tumoral , Corantes Fluorescentes/química , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/ultraestrutura
17.
J Appl Clin Med Phys ; 21(5): 26-37, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32281254

RESUMO

PURPOSE: To develop and test a three-dimensional (3D) deep learning model for predicting 3D voxel-wise dose distributions for intensity-modulated radiotherapy (IMRT). METHODS: A total of 122 postoperative rectal cancer cases treated by IMRT were considered in the study, of which 100 cases were randomly selected as the training-validating set and the remaining as the testing set. A 3D deep learning model named 3D U-Res-Net_B was constructed to predict 3D dose distributions. Eight types of 3D matrices from CT images, contoured structures, and beam configurations were fed into the independent input channel, respectively, and the 3D matrix of dose distributions was taken as the output to train the 3D model. The obtained 3D model was used to predict new 3D dose distributions. The predicted accuracy was evaluated in two aspects: (a) The dice similarity coefficients (DSCs) of different isodose volumes, the average dose difference of all voxels within the body, and 3%/5 mm global gamma passing rates of organs at risks (OARs) and planned target volume (PTV) were used to address the spatial correspondence between predicted and clinical delivered 3D dose distributions; (b) The dosimetric index (DI) including homogeneity index, conformity index, V50 , V45 for PTV and OARs between predicted and clinical truth were statistically analyzed with the paired-samples t test. The model was also compared with 3D U-Net and the same architecture model without beam configurations input (named as 3D U-Res-Net_O). RESULTS: The 3D U-Res-Net_B model predicted 3D dose distributions accurately. For the 22 testing cases, the average prediction bias ranged from -1.94% to 1.58%, and the overall mean absolute errors (MAEs) was 3.92 ± 4.16%; there was no statistically significant difference for nearly all DIs. The model had a DSCs value above 0.9 for most isodose volumes, and global 3D gamma passing rates varying from 0.81 to 0.90 for PTV and OARs, clearly outperforming 3D U-Res-Net_O and being slightly superior to 3D U-Net. CONCLUSIONS: This study developed a more general deep learning model by considering beam configurations input and achieved an accurate 3D voxel-wise dose prediction for rectal cancer treated by IMRT, a potentially easier clinical implementation for more comprehensive automatic planning.


Assuntos
Aprendizado Profundo , Radioterapia de Intensidade Modulada , Neoplasias Retais , Humanos , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/radioterapia
18.
Environ Pollut ; 259: 113820, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31918130

RESUMO

Environmental exposure to 2,3,7,8-tetrachlorodibenzofuran (TCDF), one of typical persistent organic pollutants (POPs) produced from municipal waste combustion, exerts toxic effects on human healthy. In the current study, we mainly used targeted metabolomics combined with untargeted 1H NMR-based metabolomics to investigate the effects of TCDF exposure on lipid homeostasis in mice. We found that TCDF exposure induced hepatic lipogenesis, the early-stage of non-alcoholic fatty liver disease, manifested by excessive lipids including triglycerides, fatty acids and lipotoxic ceramides accumulated in the liver together with elevated serum very low-density lipoprotein by activating the aryl hydrocarbon receptor (AHR) and its target genes such as Cyp1a1 and Cd36. We also found that TCDF exposure induced alteration of phospholipids and choline metabolites and endoplasmic reticulum (ER) markers in the liver of mice, indicating that disruption of host cell membrane structural integrity and ER stress leading to hepatic steatosis. In addition, complementary information was also obtained from histopathologic assessments and biological assays, strongly supporting toxic effects of TCDF. These results provide new evidence of TCDF toxicity associated with fatty liver disease and further our understanding of health effects of environmental pollutants exposure.


Assuntos
Benzofuranos/toxicidade , Fígado Gorduroso/induzido quimicamente , Animais , Humanos , Fígado , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica
19.
Biochem Biophys Res Commun ; 523(2): 315-321, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-31864712

RESUMO

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disease for which specific biomarkers and pathological mechanisms have yet to be identified. Methylphenidate (MPH) is commonly used to treat ADHD, but its therapeutic mechanisms and its impact on brain metabolites remain unclear. Metabolomics can help to discover biomarkers and identify pathophysiological mechanisms. We adopted an untargeted metabolomics approach based on gas chromatography-mass spectrometry to investigate the potential biomarkers and pathogenesis of ADHD. Ten Wistar-Kyoto (WKY) rats were chosen as healthy controls (vehicle, i.g.). Twenty young spontaneously hypertensive rats (SHR) were randomly allocated to the SHR group (vehicle, i.g.) and MPH group (2 mg/kg/day, i.g.). We identified 103 metabolites from the prefrontal cortex (PFC). Orthogonal partial least square-discriminate analysis showed the differential expression of these metabolites between the groups. Multivariate and univariate statistical analyses isolated 12 metabolites that differed significantly between the WKY and SHR groups: 3-hydroxymethylglutaric acid, 3-phosphoglyceric acid, adenosine monophosphate, cholesterol, lanosterol, and o-phosphoethanolamine; 3-hydroxymethylglutaric acid and cholesterol were reversed with MPH treatment. Pathway and enrichment analyses revealed that the altered metabolites belonged to the cholesterol metabolism pathways. ELISA and western blotting showed that the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase and the expression of sterol regulatory element-binding protein-2 and ATP-binding cassette transporter A1 were reduced in the PFC of the SHR; the latter two proteins were upregulated by MPH. In conclusion, metabolomics analysis identified potential biomarkers that influence cholesterol metabolism and may be implicated in the development of ADHD-like behavior. MPH can regulate cholesterol metabolism in the PFC of ADHD models. This study uncovered potential biomarkers and pathways involved in ADHD, providing new insight into its pathogenesis.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Colesterol/metabolismo , Córtex Pré-Frontal/metabolismo , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Estimulantes do Sistema Nervoso Central/uso terapêutico , Modelos Animais de Doenças , Masculino , Redes e Vias Metabólicas , Metabolômica , Metilfenidato/uso terapêutico , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
20.
BMC Plant Biol ; 19(1): 445, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31651235

RESUMO

BACKGROUND: Apple is one of the most popular fruit crops world-wide and its skin color is an important quality consideration essential for commercial value. However, the strategy on genetic breeding for red skin apple and the genetic basis of skin color differentiation is very limited and still largely unknown. RESULTS: Here, we reported a bud sport mutant of Fuji apple with red skin color and enhanced anthocyanins accumulation. Quantitative SWATH-MS (sequential window acquisition of all theoretical spectra-mass spectrometry) proteomics investigations revealed proteome changes in the apple red skin bud mutation and a total of 451 differentially expressed proteins were identified in apple skin. The mutant showed significantly increased expression levels of photosynthesis-related proteins, stress-related proteins as well as anthocyanins biosynthesis pathway. On the other hand, substantial downregulation of mitogen-activated protein kinase 4 (MAPK4) and mevalonate kinase (MVK) were detected, indicating a promising role for the red skin color development in the mutant. Furthermore, we also hypothesize that a post-transcriptional regulation of the skin color formation occurs in the mutant through the advanced SWATH-MS analysis. CONCLUSION: Our work provides important information on the application of proteomic methods for analysing proteomes changes in Fuji apple and highlights a clade of regulatory proteins potentially contributing for the molecular breeding of fruit skin color.


Assuntos
Antocianinas/metabolismo , Regulação da Expressão Gênica de Plantas , Malus/fisiologia , Proteínas de Plantas/metabolismo , Proteoma , Frutas/genética , Frutas/imunologia , Frutas/metabolismo , Frutas/fisiologia , Malus/genética , Espectrometria de Massas , Mutação , Fotossíntese , Pigmentação , Melhoramento Vegetal , Proteínas de Plantas/genética , Proteômica
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