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1.
Signal Transduct Target Ther ; 7(1): 192, 2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35729157

RESUMO

Folic acid, served as dietary supplement, is closely linked to one-carbon metabolism and methionine metabolism. Previous clinical evidence indicated that folic acid supplementation displays dual effect on cancer development, promoting or suppressing tumor formation and progression. However, the underlying mechanism remains to be uncovered. Here, we report that high-folate diet significantly promotes cancer development in mice with hepatocellular carcinoma (HCC) induced by DEN/high-fat diet (HFD), simultaneously with increased expression of methionine adenosyltransferase 2A (gene name, MAT2A; protein name, MATIIα), the key enzyme in methionine metabolism, and acceleration of methionine cycle in cancer tissues. In contrast, folate-free diet reduces MATIIα expression and impedes HFD-induced HCC development. Notably, methionine metabolism is dynamically reprogrammed with valosin-containing protein p97/p47 complex-interacting protein (VCIP135) which functions as a deubiquitylating enzyme to bind and stabilize MATIIα in response to folic acid signal. Consistently, upregulation of MATIIα expression is positively correlated with increased VCIP135 protein level in human HCC tissues compared to adjacent tissues. Furthermore, liver-specific knockout of Mat2a remarkably abolishes the advocating effect of folic acid on HFD-induced HCC, demonstrating that the effect of high or free folate-diet on HFD-induced HCC relies on Mat2a. Moreover, folate and multiple intermediate metabolites in one-carbon metabolism are significantly decreased in vivo and in vitro upon Mat2a deletion. Together, folate promotes the integration of methionine and one-carbon metabolism, contributing to HCC development via hijacking MATIIα metabolic pathway. This study provides insight into folate-promoted cancer development, strongly recommending the tailor-made folate supplement guideline for both sub-healthy populations and patients with cancer expressing high level of MATIIα expression.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Carbono , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Dieta , Ácido Fólico/farmacologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Metionina/metabolismo , Metionina Adenosiltransferase/genética , Camundongos
2.
Sensors (Basel) ; 22(11)2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35684680

RESUMO

Breast cancer grading methods based on hematoxylin-eosin (HE) stained pathological images can be summarized into two categories. The first category is to directly extract the pathological image features for breast cancer grading. However, unlike the coarse-grained problem of breast cancer classification, breast cancer grading is a fine-grained classification problem, so general methods cannot achieve satisfactory results. The second category is to apply the three evaluation criteria of the Nottingham Grading System (NGS) separately, and then integrate the results of the three criteria to obtain the final grading result. However, NGS is only a semiquantitative evaluation method, and there may be far more image features related to breast cancer grading. In this paper, we proposed a Nuclei-Guided Network (NGNet) for breast invasive ductal carcinoma (IDC) grading in pathological images. The proposed nuclei-guided attention module plays the role of nucleus attention, so as to learn more nuclei-related feature representations for breast IDC grading. In addition, the proposed nuclei-guided fusion module in the fusion process of different branches can further enable the network to focus on learning nuclei-related features. Overall, under the guidance of nuclei-related features, the entire NGNet can learn more fine-grained features for breast IDC grading. The experimental results show that the performance of the proposed method is better than that of state-of-the-art method. In addition, we released a well-labeled dataset with 3644 pathological images for breast IDC grading. This dataset is currently the largest publicly available breast IDC grading dataset and can serve as a benchmark to facilitate a broader study of breast IDC grading.


Assuntos
Neoplasias da Mama , Mama/patologia , Neoplasias da Mama/patologia , Núcleo Celular , Amarelo de Eosina-(YS) , Feminino , Hematoxilina , Humanos , Processamento de Imagem Assistida por Computador/métodos
3.
Natl Sci Rev ; 9(5): nwab212, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35663242

RESUMO

BCAT2-mediated branched-chain amino acid (BCAA) catabolism is critical for pancreatic ductal adenocarcinoma (PDAC) development, especially at an early stage. However, whether a high-BCAA diet promotes PDAC development in vivo, and the underlying mechanism of BCAT2 upregulation, remain undefined. Here, we find that a high-BCAA diet promotes pancreatic intraepithelial neoplasia (PanIN) progression in LSL-KrasG12D/+ ; Pdx1-Cre (KC) mice. Moreover, we screened with an available deubiquitylase library which contains 31 members of USP family and identified that USP1 deubiquitylates BCAT2 at the K229 site. Furthermore, BCAA increases USP1 protein at the translational level via the GCN2-eIF2α pathway both in vitro and in vivo. More importantly, USP1 inhibition recedes cell proliferation and clone formation in PDAC cells and attenuates pancreas tumor growth in an orthotopic transplanted mice model. Consistently, a positive correlation between USP1 and BCAT2 is found in KC; LSL-KrasG12D/+ ; p53flox/+ ; Pdx1-Cre mice and clinical samples. Thus, a therapeutic targeting USP1-BCAT2-BCAA metabolic axis could be considered as a rational strategy for treatment of PDAC and precisive dietary intervention of BCAA has potentially translational significance.

4.
Comput Methods Programs Biomed ; 221: 106871, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35584579

RESUMO

BACKGROUND AND OBJECTIVE: Cryo-electron tomography (cryo-ET) with subtomogram averaging (STA) is indispensable when studying macromolecule structures and functions in their native environments. Due to the low signal-to-noise ratio, the missing wedge artifacts in tomographic reconstructions, and multiple macromolecules of varied shapes and sizes, macromolecule localization and classification remain challenging. To tackle this bottleneck problem for structural determination by STA, we design an accurate macromolecule localization and classification method named voxelwise particle detector (VP-Detector). METHODS: VP-Detector is a two-stage particle detection method based on a 3D multiscale dense convolutional neural network (3D MSDNet). The proposed network uses 3D hybrid dilated convolution (3D HDC) to avoid the resolution loss caused by scaling operations. Meanwhile, it uses 3D dense connectivity to encourage the reuse of feature maps to reduce trainable parameters. In addition, the weighted focal loss is proposed to focus more attention on difficult samples and rare classes, which relieves the class imbalance caused by multiple particles of various sizes. The performance of VP-Detector is evaluated on both simulated and real-world tomograms, and it shows that VP-Detector outperforms state-of-the-art methods. RESULTS: The experiments show that VP-Detector outperforms the state-of-the-art methods on particle localization with an F1-score of 0.951 and a precision of 0.978. In addition, VP-Detector can replace manual particle picking in experiment on the real-world tomograms. Furthermore, it performs well in classifying large-, medium-, and small-weight proteins with accuracies of 1, 0.95, and 0.82, respectively. Finally, ablation studies demonstrate the effectiveness of 3D HDC, 3D dense connectivity, weighted focal loss, and training on small training sets. CONCLUSIONS: VP-Detector can achieve high accuracy in particle detection with few trainable parameters and support training on small datasets. It can also relieve the class imbalance caused by multiple particles with various shapes and sizes.


Assuntos
Elétrons , Processamento de Imagem Assistida por Computador , Microscopia Crioeletrônica/métodos , Tomografia com Microscopia Eletrônica/métodos , Processamento de Imagem Assistida por Computador/métodos , Redes Neurais de Computação
5.
Sci China Life Sci ; 2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35366151

RESUMO

Epithelial ovarian cancer (EOC) exhibits strong dependency on the tricarboxylic acid (TCA) cycle and oxidative phosphorylation to fuel anabolic process. Here, we show that malate dehydrogenase 2 (MDH2), a key enzyme of the TCA cycle, is palmitoylated at cysteine 138 (C138) residue, resulting in increased activity of MDH2. We next identify that ZDHHC18 acts as a palmitoyltransferase of MDH2. Glutamine deprivation enhances MDH2 palmitoylation by increasing the binding between ZDHHC18 and MDH2. MDH2 silencing represses mitochondrial respiration as well as ovarian cancer cell proliferation both in vitro and in vivo. Intriguingly, re-expression of wild-type MDH2, but not its palmitoylation-deficient C138S mutant, sustains mitochondrial respiration and restores the growth as well as clonogenic capability of ovarian cancer cells. Notably, MDH2 palmitoylation level is elevated in clinical cancer samples from patients with high-grade serous ovarian cancer. These observations suggest that MDH2 palmitoylation catalyzed by ZDHHC18 sustains mitochondrial respiration and promotes the malignancy of ovarian cancer, yielding possibilities of targeting ZDHHC18-mediated MDH2 palmitoylation in the treatment of EOC.

6.
J Oncol ; 2022: 2630864, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35419056

RESUMO

Objectives: To detect the expression of circular RNA (circRNA) circINTS4 in triple-negative breast cancer (TNBC) and to analyze the relationship between the expression of circRNA circINTS4 and the clinicopathological characteristics and chemotherapy resistance of patients with TNBC. Methods: Bioinformatics was used to predict that circINTS4 and POM121 could bind to miR-129-5p, and dual luciferase reporter genes proved that circINTS4 could bind to miR-129-5p and miR-129-5p could bind to POM121. RNA immunoprecipitation (RIP) and RNA pull-down experiments confirmed that circINTS4 binds to miR-129-5p. The correlation among circINTS4, miR-129-5p, and POM121 was detected by qRT-PCR. Results: In ADR-resistant TNB cells, circINTS4 was significantly up-regulated, miR-129-5p was down-regulated, and POM121 protein expression was significantly up-regulated. Experimental results showed that circINTS4 knockdown inhibited proliferation, migration, invasion, and autophagy. Knocking down miR-129-5p or overexpression of POM121 reversed the inhibitory effect of sh-circints4 on the development of ADR-resistant TNBC cells. In addition, CIRCINTS4 regulates POM121 expression by sponge-adsorbed miR-129-5p. CIRCINTS4 knockdown prevents ADR-resistant tumor growth by regulating the miR-129-5p/POM121 axis in vivo. Conclusions: CircRNA circINTS4 may act as the ceRNA of miR-129-5p to regulate the expression of target gene POM121, thereby promoting the progress of TNBC molecular mechanism and providing scientific basis for circINTS4 as a new molecular target for clinical diagnosis and drug resistance therapy of TNBC.

7.
Appl Microbiol Biotechnol ; 106(7): 2677-2688, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35338385

RESUMO

Lentinula edodes is one of the most important commercially cultivated edible mushrooms. It is well known that gypsum (CaSO4·2H2O) supplementation in sawdust medium increases the yield of L. edodes, while the physiological mechanisms remain unclear. Our previous study showed that the acidification of the medium to pH 3.5-4.0 was essential for the growth of L. edodes. In this study, it was found that the oxalic acid excreted by L. edodes was responsible for the acidification of the medium. The biosynthesis of oxalic acid was regulated by the ambient pH and buffer capacity of the medium. To acidify the sawdust medium, the concentrations of total and soluble oxalate were 51.1 mmol/kg and 10.8 mmol/kg, respectively. However, when the concentration of soluble oxalate was 8.0 mmol/kg, the mycelial growth rate decreased by 29% compared with the control. Soluble oxalate was toxic to L. edodes, while soluble sulfate was nontoxic. CaSO4 reacted with soluble oxalate to form nontoxic insoluble CaC2O4 and the strong acid H2SO4. When the CaSO4 supplemented in sawdust medium was more than 25 mmol/kg, the soluble oxalate decreased to less than 1 mmol/kg, and the mycelial growth rate increased by 32% compared with the control. In conclusion, gypsum improved the growth and yield by relieving the toxicity of oxalate and facilitating the acidification of sawdust medium. KEY POINTS: • L. edodes excretes oxalic acid to acidify the ambient environment for growth. • Soluble oxalate is toxic to L. edodes. • Gypsum increases growth by reacting with oxalate to relieve its toxicity.


Assuntos
Agaricales , Cogumelos Shiitake , Sulfato de Cálcio , Micélio , Ácido Oxálico
8.
J Mol Cell Biol ; 2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35349697

RESUMO

Folate metabolism plays an essential role in tumor development. Various cancers display therapeutic response to reagents targeting key enzymes of folate cycle, but obtaining chemo-resistance later. Therefore, novel targets in folate metabolism are highly demanded. Methylenetetrahydrofolate dehydrogenase/methylenetetrahydrofolate cyclohydrolase 2 (MTHFD2) is one of the key enzymes in folate metabolism and its expression is highly increased in multiple human cancers. However, the underlying mechanism that regulates MTHFD2 expression remains unknown. Here, we elucidate that SIRT4 deacetylates the conserved lysine residue at 50 (K50) in MTHFD2. K50 de-acetylation destabilizes MTHFD2 by elevating Cullin 3 (CUL3) E3 ligase-mediated proteasomal degradation in response to stressful stimuli of folate deprivation, leading to suppression of nicotinamide adenine dinucleotide phosphate (NADPH) production in tumor cells and accumulation of intracellular reactive oxygen species (ROS), which in turn inhibits the growth of breast cancer cells. Collectively, our study reveals that SIRT4 senses folate availability to control MTHFD2 K50 acetylation and its protein stability, bridging nutrient/folate stress and cellular redox to act on cancer cell growth.

9.
Chem Biol Drug Des ; 99(6): 884-896, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35313087

RESUMO

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that can cause cognitive impairment. Ginsenoside Rg1 (Rg1) has a significant neuroprotective effect on animals with memory impairment. However, the mechanism of how Rg1 mediates the Wnt signaling pathway and improves cognitive function by regulating oxidative stress, apoptosis, and neuroinflammation is still unclear. In this study, the spatial memory ability of tree shrews was tested by Morris water maze, the expression levels of amyloid protein (Aß1-42), ionized calcium-binding adapter molecule 1 (iba-1), nitrotyrosine (NT), and 8-hydroxyguanine (8-OHG) were detected by immunohistochemistry. Subsequently, the activity of catalase (CAT) and the glutathione peroxidase (GSH-Px) was, respectively, measured by the ammonium molybdate method and the 5,5'-dithiobis (2-nitrobenzoic acid). Furthermore, the malondialdehyde (MDA) concentration was determined by the thiobarbituric acid test. Finally, the expression levels of Beta-secretase (BACE1), superoxide dismutase (SOD), BCL2-Associated X (Bax), B-cell lymphoma-2 (Bcl-2), caspase-anti-apoptotic factor Cleaved-caspase-3 (Caspase-3), microtubule-associated proteins 2 (MAP2), Neuronal nuclear antigen (NeuN), as well as the phosphorylation of GSK-3ß and ß-catenin were detected by Western blot. This study implied that Rg1 reduced the phosphorylation of Tau protein, the deposition of Aß1-42, and the expression of BACE1. It also showed that Rg1 increased the antioxidant activity of SOD, CAT, GPx, and instead reduced the oxidation products of NT, 8-OHG, and MDA, as wells as the inflammatory factor interleukin-1 and iba-1. It further showed that Rg1 increased the ratio of Bcl-2 to Bax and expression of neuronal markers MAP2 and NeuN, but instead reduced the expression of Caspase-3, GSK-3ß, and ß-catenin. In conclusion, by regulating the Wnt/GSK-3ß/ß-catenin signaling pathway, Rg1 of moderate and high dose could alleviate oxidative stress damage, improve neuroinflammation, protect neurons, finally improve the cognitive impairment of the AD tree shrew. This study provides theoretical basis for the Rg1 clinical application in AD.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Apoptose , Ácido Aspártico Endopeptidases/metabolismo , Caspase 3/metabolismo , Ginsenosídeos , Glicogênio Sintase Quinase 3 beta/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Superóxido Dismutase/metabolismo , Via de Sinalização Wnt , Proteína X Associada a bcl-2/metabolismo , beta Catenina/metabolismo
10.
Exp Ther Med ; 23(3): 204, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35126707

RESUMO

The melanoma antigen gene family A (MAGEA) family of proteins comprises of cancer-testis antigens that are highly expressed in a number of tumours but are minimally expressed in normal cells. Due to its expression characteristics, this protein family has become a popular target for anti-cancer drugs and immunotherapy research over recent years. Although, elevated expression levels of MAGEA6 has been found in different types of tumours, there remains to be insufficient information on the function of MAGEA6 and its associated gene regulation pathways. The present study used Transwell, Cell Counting Kit-8 and wound healing assays to analyse the effects of MAGEA6 on Eca109 cell invasion, migration and proliferation. The main functions and pathways involved in MAGEA6 were predicted by Illumina Hiseq screening for mutually regulated genes and core genes. Eca109 cell line with a high expression of MAGEA6 was a stable cell line obtained by transfection in the early stage, and this cell line was used in subsequent experiments. Transcriptome sequencing was performed on this cell line and the Eca109 cell line that normally expressed MAGEA6. It was revealed that a high expression of MAGEA6 conferred a significant stimulating effect on cell proliferation whilst also significantly increasing cell invasion and migration. Transcriptomic analysis identified 14 differentially expressed genes and 13 core regulatory genes closely associated with MAGEA6 expression regulation, such as methylsterol monooxygenase 1 (MSMO1). The present study suggest that MAGEA6 positively regulated MSMO1 expression, which may serve an oncogenic role in cells through this regulatory effect. Overall, this provided a novel route of investigation for an in-depth study of the regulatory function of MAGEA6.

11.
Research (Wash D C) ; 2022: 9869518, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35136860

RESUMO

Microfluidic-based organs-on-chips (OoCs) are a rapidly developing technology in biomedical and chemical research and have emerged as one of the most advanced and promising in vitro models. The miniaturization, stimulated tissue mechanical forces, and microenvironment of OoCs offer unique properties for biomedical applications. However, the large amount of data generated by the high parallelization of OoC systems has grown far beyond the scope of manual analysis by researchers with biomedical backgrounds. Deep learning, an emerging area of research in the field of machine learning, can automatically mine the inherent characteristics and laws of "big data" and has achieved remarkable applications in computer vision, speech recognition, and natural language processing. The integration of deep learning in OoCs is an emerging field that holds enormous potential for drug development, disease modeling, and personalized medicine. This review briefly describes the basic concepts and mechanisms of microfluidics and deep learning and summarizes their successful integration. We then analyze the combination of OoCs and deep learning for image digitization, data analysis, and automation. Finally, the problems faced in current applications are discussed, and future perspectives and suggestions are provided to further strengthen this integration.

12.
Bioinformatics ; 2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35134862

RESUMO

MOTIVATION: Cryo-electron microscopy (cryo-EM) is a widely-used technology for ultrastructure determination, which constructs the three-dimensional (3D) structures of protein and macromolecular complex from a set of two-dimensional (2D) micrographs. However, limited by the electron beam dose, the micrographs in cryo-EM generally suffer from the extremely low signal-to-noise ratio (SNR), which hampers the efficiency and effectiveness of downstream analysis. Especially, the noise in cryo-EM is not simple additive or multiplicative noise whose statistical characteristics are quite different from the ones in natural image, extremely shackling the performance of conventional denoising methods. RESULTS: Here, we introduce the Noise-Transfer2Clean (NT2C), a denoising deep neural network (DNN) for cryo-EM to enhance image contrast and restore specimen signal, whose main idea is to improve the denoising performance by correctly learning the noise distribution of cryo-EM images and transferring the statistical nature of noise into the denoiser. Especially, to cope with the complex noise model in cryo-EM, we design a contrast-guided noise and signal re-weighted algorithm to achieve clean-noisy data synthesis and data augmentation, making our method authentically achieve signal restoration based on noise's true properties. Our work verifies the feasibility of denoising based on mining the complex cryo-EM noise patterns directly from the noise patches. Comprehensive experimental results on simulated datasets and real datasets show that NT2C achieved a notable improvement in image denoising, especially in background noise removal, compared with the commonly used methods. Moreover, a case study on the real dataset demonstrates that NT2C can greatly alleviate the obstacles caused by the SNR to particle picking and simplify the identifying of particles. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. AVAILABILITY: The code is available at https://github.com/Lihongjia-ict/NoiseTransfer2Clean/.

13.
Bioengineering (Basel) ; 9(2)2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35200397

RESUMO

PURPOSE: We aimed to investigate RF-EMR-induced cell malignant transformation. METHODS: We divided Balb/c-3T3 cells into sham and expo groups. The expo groups were exposed to a 1800 MHz RF continuous wave for 40 and 60 days, for 4 h per day. The sham group was sham-exposed. Cells were harvested for a cell transformation assay, transplantation in severe combined immune deficient (SCID) mice, soft agar clone formation detection, and a transwell assay. The mRNA microarray assay was used to declare key genes and pathways. RESULTS: The exposed Balb/c-3T3 cells showed a strong increase in cell proliferation and migration. Malignant transformation was observed in expo Balb/c-3T3 cells exposed for 40 days and 60 days, which was symbolized with visible foci and clone formation. Expo Balb/c-3T3 cells that were exposed for 40 days and 60 days produced visible tumors in the SCID mice. Lipid metabolism was the key biological process and pathway involved. The mevalonate (MVA) pathway was the key metabolic pathway. The interacted miRNAs could be further research targets to examine the molecular mechanism of the carcinogenic effects of long-term exposure. CONCLUSION: Exposure for 40 and 60 days to 1800 MHz RF-EMR induced malignant transformation in Balb/c-3T3 cells at the SAR of 8.0 W/kg. We declared that lipid metabolism was the pivotal biological process and pathway. The MVA pathway was the key metabolic pathway.

14.
Chem Biol Interact ; 353: 109796, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35007526

RESUMO

Coronavirus disease 2019 (COVID-19) was declared a serious global public health emergency. Hospitalization and mortality rates of lung cancer patients diagnosed with COVID-19 are higher than those of patients presenting with other cancers. However, the reasons for the outcomes being disproportionately severe in lung adenocarcinoma (LUAD) patients with COVID-19 remain elusive. The present study aimed to identify the possible causes for disproportionately severe COVID-19 outcomes in LUAD patients and determine a therapeutic target for COVID-19 patients with LUAD. We used publicly available data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and various bioinformatics tools to identify and analyze the genes implicated in SARS-CoV-2 infection in LUAD patients. Upregulation of the SARS-CoV-2 infection-related molecules dipeptidyl peptidase 4, basigin, cathepsin B (CTSB), methylenetetrahydrofolate dehydrogenase, and peptidylprolyl isomerase B rather than angiotensin-converting enzyme 2 may explain the relatively high susceptibility of LUAD patients to SARS-CoV-2 infection. CTSB was highly expressed in the LUAD tissues after SARS-CoV-2 infection, and its expression was positively correlated with immune cell infiltration and proinflammatory cytokine expression. These findings suggest that CTSB plays a vital role in the hyperinflammatory response in COVID-19 patients with LUAD and is a promising target for the development of a novel drug therapy for COVID-19 patients.


Assuntos
Adenocarcinoma de Pulmão/virologia , COVID-19/genética , Catepsina B/genética , Neoplasias Pulmonares/virologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/mortalidade , Enzima de Conversão de Angiotensina 2/genética , Animais , Basigina/genética , Linfócitos T CD8-Positivos/virologia , COVID-19/imunologia , COVID-19/mortalidade , Cricetinae , Ciclofilinas/genética , Citocinas/sangue , Dipeptidil Peptidase 4/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Antígenos de Histocompatibilidade Menor/genética , Terapia de Alvo Molecular , Prognóstico , Mapas de Interação de Proteínas/genética , Regulação para Cima
15.
Biochem Biophys Res Commun ; 590: 163-168, 2022 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-34979317

RESUMO

Liquid-phase electron microscopy is highly desirable for observing biological samples in their native liquid state at high resolution. We developed liquid imaging approaches for biological cells using scanning electron microscopy. Novel approaches included scanning transmission electron imaging using a liquid-cell apparatus (LC-STEM), as well as correlative cathodoluminescence and electron microscopy (CCLEM) imaging. LC-STEM enabled imaging at a ∼2 nm resolution and excellent contrast for the precise recognition of localization, distribution, and configuration of individually labeled membrane proteins on the native cells in solution. CCLEM improved the resolution of fluorescent images down to 10 nm. Liquid SEM technologies will bring unique and wide applications to the study of the structure and function of cells and membrane proteins in their near-native states at the monomolecular level.


Assuntos
Proteínas de Membrana/ultraestrutura , Microscopia Eletrônica de Varredura , Linhagem Celular Tumoral , Receptores ErbB/ultraestrutura , Fluorescência , Humanos
16.
Nat Metab ; 4(1): 106-122, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35075301

RESUMO

The link between branched-chain amino acids (BCAAs) and obesity has been known for decades but the functional role of BCAA metabolism in white adipose tissue (WAT) of obese individuals remains vague. Here, we show that mice with adipose tissue knockout of Bcat2, which converts BCAAs to branched-chain keto acids (BCKAs), are resistant to high-fat diet-induced obesity due to increased inguinal WAT browning and thermogenesis. Mechanistically, acetyl-CoA derived from BCKA suppresses WAT browning by acetylation of PR domain-containing protein 16 (PRDM16) at K915, disrupting the interaction between PRDM16 and peroxisome proliferator-activated receptor-γ (PPARγ) to maintain WAT characteristics. Depletion of BCKA-derived acetyl-CoA robustly prompts WAT browning and energy expenditure. In contrast, BCKA supplementation re-establishes high-fat diet-induced obesity in Bcat2 knockout mice. Moreover, telmisartan, an anti-hypertension drug, significantly represses Bcat2 activity via direct binding, resulting in enhanced WAT browning and reduced adiposity. Strikingly, BCKA supplementation reverses the lean phenotype conferred by telmisartan. Thus, we uncover the critical role of the BCAA-BCKA axis in WAT browning.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Proteínas de Ligação a DNA/metabolismo , Cetoácidos/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Animais , Sítios de Ligação , Temperatura Corporal , Proteínas de Ligação a DNA/genética , Dieta Hiperlipídica , Metabolismo Energético , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Camundongos , Camundongos Knockout , Modelos Moleculares , Obesidade/etiologia , Obesidade/metabolismo , PPAR gama/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , Termogênese , Transaminases/antagonistas & inibidores , Transaminases/química , Transaminases/metabolismo , Fatores de Transcrição/genética
17.
Mini Rev Med Chem ; 22(1): 43-51, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33797364

RESUMO

Alzheimer's Disease (AD) is one of the most common neurodegenerative diseases with chronic, progressive, and irreversible characteristics, affecting nearly 50 million older adults worldwide. The pathogenesis of AD includes the formation of senile plaques, the abnormal aggregation of tau protein and the gradual degeneration and death of cerebral cortical cells. The main symptoms are memory loss, cognitive decline and behavioral disorders. Studies indicate that cannabidiol (CBD) possesses various pharmacological activities, including anti-inflammatory, anti-oxidation and neuroprotective activities. It has been suggested as a potential multi-target medicine for the treatment of AD. In this review, we aim to summarize the underlying mechanisms and protective effects of CBD on signaling pathways and central receptors involved in the pathogenesis of AD, including the endocannabinoid system (eCBs), the Transient receptor potential vanilloid type 1(TRPV1) receptor, and the Peroxisome Proliferator-Activated Receptor (PPAR) receptor.


Assuntos
Doença de Alzheimer , Canabidiol , Idoso , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/prevenção & controle , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Endocanabinoides , Humanos
18.
Food Chem ; 371: 131165, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34601213

RESUMO

Takifugu rubripes is well-known for its unique flavour but can also develop a putrid off-note. To eliminate off-note and promote desirable flavour, four cooking processes (boiling, steaming, microwave-heating and roasting) were explored to determine their effects on cooked T. rubripes. The temperature and water dynamics, physico-chemical properties were analysed and correlated with sensory qualities. The changes of centre temperature dynamics during cooking decreased the water mobility and led to varied sensory properties. Six out of ten orthonasal aroma attributes and four out of five mouthfeel attributes were significantly different among samples (p < 0.05). Based on partial least squares regression analysis, orthonasal aroma attributes "roasted" and "earthy/putrid fish" highly correlated with the volatile compounds generated from Maillard reaction and lipid oxidation, respectively; meanwhile mouthfeel attributes of chewy/fibre and tender/juicy were highly associated with water loss and moisture, respectively. This study provides insights for optimising cooking conditions to create desirable fish flavour.


Assuntos
Culinária , Takifugu , Animais , Odorantes/análise , Percepção , Paladar
19.
Materials (Basel) ; 14(21)2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34771769

RESUMO

The high-temperature dynamic compressive properties of a 30 vol.% SiCp/6092Al composite, fabricated using powder metallurgy, were experimentally investigated using the split Hopkinson pressure bar system with an electric furnace. Three different ambient temperatures, namely, room temperature, 200 °C, and 350 °C, were adopted, and the dynamic tests of the composite specimens were conducted at strain rates ranging from 1500 to 4500 s-1. The experimental results showed that the flow stress of the composite was generally insensitive to strain rates at room temperature. However, the composite started exhibiting different strain-rate-dependent behaviors as the temperature increased, and the flow stress nonlinearly varied with increasing temperature. In addition, the microscopic images of the specimens showed that the microscopic failure mechanisms of the composite were greatly influenced by the ambient temperature and strain rate. Specifically, the percentage of failed particles decreased with rising temperature and the dominating failure mode of particles changed significantly as the strain rate increased.

20.
J Mater Chem B ; 9(39): 8202-8210, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34590109

RESUMO

Citrate-based mussel-inspired whitlockite composite adhesives (CMWAs) were developed and administered to the bone-tendon interface in anterior cruciate ligament (ACL) reconstruction. CMWAs could improve the initial bone-tendon bonding strength, promote the bony inward growth from the bone tunnel and enhance the chondrogenesis and osteogenesis of the bone-tendon interface, thus augmenting bone-to-tendon healing.


Assuntos
Materiais Biocompatíveis/química , Bivalves/química , Fosfatos de Cálcio/química , Citratos/química , Adesivos , Animais , Reconstrução do Ligamento Cruzado Anterior , Células da Medula Óssea , Osso e Ossos , Células-Tronco Mesenquimais , Estrutura Molecular , Osteogênese , Ratos , Estresse Mecânico , Tendões
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