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1.
Nat Commun ; 11(1): 51, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896758

RESUMO

Neuromorphic computing based on spikes offers great potential in highly efficient computing paradigms. Recently, several hardware implementations of spiking neural networks based on traditional complementary metal-oxide semiconductor technology or memristors have been developed. However, an interface (called an afferent nerve in biology) with the environment, which converts the analog signal from sensors into spikes in spiking neural networks, is yet to be demonstrated. Here we propose and experimentally demonstrate an artificial spiking afferent nerve based on highly reliable NbOx Mott memristors for the first time. The spiking frequency of the afferent nerve is proportional to the stimuli intensity before encountering noxiously high stimuli, and then starts to reduce the spiking frequency at an inflection point. Using this afferent nerve, we further build a power-free spiking mechanoreceptor system with a passive piezoelectric device as the tactile sensor. The experimental results indicate that our afferent nerve is promising for constructing self-aware neurorobotics in the future.

2.
Cell Prolif ; : e12744, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31840352

RESUMO

OBJECTIVES: Mixed lineage leukaemia protein-1 (MLL1) mediates histone 3 lysine 4 (H3K4) trimethylation (me3) and plays vital roles during early embryonic development and hematopoiesis. In our previous study, we found its expression was positively correlated with embryonic myogenic ability in pigs, indicating its potential roles in mammalian muscle development. The present work aimed to explore the roles and regulation mechanisms of MLL1 in myogenesis. MATERIALS AND METHODS: The expression of MLL1 in C2C12 cells was experimentally manipulated using small interfering RNAs (siRNA). 5-ethynyl-2'-deoxyuridine (EdU) assay, cell cycle assay, immunofluorescence, qRT-PCR and Western blot were performed to assess myoblast proliferation and differentiation. Chromatin immunoprecipitation assay was conducted to detect H3K4me3 enrichment on myogenic factor 5 (Myf5) promoter. A cardiotoxin (CTX)-mediated muscle regeneration model was used to investigate the effects of MLL1 on myogenesis in vivo. RESULTS: MLL1 was highly expressed in proliferating C2C12 cells, and expression decreased after differentiation. Knocking down MLL1 suppressed myoblast proliferation and impaired myoblast differentiation. Furthermore, knockdown of MLL1 resulted in the arrest of cell cycle in G1 phase, with decreased expressions of Myf5 and Cyclin D1. Mechanically, MLL1 transcriptionally regulated Myf5 by mediating H3K4me3 on its promoter. In vivo data implied that MLL1 was required for Pax7-positive satellite cell proliferation and muscle repair. CONCLUSION: MLL1 facilitates proliferation of myoblasts and Pax7-positive satellite cells by epigenetically regulating Myf5 via mediating H3K4me3 on its promoter.

3.
Cell Death Differ ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685980

RESUMO

Zinc finger protein 422 (Zfp422) is a widely expressed zinc finger protein that serves as a transcriptional factor to regulate downstream gene expression, but until now, little is known about its roles in myogenesis. We found here that Zfp422 plays a critical role in skeletal muscle development and regeneration. It highly expresses in mouse skeletal muscle during embryonic development. Specific knockout of Zfp422 in skeletal muscle impaired embryonic muscle formation. Satellite cell-specific Zfp422 deletion severely inhibited muscle regeneration. Myoblast differentiation and myotube formation were suppressed in Zfp422-deleted C2C12 cells, isolated primary myoblasts, and satellite cells. Chromatin Immunoprecipitation Sequencing (ChIP-Seq) revealed that Zfp422 regulated ephrin type-A receptor 7 (EphA7) expression by binding an upstream 169-bp DNA sequence, which was proved to be an enhancer of EphA7. Knocking EphA7 down in C2C12 cells or deleting Zfp422 in myoblasts will inhibit cell apoptosis which is required for myoblast differentiation. These results indicate that Zfp422 is essential for skeletal muscle differentiation and fusion, through regulating EphA7 expression to maintain proper apoptosis.

4.
BMC Genet ; 20(1): 72, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477002

RESUMO

BACKGROUND: Myogenic Differentiation 1 (MyoD) is a crucial master switch in regulating muscle-specific gene transcription. Forced expression of myoD is equipped to induce several cell lineages into myoblast, which then differentiate and fuse into myotube. Pig is one of the most significant livestock supplying meat, and has been classified into lean, fat and miniature pig breeds. However, the mechanisms underlying muscle mass variation among different pig breeds have remained unclear. Considering the important effect of MyoD on muscle development, it remains to be investigated whether the difference in muscle mass is caused by its single nucleotide polymorphisms (SNPs) which are the major differences among pig breeds at DNA level. RESULTS: In this study, we identified the locations of porcine myoD regulatory regions including proximal regulatory region (PRR), distal regulatory region (DRR), and core enhancer (CE) region. There are 8 SNPs in the regulatory regions and 6 SNPs in gene body region, which were identified from lean, fat and miniature pig populations. However, these SNPs have no effects on its temporal expression and transcriptional activity which might lead to the distinction in postnatal muscle mass. In addition, overexpression of myoD clones across from amphibious to mammals including xenopus tropicalis, chicken, mouse and pig whose gene identities vary from 68 to 84%, could promote myogenesis in NIH3T3 fibroblasts cells. CONCLUSIONS: These results proved that myoD nucleotide variations from different pig populations have no effect on muscle mass, suggesting that the function of myoD is highly conserved not only among different pig breeds, but also across different species. Thus, it would be futile to discover SNPs affecting muscle mass in pig populations with normal muscle development.

5.
J Anim Sci ; 97(5): 1967-1978, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31222274

RESUMO

Pig is one of the major dietary protein sources for human consumption, from which muscle is the largest protein origin. However, molecular mechanisms concerning early porcine embryonic muscle development distinctions between pig breeds are still unclear. In this study, an integrated analysis of transcriptome and miRNAome was conducted using longissimus dorsi muscle of 4 early embryonic stages around the primary myofiber formation time (18-, 21-, 28-, and 35-d post coitus) from 2 pig breeds (Landrace [LR] and Wuzhishan [WZS]) differing in meat mass. The global miRNA/mRNA expression profile showed that WZS prepared for myogenic developmental processes earlier than LR. After identifying and analyzing the interaction network of top 100 up-/down-regulated miRNA and their target genes, we were able to find 3 gene clusters: chromatin modification-related (Chd2, H3f3a, Chd6, and Mll1), myogenesis-related (Pax3, Pbx1, Mef2a, and Znf423), and myosin component-related (Mylk, Myo5a, Mylk4, Myh9, and Mylk2) gene clusters. These genes may involve in miRNA-gene myogenic regulatory network that plays vital role in regulating distinct early porcine embryonic myogenic processes between LR and WZS. In summary, our study reveals an epigenetic-mediated myogenic regulatory axial that will help us to decipher molecular mechanisms concerning early porcine embryonic muscle development distinctions between pig breeds.


Assuntos
Epigênese Genética , Regulação da Expressão Gênica no Desenvolvimento/genética , MicroRNAs/genética , RNA Mensageiro/genética , Suínos/genética , Transcriptoma , Animais , Desenvolvimento Embrionário/genética , Feminino , Perfilação da Expressão Gênica/veterinária , Redes Reguladoras de Genes , Masculino , Desenvolvimento Muscular/genética , Especificidade da Espécie , Suínos/embriologia , Suínos/crescimento & desenvolvimento
6.
FASEB J ; 33(8): 9638-9655, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31145867

RESUMO

Here, we performed whole-genome bisulfite sequencing of longissimus dorsi muscle from Landrace and Wuzhishan (WZS) miniature pigs during 18, 21, and 28 d postcoitum. It was uncovered that in regulatory regions only around transcription start sites (TSSs), gene expression and methylation showed negative correlation, whereas in gene bodies, positive correlation occurred. Furthermore, earlier myogenic gene demethylation around TSSs and earlier hypermethylation of myogenic genes in gene bodies were considered to trigger their earlier expression in miniature pigs. Furthermore, by analyzing the methylation pattern of the myogenic differentiation 1(MyoD) promoter and distal enhancer, we found that earlier demethylation of the MyoD distal enhancer in WZSs contributes to its earlier expression. Moreover, DNA demethylase Tet1 was found to be involved in the demethylation of the myogenin promoter and promoted immortalized mouse myoblast cell line (C2C12) and porcine embryonic myogenic cell differentiation. This study reveals that earlier demethylation of myogenic genes contributes to precocious terminal differentiation of myoblasts in miniature pigs.-Zhang, X., Nie, Y., Cai, S., Ding, S., Fu, B., Wei, H., Chen, L., Liu, X., Liu, M., Yuan, R., Qiu, B., He, Z., Cong, P., Chen, Y., Mo, D. Earlier demethylation of myogenic genes contributes to embryonic precocious terminal differentiation of myoblasts in miniature pigs.

7.
J Agric Food Chem ; 67(16): 4700-4708, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30929441

RESUMO

Fat-related traits have great influences on pork quality. As different fat tissues have different biochemical profiles depending on their location, intramuscular fat contributes to gustatory qualities, while subcutaneous fat is considered as a negative factor associated with growth performance. In this study, both primary intramuscular and subcutaneous vascular stem cells (IVSCs and SVSCs) could be differentiated into mature adipocytes, though the IVSC differentiation efficiency was lower. By comparative analysis of transcriptomes, 2524 differentially expressed genes (DEGs) were found between two VSCs before differentiation, while only 551 DEGs were found and enriched in two pathways including biosynthesis of unsaturated fatty acids after differentiation. This result indicated that differentiated VSCs were more similar. During differentiation, more DEGs existed in IVSCs than that in SVSCs, suggesting that adipogenesis of IVSCs might be more complex. Additionally, the expression level of DEGs involved in the adipogenic process helps to explain the difference of differentiation efficiency between IVSCs and SVSCs.


Assuntos
Adipócitos/citologia , Adipogenia , Células-Tronco/citologia , Gordura Subcutânea/citologia , Adipócitos/metabolismo , Animais , Ácidos Graxos Insaturados/biossíntese , Perfilação da Expressão Gênica , Carne Vermelha/análise , Células-Tronco/metabolismo , Gordura Subcutânea/irrigação sanguínea , Gordura Subcutânea/metabolismo , Suínos , Transcriptoma
8.
Materials (Basel) ; 11(11)2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30373122

RESUMO

Synaptic devices with bipolar analog resistive switching behavior are the building blocks for memristor-based neuromorphic computing. In this work, a fully complementary metal-oxide semiconductor (CMOS)-compatible, forming-free, and non-filamentary memristive device (Pd/Al2O3/TaOx/Ta) with bipolar analog switching behavior is reported as an artificial synapse for neuromorphic computing. Synaptic functions, including long-term potentiation/depression, paired-pulse facilitation (PPF), and spike-timing-dependent plasticity (STDP), are implemented based on this device; the switching energy is around 50 pJ per spike. Furthermore, for applications in artificial neural networks (ANN), determined target conductance states with little deviation (<1%) can be obtained with random initial states. However, the device shows non-linear conductance change characteristics, and a nearly linear conductance change behavior is obtained by optimizing the training scheme. Based on these results, the device is a promising emulator for biology synapses, which could be of great benefit to memristor-based neuromorphic computing.

9.
Biochem Biophys Res Commun ; 503(2): 970-976, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-29932923

RESUMO

MicroRNAs are a class of highly conserved ∼20 nucleotides non-coding RNAs that post-transcriptionally regulate gene expression. Many miRNAs were studied in the development of skeletal muscle, such as miR-1, miR-206, and miR-133. In our previous study, miR-127-3p was found highly expressed in porcine fetal skeletal muscle, whereas the detailed functions of miR-127-3p in muscle development is still unclear. In this study, we detected that miR-127-3p also highly expressed in skeletal muscle, cardiac muscle of adult mice and proliferative C2C12 cell lines. Overexpression of miR-127-3p almost has no effects on differentiation of C2C12 cell lines. However, miR-127-3p significantly inhibited the cell proliferation of C2C12 cells. Moreover, we identified KMT5a as a target gene that was down-regulated in both mRNA and protein level when miR-127-3p mimics were introduced. Furthermore, KMT5a overexpression in miR-127-3p treated cells rescued the influence of miR-127-3p on C2C12 proliferation. In brief, our data reveals that miR-127-3p regulates the proliferation of myocytes through KMT5a.


Assuntos
Proliferação de Células , Regulação para Baixo , Histona-Lisina N-Metiltransferase/genética , MicroRNAs/genética , Células Musculares/citologia , Animais , Linhagem Celular , Células HEK293 , Humanos , Camundongos , Células Musculares/metabolismo , Regulação para Cima
10.
Nanoscale ; 10(13): 5875-5881, 2018 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-29508884

RESUMO

Neuromorphic engineering is a promising technology for developing new computing systems owing to the low-power operation and the massive parallelism similarity to the human brain. Optimal function of neuronal networks requires interplay between rapid forms of Hebbian plasticity and homeostatic mechanisms that adjust the threshold for plasticity, termed metaplasticity. Metaplasticity has important implications in synapses and is barely addressed in neuromorphic devices. An understanding of metaplasticity might yield new insights into how the modification of synapses is regulated and how information is stored by synapses in the brain. Here, we propose a method to imitate the metaplasticity inhibition of long-term potentiation (MILTP) for the first time based on memristors. In addition, the metaplasticity facilitation of long-term potentiation (MFLTP) and the metaplasticity facilitation of long-term depression (MFLTD) are also achieved. Moreover, the mechanisms of metaplasticity in memristors are discussed. Additionally, the proposed method to mimic the metaplasticity is verified by three different memristor devices including oxide-based resistive memory (OxRAM), interface switching random access memory, and conductive bridging random access memory (CBRAM). This is a further step toward developing fully bio-realistic artificial synapses using memristors. The findings in this study will deepen our understanding of metaplasticity, as well as provide new insight into bio-realistic neuromorphic engineering.


Assuntos
Potenciação de Longa Duração , Modelos Neurológicos , Plasticidade Neuronal , Neurônios/fisiologia , Sinapses/fisiologia , Equipamentos e Provisões Elétricas , Humanos
11.
Adv Mater ; 30(14): e1705193, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29436065

RESUMO

Cation-based resistive switching (RS) devices, dominated by conductive filaments (CF) formation/dissolution, are widely considered for the ultrahigh density nonvolatile memory application. However, the current-retention dilemma that the CF stability deteriorates greatly with decreasing compliance current makes it hard to decrease operating current for memory application and increase driving current for selector application. By centralizing/decentralizing the CF distribution, this current-retention dilemma of cation-based RS devices is broken for the first time. Utilizing the graphene impermeability, the cation injecting path to the RS layer can be well modulated by structure-defective graphene, leading to control of the CF quantity and size. By graphene defect engineering, a low operating current (≈1 µA) memory and a high driving current (≈1 mA) selector are successfully realized in the same material system. Based on systematically materials analysis, the diameter of CF, modulated by graphene defect size, is the major factor for CF stability. Breakthrough in addressing the current-retention dilemma will instruct the future implementation of high-density 3D integration of RS memory immune to crosstalk issues.

12.
Sci Rep ; 7(1): 2516, 2017 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-28566753

RESUMO

Pigs supply vital dietary proteins for human consumption, and their economic value depends largely on muscle production. MicroRNAs are known to play important roles in skeletal muscle development. However, their relationship to distinct muscle production between pig breeds remains unknown. Here, we performed an integrated analysis of microRNA-mRNA expression profiles for Landrace (LR, lean) pigs and the Chinese indigenous Lantang pig (LT, lard-type) during 8 stages of skeletal muscle developmental, including at 35, 49, 63, 77 dpc (days post coitum) and 2, 28, 90, 180 dpn (days postnatal). As differentially expressed-miRNA expression profiles can be well classified into two clusters by PCA analysis, we grouped the embryonic stages as G1 and the postnatal stages as G2. A total of 203 genes were predicted miRNA targets, and a STEM analysis showed distinct expression patterns between G1 and G2 in both breeds based on their transcriptomic data. Furthermore, a STRING analysis predicted interactions between 22 genes and 35 miRNAs, including some crucial myogenic factors and myofibrillar genes. Thus, it can be reasonably speculated that myogenic miRNAs may regulate myofibrillar genes in myofiber formation during embryonic stages and muscle hypertrophy during postnatal stages, leading to distinct differences in muscle production between breeds.


Assuntos
MicroRNAs/genética , Desenvolvimento Muscular/genética , RNA Mensageiro/genética , Transcriptoma/genética , Animais , Cruzamento , Regulação da Expressão Gênica no Desenvolvimento/genética , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Sus scrofa/genética , Suínos
13.
Eur J Med Chem ; 137: 450-461, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28624700

RESUMO

The worldwide outbreak of severe acute respiratory syndrome (SARS) in 2003 had caused a high rate of mortality. Main protease (Mpro) of SARS-associated coronavirus (SARS-CoV) is an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. During the course of screening new anti-SARS agents, we have identified that a series of unsymmetrical aromatic disulfides inhibited SARS-CoV Mpro significantly for the first time. Herein, 40 novel unsymmetrical aromatic disulfides were synthesized chemically and their biological activities were evaluated in vitro against SARS-CoV Mpro. These novel compounds displayed excellent IC50 data in the range of 0.516-5.954 µM. Preliminary studies indicated that these disulfides are reversible and mpetitive inhibitors. A possible binding mode was generated via molecular docking simulation and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationships. The present research therefore has provided some meaningful guidance to design and identify anti-SARS drugs with totally new chemical structures.


Assuntos
Antivirais/farmacologia , Dissulfetos/farmacologia , Descoberta de Drogas , Hidrocarbonetos Aromáticos/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteases/farmacologia , Relação Quantitativa Estrutura-Atividade , Vírus da SARS/efeitos dos fármacos , Proteínas Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Cisteína Endopeptidases/metabolismo , Dissulfetos/síntese química , Dissulfetos/química , Relação Dose-Resposta a Droga , Hidrocarbonetos Aromáticos/síntese química , Hidrocarbonetos Aromáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Vírus da SARS/enzimologia , Proteínas Virais/metabolismo
14.
Biochem Biophys Res Commun ; 484(3): 592-597, 2017 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-28153733

RESUMO

Myotubularin related protein 7 (MTMR7) is a key member of the highly conserved myotubularin related proteins (MTMRs) family, which has phosphatase activity. MTMR7 was increased during myoblast differentiation and exhibited high expression level at primary fibers formation stages in pigs. This suggests that MTMR7 may be involved in myogenesis. In our study, we investigated the roles of MTMR7 on proliferation and differentiation of C2C12 myoblasts. Knocking down MTMR7 not only enhanced myoblast early differentiation via altering the expression of Myf5, but also promoted myoblast proliferation through increasing cyclinA2 expression. The improved proliferation capacity was related to the increased phosphorylation of AKT. Taken together, our research demonstrates that MTMR7 plays an important role in proliferation and early differentiation of C2C12 myoblast.


Assuntos
Proliferação de Células/fisiologia , Ciclina A2/metabolismo , Desenvolvimento Muscular/fisiologia , Mioblastos/citologia , Mioblastos/fisiologia , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Animais , Diferenciação Celular/fisiologia , Linhagem Celular , Inativação Gênica/fisiologia , Camundongos , Proteínas Tirosina Fosfatases não Receptoras/genética
15.
Sci Rep ; 7: 41608, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-28148961

RESUMO

Differentiation of myoblasts is essential in the development and regeneration of skeletal muscles to form multinucleated, contractile muscle fibers. However, the process of myoblast differentiation in mammals is complicated and requires to be further investigated. In this study, we found Palmdelphin (Palmd), a cytosolic protein, promotes myoblast differentiation. Palmd is predominantly expressed in the cytosol of myoblasts and is gradually up-regulated after differentiation. Knockdown of Palmd by small interfering RNA (siRNA) in C2C12 markedly inhibits myogenic differentiation, suggesting a specific role of Palmd in the morphological changes of myoblast differentiation program. Overexpression of Palmd in C2C12 enhances myogenic differentiation. Remarkably, inhibition of Palmd results in impaired myotube formation during muscle regeneration after injury. These findings reveal a new cytosolic protein that promotes mammalian myoblast differentiation and provide new insights into the molecular regulation of muscle formation.


Assuntos
Diferenciação Celular/genética , Proteínas de Membrana/genética , Desenvolvimento Muscular/genética , Mioblastos/citologia , Mioblastos/metabolismo , Regeneração , Animais , Linhagem Celular , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Imuno-Histoquímica , Proteínas de Membrana/metabolismo , Camundongos , Músculo Esquelético/lesões , Músculo Esquelético/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética
16.
J Cell Sci ; 129(22): 4305-4316, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27672022

RESUMO

Although the mechanism underlying modulation of transcription factors in myogenesis has been well elucidated, the function of the transcription cofactors involved in this process remains poorly understood. Here, we identified HMGB2 as an essential nuclear transcriptional co-regulator in myogenesis. HMGB2 was highly expressed in undifferentiated myoblasts and regenerating muscle. Knockdown of HMGB2 inhibited myoblast proliferation and stimulated its differentiation. HMGB2 depletion downregulated Myf5 and cyclin A2 at the protein but not mRNA level. In contrast, overexpression of HMGB2 promoted Myf5 and cyclin A2 protein upregulation. Furthermore, we found that the RNA-binding protein IGF2BP2 is a downstream target of HMGB2, as previously shown for HMGA2. IGF2BP2 binds to mRNAs of Myf5 or cyclin A2, resulting in translation enhancement or mRNA stabilization, respectively. Notably, overexpression of IGF2BP2 could partially rescue protein levels of Myf5 and cyclin A2, in response to HMGB2 decrease. Moreover, depletion of HMGB2 in vivo severely attenuated muscle repair; this was due to a decrease in satellite cells. Taken together, these results highlight the previously undiscovered and crucial role of the HMGB2-IGF2BP2 axis in myogenesis and muscle regeneration.


Assuntos
Proteína HMGB2/metabolismo , Músculo Esquelético/metabolismo , Proteínas de Ligação a RNA/metabolismo , Regeneração , Células Satélites de Músculo Esquelético/metabolismo , Animais , Animais Recém-Nascidos , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Linhagem Celular , Núcleo Celular/metabolismo , Proliferação de Células , Ciclina A2/genética , Ciclina A2/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Desenvolvimento Muscular , Fator Regulador Miogênico 5/genética , Fator Regulador Miogênico 5/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
17.
Biochim Biophys Acta ; 1859(11): 1459-1469, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27452504

RESUMO

Activating transcription factor 4 (ATF4), which is highly expressed in 3T3-L1 adipocytes after adipogenic induction, is essential for adipocytes differentiation. ATF4 also plays a vital role in regulating fatty acids biosynthesis, whereas the detailed mechanism of this process is still unclear. Here we demonstrated that siRNA-based ATF4 depletion in 3T3-L1 adipocytes significantly reduced the accumulation of fatty acids and triglycerides. Moreover, SREBP1c protein, which is an important transcription factor of lipogenesis, appreciably decreased while Srebp1c mRNA increased. Then we identified that ATF4 could maintain SREBP1c protein stability by directly activating the expression of USP7 which deubiquitinates SREBP1c and increases its protein content in cell. Besides, USP7 could restore the synthesis of fatty acids and triglycerides in the absence of ATF4. On the other hand, we found that ATF4 might inhibit the transcription of Srebp1c through TRB3, which is repressed by IBMX and DEX during early adipogenesis. Thus, our data indicate that ATF4 regulates SREBP1c expression to control fatty acids synthesis.


Assuntos
Fator 4 Ativador da Transcrição/fisiologia , Adipócitos/citologia , Diferenciação Celular , Ácidos Graxos/biossíntese , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Células 3T3-L1 , Animais , Camundongos , Transcrição Genética/fisiologia , Peptidase 7 Específica de Ubiquitina , Proteases Específicas de Ubiquitina/metabolismo
18.
BMC Genomics ; 17: 137, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-26911206

RESUMO

BACKGROUND: Pig (Sus scrofa) is a major source of dietary proteins for human consumption and is becoming a valuable model in agricultural and biomedical research. The recently developed isobaric tag for relative and absolute quantitation (iTRAQ) method allows sensitive and accurate protein quantification. Here, we performed the first iTRAQ-based quantitative proteomic analyses of Landrace (LR) and Wuzhishan (WZS) pig longissimus dorsi muscle tissues during early embryonic development. RESULTS: The iTRAQ-based early embryonic longissimus dorsi muscle study of LR and WZS ranging from 21 to 42 days post coitus (dpc) identified a total of 4431 proteins from 17,214 peptides, which were matched with 36,4025 spectra at a false discovery rate of 5%. In both WZS and LR, the largest amount of differentially expressed proteins (DEPs) were found between 28 and 35 dpc. 252 breed-DEPs were selected by GO analysis, including 8 myofibrillar proteins. Only MYHCI/IIA mRNA were detected due to early embryonic stages, and significantly higher expression of them were found in WZS during these 4 stages. MYHCI was first found in WZS at 28 dpc and expressed in both breeds at later stages, while MYHCII protein was not detected until 35 dpc in both breeds. Thus, 33 myogenic breed-DEPs selected from last two stages were analyzed by STRING, which showed that some myofibrillar proteins (MYH1, TPM4, MYH10, etc.) and functional proteins (CSRP2, CASQ2, OTC, etc.), together with candidate myogenic proteins (H3F3A, HDGFRP2, etc.), probably participate in the regulatory network of myofiber formation. CONCLUSION: Our iTRAQ-based early embryonic longissimus dorsi muscle study of LR and WZS provides new data on the in vivo muscle development distinctions during early embryonic development, which contributes to the improved understanding in the regulation mechanism of early myogenesis in agricultural animals.


Assuntos
Desenvolvimento Embrionário , Desenvolvimento Muscular , Fibras Musculares Esqueléticas/fisiologia , Proteômica , Animais , Músculo Esquelético/embriologia , Suínos/embriologia , Porco Miniatura/embriologia
19.
Eur J Med Chem ; 101: 419-30, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26185006

RESUMO

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) have caused an increasing mortality rate, which means that antibiotic resistance is becoming an important health issue. In the course to screen new agents for resistant bacteria, we identified that a series of isatin-ß-thiosemicarbazones (IBTs) could inhibit the growth of MRSA and VRE. This was the first time that the "familiar" IBT compounds exhibited significant anti Gram-positive pathogen activity. Against a clinical isolated MRSA strain, 20 of the 51 synthesized compounds showed minimum inhibitory concentration (MIC) data of 0.78 mg/L and another 12 novel compounds had MICs of 0.39 mg/L. Moreover, these compounds also inhibited Enterococcus faecalis and VRE at similar levels, indicating that IBTs might have different mode of action compared with vancomycin. For these IBTs, comparative field analysis (CoMFA) models were further established to understand the structure-activity relationships in order to design new compounds from steric and electrostatic contributions. This work has suggested that IBTs can be considered as potential lead compounds to discover antibacterial inhibitors to combat drug resistance.


Assuntos
Antibacterianos/farmacologia , Isatina/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Tiossemicarbazonas/farmacologia , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Isatina/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tiossemicarbazonas/química
20.
Int J Biol Sci ; 11(1): 99-108, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25552934

RESUMO

CEP2 (CDC42EP2) is a member of the CDC42 subfamily that belongs to the Rho family. The Rho family plays an important role in a variety of cellular processes including skeletal myogenesis. Here, we find the expression of CEP2 increased significantly during C2C12 myogenesis. Overexpression of CEP2 could attenuate myoblast differentiation, while knockdown of CEP2 by siRNA results in enhancing myogenesis. Furthermore, we demonstrate for the first time that CEP2 attenuates myoblast differentiation via suppression of muscle regulatory factors (MRFs) rather than influencing myoblast proliferation. These results indicate that CEP2 acts as a repressor during myogenesis, which provides new insights into the role of CEP2 in muscle development.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Desenvolvimento Muscular/fisiologia , Mioblastos/fisiologia , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Análise de Variância , Animais , Western Blotting , Imunofluorescência , Camundongos , Mioblastos/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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