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1.
Funct Integr Genomics ; 19(4): 645-658, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30859354

RESUMO

Although many of the genetic loci associated with breast cancer risk have been reported, there is a lack of systematic analysis of regulatory networks composed of different miRNAs and mRNAs on survival analysis in breast cancer. To reconstruct the microRNAs-genes regulatory network in breast cancer, we employed the expression data from The Cancer Genome Atlas (TCGA) related to five essential miRNAs including miR-21, miR-22, miR-210, miR-221, and miR-222, and their associated functional genomics data from the GEO database. Then, we performed an integration analysis to identify the essential target factors and interactions for the next survival analysis in breast cancer. Based on the results of our integrated analysis, we have identified significant common regulatory signatures including differentially expressed genes, enriched pathways, and transcriptional regulation such as interferon regulatory factors (IRFs) and signal transducer and activator of transcription 1 (STAT1). Finally, a reconstructed regulatory network of five miRNAs and 34 target factors was established and then applied to survival analysis in breast cancer. When we used expression data for individual miRNAs, only miR-21 and miR-22 were significantly associated with a survival change. However, we identified 45 significant miRNA-gene pairs that predict overall survival in breast cancer out of 170 one-on-one interactions in our reconstructed network covering all of five miRNAs, and several essential factors such as PSMB9, HLA-C, RARRES3, UBE2L6, and NMI. In our study, we reconstructed regulatory network of five essential microRNAs for survival analysis in breast cancer by integrating miRNA and mRNA expression datasets. These results may provide new insights into regulatory network-based precision medicine for breast cancer.

2.
Medicine (Baltimore) ; 97(28): e11343, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29995770

RESUMO

BACKGROUND: Alzheimer disease (AD) is a common neurodegenerative disorder with distinct pathological features, with aging considered the greatest risk factor. We explored how aging contributes to increased AD risk, and determined concurrent and coordinate changes (including genetic and phenotypic modifications) commonly exhibited in both normal aging and AD. METHODS: Using the Gene Expression Omnibus (GEO) database, we collected 1 healthy aging-related and 3 AD-related datasets of the hippocampal region. The normal aging dataset was divided into 3 age groups: young (20-40 years old), middle-aged (40-60 years old), and elderly (>60 years old). These datasets were used to analyze the differentially expressed genes (DEGs). The Gene Ontology (GO) terms, pathways, and function network analysis of these DEGs were analyzed. RESULTS: One thousand two hundred ninety-one DEGs were found to be shared in the natural aging groups and AD patients. Among the shared DEGs, ATP6V1E1, GNG3, NDUFV2, GOT1, USP14, and NAV2 have been previously found in both normal aging individuals and AD patients. Furthermore, using Java Enrichment of Pathways Extended to Topology (JEPETTO) analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we determined that changes in aging-related KEGG annotations may contribute to the aging-dependence of AD risk. Interestingly, NRXN3, the second most commonly deregulated gene identified in the present study, is known to carry a mutation in AD patients. According to functional network analysis, NRXN3 plays a critical role in synaptic functions involved in the cognitive decline associated with normal aging and AD. CONCLUSION: Our results indicate that the low expression of aging-related NRXN3 may increase AD risk, though the potential mechanism requires further clarification.


Assuntos
Envelhecimento/genética , Doença de Alzheimer/genética , Proteínas do Tecido Nervoso/genética , Adulto , Idoso , Doença de Alzheimer/metabolismo , Regulação para Baixo , Expressão Gênica , Humanos , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto Jovem
3.
PeerJ ; 6: e4756, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29770277

RESUMO

Background: Alzheimer' disease (AD) is an ultimately fatal degenerative brain disorder that has an increasingly large burden on health and social care systems. There are only five drugs for AD on the market, and no new effective medicines have been discovered for many years. Chinese medicinal plants have been used to treat diseases for thousands of years, and screening herbal remedies is a way to develop new drugs. Methods: We used molecular docking to screen 30,438 compounds from Traditional Chinese Medicine (TCM) against a comprehensive list of AD target proteins. TCM compounds in the top 0.5% of binding affinity scores for each target protein were selected as our research objects. Structural similarities between existing drugs from DrugBank database and selected TCM compounds as well as the druggability of our candidate compounds were studied. Finally, we searched the CNKI database to obtain studies on anti-AD Chinese plants from 2007 to 2017, and only clinical studies were included. Results: A total of 1,476 compounds (top 0.5%) were selected as drug candidates. Most of these compounds are abundantly found in plants used for treating AD in China, especially the plants from two genera Panax and Morus. We classified the compounds by single target and multiple targets and analyzed the interactions between target proteins and compounds. Analysis of structural similarity revealed that 17 candidate anti-AD compounds were structurally identical to 14 existing approved drugs. Most of them have been reported to have a positive effect in AD. After filtering for compound druggability, we identified 11 anti-AD compounds with favorable properties, seven of which are found in anti-AD Chinese plants. Of 11 anti-AD compounds, four compounds 5,862, 5,863, 5,868, 5,869 have anti-inflammatory activity. The compound 28,814 mainly has immunoregulatory activity. The other six compounds have not yet been reported for any biology activity at present. Discussion: Natural compounds from TCM provide a broad prospect for the screening of anti-AD drugs. In this work, we established networks to systematically study the connections among natural compounds, approved drugs, TCM plants and AD target proteins with the goal of identifying promising drug candidates. We hope that our study will facilitate in-depth research for the treatment of AD in Chinese medicine.

4.
Oncol Lett ; 15(2): 2316-2322, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29434939

RESUMO

The lack of early diagnostic markers and novel therapeutic targets for clear cell renal cell carcinoma (ccRCC) negatively affects patient prognosis. Cancer metabolism is an attractive area for the understanding of the molecular mechanism of carcinogenesis. The present study attempted to identify metabolic changes from the view of the expression of metabolism-associated genes between control samples and those of ccRCC at different disease stages. Data concerning ccRCC gene expression obtained by RNA-sequencing was obtained from The Cancer Genome Atlas and data on metabolism-associated genes were extracted using the Recon2 model. Following analysis of differential gene expression, multiple differentially expressed metabolic genes at each tumor-node-metastasis disease stage were identified, compared with control non-disease samples: Metabolic genes (305) were differentially expressed in stage I disease, 323 in stage II disease, 355 in stage III disease and 363 in stage IV disease. Following enrichment analysis for differential metabolic genes, 22 metabolic pathways were identified to be dysregulated in multiple stages of ccRCC. Abnormalities in hormone, vitamin, glucose and lipid metabolism were present in the early stages of the disease, with dysregulation to reactive oxygen species detoxification and amino acid metabolism pathways occurring with advanced disease stages, particularly to valine, leucine, and isoleucine metabolism, which was substantially dysregulated in stage IV disease. The xenobiotic metabolism pathway, associated with multiple cytochrome P450 family genes, was dysregulated in each stage of the disease. This pathway is worthy of substantial attention since it may aid understanding of drug resistance in ccRCC. The results of the present study offer information to aid further research into early diagnostic biomarkers and therapeutic targets of ccRCC.

5.
Nat Commun ; 8(1): 2190, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29259187

RESUMO

Encoding specificity theory predicts most effective recall by the original conditions at encoding, while generalization endows recall flexibly under circumstances which deviate from the originals. The CA1 regions have been implicated in memory and generalization but whether and which locally separated mechanisms are involved is not clear. We report here that fear memory is quickly formed, but generalization develops gradually over 24 h. Generalization but not fear memory is impaired by inhibiting ipsilateral (ips) or contralateral (con) CA1, and by optogenetic silencing of the ipsCA1 projections onto conCA1. By contrast, in vivo fEPSP recordings reveal that ipsCA1-conCA1 synaptic efficacy is increased with delay over 24 h when generalization is formed but it is unchanged if generalization is disrupted. Direct excitation of ipsCA1-conCA1 synapses using chemogenetic hM3Dq facilitates generalization formation. Thus, rapid generalization is an active process dependent on bilateral CA1 regions, and encoded by gradual synaptic learning in ipsCA1-conCA1 circuit.


Assuntos
Região CA1 Hipocampal/fisiologia , Condicionamento (Psicologia)/fisiologia , Medo/psicologia , Generalização (Psicologia)/fisiologia , Memória/fisiologia , Animais , Potenciação de Longa Duração/fisiologia , Masculino , Rememoração Mental/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Vias Neurais/fisiologia , Optogenética , Ratos , Ratos Sprague-Dawley , Sinapses/fisiologia
6.
Clin Lab ; 63(3): 523-533, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28271696

RESUMO

BACKGROUND: Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases (CVDs). We aimed to investigate the joint effect of homocysteine metabolism gene polymorphisms, as well as the folate deficiency on the risk of HHcy in a Chinese hypertensive population. METHODS: This study enrolled 480 hypertensive patients aged 28 - 75 from six hospitals in different Chinese regions from 9/2005 - 12/2005. Known genotypes of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G were detected by PCRRFLP methods. Serum Hcy was measured by high-performance liquid chromatography and serum folate was measured by chemiluminescent immunoassay. RESULTS: MTHFR C677T and MTR A2756G can independently elevate the risk of HHcy (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA, p = 0.026, respectively), whereas MTHFR A1298C decreased HHcy risk (AC + CC vs. AA, p < 0.001) and showed a protective effect against HHcy risk. Importantly, the joint effect of these risk genotypes showed significantly higher odds of HHcy than non-risk genotypes, especially the patients with four risk genotypes. It is noteworthy that this deleterious effect was aggravated by folate deficiency. These findings were verified by generalized multifactor dimensionality reduction model (p = 0.001) and a cumulative effects model (p < 0.001). CONCLUSIONS: We have first demonstrated that the joint effect of homocysteine metabolism gene polymorphisms and folate deficiency lead to dramatic elevations in the HHcy risk.


Assuntos
Hiper-Homocisteinemia , Polimorfismo Genético , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase , Adulto , Idoso , Ferredoxina-NADP Redutase , Ácido Fólico , Genótipo , Homocisteína , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2) , Pessoa de Meia-Idade , Fatores de Risco
7.
J Alzheimers Dis ; 56(4): 1525-1539, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28222515

RESUMO

Many lines of evidence suggest that Parkinson's disease (PD) and Alzheimer's disease (AD) have common characteristics, such as mitochondrial dysfunction and oxidative stress. As the underlying molecular mechanisms are unclear, we perform a meta-analysis with 9 microarray datasets of PD studies and 7 of AD studies to explore it. Functional enrichment analysis revealed that PD and AD both showed dysfunction in the synaptic vesicle cycle, GABAergic synapses, phagosomes, oxidative phosphorylation, and TCA cycle pathways, and AD had more enriched genes. Comparing the differentially expressed genes between AD and PD, we identified 54 common genes shared by more than six tissues. Among them, 31 downregulated genes contained the antioxidant response element (ARE) consensus sequence bound by NRF2. NRF2 is a transcription factor, which protects cells against oxidative stress through coordinated upregulation of ARE-driven genes. To our surprise, although NRF2 was upregulated, its target genes were all downregulated. Further exploration found that MAFF was upregulated in all tissues and significantly negatively correlated with the 31 NRF2-dependent genes in diseased conditions. Previous studies have demonstrated over-expressed small MAFs can form homodimers and act as transcriptional repressors. Therefore, MAFF might play an important role in dysfunction of NRF2 regulatory network in PD and AD.


Assuntos
Doença de Alzheimer/genética , Fator 2 Relacionado a NF-E2/genética , Doença de Parkinson/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Humanos , Fator de Transcrição MafF/genética , Fator de Transcrição MafF/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Doença de Parkinson/metabolismo , Transdução de Sinais
8.
Sci Rep ; 7: 41406, 2017 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-28117389

RESUMO

Stroke is a worldwide epidemic disease with high morbidity and mortality. The continuously exploration of anti-stroke medicines and molecular mechanism has a long way to go. In this study, in order to screen candidate anti-stroke compounds, more than 60000 compounds from traditional Chinese medicine (TCM) database were computationally analyzed then docked to the 15 known anti-stroke targets. 192 anti-stroke plants for clinical therapy and 51 current anti-stroke drugs were used to validate docking results. Totally 2355 candidate anti-stroke compounds were obtained. Among these compounds, 19 compounds are structurally identical with 16 existing drugs in which part of them have been used for anti-stroke treatment. Furthermore, these candidate compounds were significantly enriched in anti-stroke plants. Based on the above results, the compound-target-plant network was constructed. The network reveals the potential molecular mechanism of anti-stroke for these compounds. Most of candidate compounds and anti-stroke plants are tended to interact with target NOS3, PSD-95 and PDE5A. Finally, using ADMET filter, we identified 35 anti-stroke compounds with favorable properties. The 35 candidate anti-stroke compounds offer an opportunity to develop new anti-stroke drugs and will improve the research on molecular mechanism of anti-stroke.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Acidente Vascular Cerebral/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Humanos , Simulação de Acoplamento Molecular , Fitoterapia
9.
Oncotarget ; 8(4): 6775-6786, 2017 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-28036274

RESUMO

Breast cancer is the most commonly diagnosed malignancy in women. Several key genes and pathways have been proven to correlate with breast cancer pathology. This study sought to explore the differences in key transcription factors (TFs), transcriptional regulation networks and dysregulated pathways in different tissues in breast cancer. We employed 14 breast cancer datasets from NCBI-GEO and performed an integrated analysis in three different tissues including breast, blood and saliva. The results showed that there were eight genes (CEBPD, EGR1, EGR2, EGR3, FOS, FOSB, ID1 and NFIL3) down-regulated in breast tissue but up-regulated in blood tissue. Furthermore, we identified several unreported tissue-specific TFs that may contribute to breast cancer, including ATOH8, DMRT2, TBX15 and ZNF367. The dysregulation of these TFs damaged lipid metabolism, development, cell adhesion, proliferation, differentiation and metastasis processes. Among these pathways, the breast tissue showed the most serious impairment and the blood tissue showed a relatively moderate damage, whereas the saliva tissue was almost unaffected. This study could be helpful for future biomarker discovery, drug design, and therapeutic and predictive applications in breast cancers.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Biologia Computacional/métodos , Mineração de Dados/métodos , Perfilação da Expressão Gênica/métodos , Fatores de Transcrição/genética , Transcriptoma , Algoritmos , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Predisposição Genética para Doença , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Saliva/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição/sangue
10.
J Nutr Sci Vitaminol (Tokyo) ; 62(4): 265-271, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27725412

RESUMO

Alanine aminotransferase (ALT), aspartate transaminase (AST), and glutamyl transpeptidase (GGT) were three key enzymes in the hepatic metabolism. This study aimed to investigate the effect of homocysteine (Hcy) metabolism gene polymorphisms and serum Hcy and folate level on the hepatic functions in a Chinese hypertensive population. A representative sample with 480 subjects aged 28-75 was enrolled in 2005.9-2005.12 from six hospitals in different Chinese regions. Serum ALT, AST and GGT were measured by using an automatic biochemistry analyzer. Serum Hcy was measured by high-performance liquid chromatography, and serum folate was measured by chemiluminescent immunoassay. Known genotypes were detected by PCR-RFLP methods. The results showed that the MTHFR C677T mutation was related a decreased serum AST level (r=-0.11, p=0.026), whereas the MTHFR A1298C mutation elevated serum AST level (r=0.11, p=0.032). Furthermore, multiple regression analysis showed that folate deficiency was associated with higher serum ALT (ß (SE): 0.13 (0.06), p=0.031) and GGT level (ß (SE): 0.18 (0.07), p=0.011). However, serum Hcy level may not affect the hepatic functions. Our data suggested that hepatic functions were affected by MTHFR gene polymorphisms and serum folate level. Further studies are needed to confirm these correlations in a larger population.


Assuntos
Alanina Transaminase/sangue , Grupo com Ancestrais do Continente Asiático/genética , Deficiência de Ácido Fólico/sangue , Hipertensão/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , gama-Glutamiltransferase/sangue , Adulto , Idoso , Aspartato Aminotransferases/sangue , China , Estudos Transversais , Feminino , Ácido Fólico/sangue , Genótipo , Homocisteína/sangue , Humanos , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
12.
PeerJ ; 4: e2470, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27672514

RESUMO

Ischemic stroke is a common neurological disorder and the burden in the world is growing. This study aims to explore the effect of sex and age difference on ischemic stroke using integrated microarray datasets. The results showed a dramatic difference in whole gene expression profiles and influenced pathways between males and females, and also in the old and young individuals. Furthermore, compared with old males, old female patients showed more serious biological function damage. However, females showed less affected pathways than males in young subjects. Functional interaction networks showed these differential expression genes were mostly related to immune and inflammation-related functions. In addition, we found ARG1 and MMP9 were up-regulated in total and all subgroups. Importantly, IL1A, ILAB, IL6 and TNF and other anti-stroke target genes were up-regulated in males. However, these anti-stroke target genes showed low expression in females. This study found huge sex and age differences in ischemic stroke especially the opposite expression of anti-stroke target genes. Future studies are needed to uncover these pathological mechanisms, and to take appropriate pre-prevention, treatment and rehabilitation measures.

13.
Mol Inform ; 35(2): 81-91, 2016 02.
Artigo em Inglês | MEDLINE | ID: mdl-27491793

RESUMO

GPCR-based drug discovery is hindered by a lack of effective screening methods for most GPCRs that have neither ligands nor high-quality structures. With the aim to identify lead molecules for these GPCRs, we developed a new method called Pharmacophore-Map-Pick to generate pharmacophore models for all human GPCRs. The model of ADRB2 generated using this method not only predicts the binding mode of ADRB2-ligands correctly but also performs well in virtual screening. Findings also demonstrate that this method is powerful for generating high-quality pharmacophore models. The average enrichment for the pharmacophore models of the 15 targets in different GPCR families reached 15-fold at 0.5 % false-positive rate. Therefore, the pharmacophore models can be applied in virtual screening directly with no requirement for any ligand information or shape constraints. A total of 2386 pharmacophore models for 819 different GPCRs (99 % coverage (819/825)) were generated and are available at http://bsb.kiz.ac.cn/GPCRPMD.


Assuntos
Descoberta de Drogas , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Conformação Proteica
14.
PLoS One ; 11(5): e0155140, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27152421

RESUMO

Dekkera yeasts have often been considered as alternative sources of ethanol production that could compete with S. cerevisiae. The two lineages of yeasts independently evolved traits that include high glucose and ethanol tolerance, aerobic fermentation, and a rapid ethanol fermentation rate. The Saccharomyces yeasts attained these traits mainly through whole genome duplication approximately 100 million years ago (Mya). However, the Dekkera yeasts, which were separated from S. cerevisiae approximately 200 Mya, did not undergo whole genome duplication (WGD) but still occupy a niche similar to S. cerevisiae. Upon analysis of two Dekkera yeasts and five closely related non-WGD yeasts, we found that a massive loss of cis-regulatory elements occurred in an ancestor of the Dekkera yeasts, which led to improved mitochondrial functions similar to the S. cerevisiae yeasts. The evolutionary analysis indicated that genes involved in the transcription and translation process exhibited faster evolution in the Dekkera yeasts. We detected 90 positively selected genes, suggesting that the Dekkera yeasts evolved an efficient translation system to facilitate adaptive evolution. Moreover, we identified that 12 vacuolar H+-ATPase (V-ATPase) function genes that were under positive selection, which assists in developing tolerance to high alcohol and high sugar stress. We also revealed that the enzyme PGK1 is responsible for the increased rate of glycolysis in the Dekkera yeasts. These results provide important insights to understand the independent adaptive evolution of the Dekkera yeasts and provide tools for genetic modification promoting industrial usage.


Assuntos
Evolução Biológica , Genoma Fúngico , Leveduras/genética , Sequência de Aminoácidos , Proteínas Fúngicas/química , Seleção Genética , Homologia de Sequência de Aminoácidos
15.
Sci Rep ; 6: 25462, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-27145869

RESUMO

There is a constant demand to develop new, effective, and affordable anti-cancer drugs. The traditional Chinese medicine (TCM) is a valuable and alternative resource for identifying novel anti-cancer agents. In this study, we aim to identify the anti-cancer compounds and plants from the TCM database by using cheminformatics. We first predicted 5278 anti-cancer compounds from TCM database. The top 346 compounds were highly potent active in the 60 cell lines test. Similarity analysis revealed that 75% of the 5278 compounds are highly similar to the approved anti-cancer drugs. Based on the predicted anti-cancer compounds, we identified 57 anti-cancer plants by activity enrichment. The identified plants are widely distributed in 46 genera and 28 families, which broadens the scope of the anti-cancer drug screening. Finally, we constructed a network of predicted anti-cancer plants and approved drugs based on the above results. The network highlighted the supportive role of the predicted plant in the development of anti-cancer drug and suggested different molecular anti-cancer mechanisms of the plants. Our study suggests that the predicted compounds and plants from TCM database offer an attractive starting point and a broader scope to mine for potential anti-cancer agents.


Assuntos
Antineoplásicos Fitogênicos/química , Mineração de Dados/estatística & dados numéricos , Bases de Dados Factuais , Medicamentos de Ervas Chinesas/química , Plantas Medicinais/química , Antineoplásicos Fitogênicos/classificação , Simulação por Computador , Medicamentos de Ervas Chinesas/classificação , Humanos , Medicina Tradicional Chinesa , Neoplasias/tratamento farmacológico , Plantas Medicinais/classificação , Relação Estrutura-Atividade
16.
PeerJ ; 4: e1791, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26989626

RESUMO

Besides its anti-inflammatory, analgesic and anti-pyretic properties, aspirin is used for the prevention of cardiovascular disease and various types of cancer. The multiple activities of aspirin likely involve several molecular targets and pathways rather than a single target. Therefore, systematic identification of these targets of aspirin can help us understand the underlying mechanisms of the activities. In this study, we identified 23 putative targets of aspirin in the human proteome by using binding pocket similarity detecting tool combination with molecular docking, free energy calculation and pathway analysis. These targets have diverse folds and are derived from different protein family. However, they have similar aspirin-binding pockets. The binding free energy with aspirin for newly identified targets is comparable to that for the primary targets. Pathway analysis revealed that the targets were enriched in several pathways such as vascular endothelial growth factor (VEGF) signaling, Fc epsilon RI signaling and arachidonic acid metabolism, which are strongly involved in inflammation, cardiovascular disease and cancer. Therefore, the predicted target profile of aspirin suggests a new explanation for the disease prevention ability of aspirin. Our findings provide a new insight of aspirin and its efficacy of disease prevention in a systematic and global view.

17.
J Alzheimers Dis ; 51(2): 417-25, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26890750

RESUMO

Alzheimer's disease (AD) and schizophrenia (SZ) are both accompanied by impaired learning and memory functions. This study aims to explore the expression profiles of learning or memory genes between AD and SZ. We downloaded 10 AD and 10 SZ datasets from GEO-NCBI for integrated analysis. These datasets were processed using RMA algorithm and a global renormalization for all studies. Then Empirical Bayes algorithm was used to find the differentially expressed genes between patients and controls. The results showed that most of the differentially expressed genes were related to AD whereas the gene expression profile was little affected in the SZ. Furthermore, in the aspects of the number of differentially expressed genes, the fold change and the brain region, there was a great difference in the expression of learning or memory related genes between AD and SZ. In AD, the CALB1, GABRA5, and TAC1 were significantly downregulated in whole brain, frontal lobe, temporal lobe, and hippocampus. However, in SZ, only two genes CRHBP and CX3CR1 were downregulated in hippocampus, and other brain regions were not affected. The effect of these genes on learning or memory impairment has been widely studied. It was suggested that these genes may play a crucial role in AD or SZ pathogenesis. The different gene expression patterns between AD and SZ on learning and memory functions in different brain regions revealed in our study may help to understand the different mechanism between two diseases.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Aprendizagem/fisiologia , Memória/fisiologia , Esquizofrenia/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Teorema de Bayes , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Humanos , Análise em Microsséries , Pessoa de Meia-Idade , Esquizofrenia/genética , Psicologia do Esquizofrênico , Adulto Jovem
19.
Sci Rep ; 5: 15578, 2015 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-26493375

RESUMO

Light is recently recognized as a modulator able to activate the hippocampus and modulate memory processing, but little is known about the molecular mechanisms. Here, we report that in mice, a short pulse of white light before learning dramatically improves consolidation of contextual fear memory during the night. The light exposure increases hippocampal active p21-activated kinase 1 (PAK1) and CA1 long-term potentiation (LTP). These light effects are abolished in PAK1 knockout and dominant-negative transgenic mice, but preserved by expression of constitutively active PAK1 in the hippocampus. Our results indicate that light can act as a switch of PAK1 activity that modulate CA1 LTP and thereby memory consolidation without affecting learning and short-term memory.


Assuntos
Luz , Memória , Animais , Hipocampo/enzimologia , Hipocampo/fisiologia , Hipocampo/efeitos da radiação , Potenciação de Longa Duração , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo
20.
Lipids Health Dis ; 14: 101, 2015 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-26337056

RESUMO

BACKGROUND: Dyslipidemia is a well-established risk factor for cardiovascular disease. Serum lipids were affected by several gene polymorphisms, folate, homocysteine and other metabolite levels. We aim to investigate the effects of homocysteine metabolism enzyme polymorphisms (MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) and their interactions with folate, homocysteine on serum lipid levels in Chinese patients with hypertension. METHODS: Participants were 480 hypertensive adults that enrolled in September to December 2005 from six different Chinese hospitals (Harbin, Shanghai, Shenyang, Beijing, Xi'an, and Nanjing). Known MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G genotypes were determined by PCR-RFLP methods. Serum folate was measured by chemiluminescent immunoassay, homocysteine was measured by high-performance liquid chromatography, serum lipids parameters were determined by an automatic biochemistry analyzer, low-density lipoprotein was calculated by Friedewald's equation. Unitary linear regression model was used to assess the associations of gene polymorphisms, folate and homocysteine on serum lipid profiles. Unconditional logistic regression model was applied to test the interactions of folate, homocysteine and gene polymorphisms on dyslipidemia. RESULTS: No correlations between gene polymorphisms and homocysteine on serum lipid profiles. Compared with normal folate patients, patients with low folate showed higher odds of hypertriglyceridemia (OR = 2.02, 95 % CI: 1.25-3.25, P = 0.004) and low levels of high-density lipoprotein cholesterol (OR = 1.88, 95 % CI: 1.07-3.28, P = 0.027). Each of four gene polymorphisms (MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) combined with low folate showed higher odds of hypertriglyceridemia (P for trend: 0.049, 0.004, 0.007 and 0.005, respectively). MTHFR C677T and A1298C with low folate showed higher odds of low levels of high-density lipoprotein cholesterol (P for trend: 0.008 and 0.031). CONCLUSIONS: Low folate status and homocysteine metabolism gene polymorphisms (MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) may have a synergistic effect increased the incidence of dyslipidemia in Chinese hypertensive population.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Dislipidemias/genética , Ferredoxina-NADP Redutase/genética , Ácido Fólico/sangue , Homocisteína/sangue , Hipertensão/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/sangue , Idoso , China , Estudos Transversais , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/patologia , Feminino , Ferredoxina-NADP Redutase/sangue , Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Hipertensão/sangue , Hipertensão/complicações , Hipertensão/patologia , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Modelos Logísticos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/sangue , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue
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