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1.
Neurotox Res ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31721051

RESUMO

The cuprizone (CPZ)-induced demyelination is a relatively reproducible animal model and has been extremely useful for identifying the specific cellular and molecular signals that regulate oligodendrocyte survival and efficiency of oligodendrogenesis and remyelination. Here, we reported the temporal and spatial dynamics of astroglial reaction and immune response in CPZ-induced demyelinating model. CPZ did not induce significant microglia and astrocyte reaction after 2 weeks of feeding. After 4-6 weeks of CPZ feeding, microglia and astrocytes were markedly migrated and accumulated in myelin sheath. Simultaneously, the expression of tight junction protein ZO-1 was declined and the infiltration of CD4+IFNγ+ and CD4+IL-17+ T cells was increased in the brain, accompanied by increased production of IFN-γ and IL-17 in the extract of brain. However, the levels of IFN-γ and IL-17 were reduced, while IL-6 and TNF-α were elevated in the supernatant of splenocytes. At the 4th and 6th weeks of feeding, CPZ caused astrocyte activation and upregulated the expression of BDNF, CNTF, and IGF-II, providing a neurotrophic microenvironment in the brain. At this stage, NG2+ and PDGF-Rα+ oligodendroglia progenitor cells were enhanced in the corpus callosum, but the myelin sheath is still severely lost. Therefore, targeting microglia to improve the inflammatory microenvironment should contribute to the remyelination.

2.
Plant J ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31642116

RESUMO

Development of salt-tolerant genotypes is pivotal for the effective utilization of salinized land and to increase global crop productivity. Several cotton species comprise the most important source of textile fibers globally, and these are increasingly grown on marginal or increasingly saline agroecosystems. The allopolyploid cotton species also provide a model system for polyploid research, of relevance here because polyploidy was suggested to be associated with increased adaptation to stress. To evaluate genetic variation of salt tolerance among cotton species, 17 diverse accessions of allopolyploid (AD-genome) and diploid (A-, D-genome) Gossypium were evaluated for a total of 29 morphological and physiological traits associated with salt tolerance. For most morphological and physiological traits, cotton accessions showed highly variable responses to two weeks of exposure to moderate (50 mM NaCl) and high (100 mM NaCl) hydroponic salinity treatments. Results showed that the most salt tolerant species were the NE Brazilian allopolyploid G. mustelinum, the D-genome diploid G. klotzschianum from the Galapagos Islands, following by the African/Asian, A-genome diploids. Generally, A-genome accessions outperformed D-genome cottons under salinity conditions. Allopolyploid accessions did not show significant differences from either diploid genomic group in salt tolerance, but they were more similar to one of the two progenitor lineages. Our findings demonstrate that allopolyploidy per se need not be associated with increased salinity stress tolerance, and provide information relevant to utilization of the secondary Gossypium gene pool for breeding improved salt tolerance.

3.
Folia Neuropathol ; 57(2): 170-181, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556576

RESUMO

Astragaloside IV (AST-IV) is a major active ingredient of astragalus, with a neuroprotective effect. The current study is aimed to investigate the impact of AST-IV on the M1/M2 microglial activation in response to lipopolysaccharide (LPS) stimulation, how AST-IV attenuated microglia-mediated neuronal damage, and the molecular mechanisms underlying AST-IV's protection of neurons against microglia-mediated neuronal damage. Our results showed that AST-IV partially protected microglia from death evoked by LPS and downregulated the release of pro-inflammatory (M1) mediators including interleukin (IL)-1ß, IL-6, tumour necrosis factor α (TNF-α) and nitric oxide, as well as the expression of Toll-like receptors 4 (TLR4), MyD88, and nuclear factor κB (NF-κB) of these cells. In contrast, AST-IV elevated the production of anti-inflammatory cytokine IL-10 and expression of arginase 1, an M2 marker of microglia, whose conditioned medium promoted PC12 neurons survival. These results indicate that AST-IV exerts an anti-inflammatory effect on microglia, possibly through inhibiting TLR4/NF-κB signalling pathways, and protects neurons from microglia-mediated cell death through conversion of microglia from inflammatory M1 to an anti-inflammatory M2 phenotype.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31425046

RESUMO

In recent years, lncRNAs (long non-coding RNAs) have been proved to be closely related to many diseases that are seriously harmful to human health. Although researches on clarifying the relationships between lncRNAs and diseases are developing rapidly, associations between the lncRNAs and diseases are still remaining largely unknown. In this manuscript, a novel Local Random Walk based prediction model called LRWHLDA is proposed for inferring potential associations between human lncRNAs and diseases. In LRWHLDA, a new heterogeneous network is established first, which allows that LRWHLDA can be implemented in the case of lacking known lncRNA-disease associations. And then,an improved local random walk method is designed for prediction of novel lncRNA-disease associations, which can help LRWHLDA achieve high prediction accuracy but with low time complexity. Finally, in order to evaluate the prediction performance of LRWHLDA, different frameworks such as LOOCV, 2-fold CV and 5-fold CV have been implemented, simulation results indicate that LRWHLDA can achieve reliable AUCs of 0.8061, 0.8357, and 0.8556 under the frameworks of 2-fold CV, 5-fold CV and LOOCV respectively. Hence, it is easy to know that LRWHLDA contains the potential to be a representative of emerging methods in the field of research on potential lncRNA-disease association prediction.

5.
Adv Healthc Mater ; 8(17): e1900378, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31290279

RESUMO

Photoacoustic imaging (PAI) has evolved to a stage that high-performance exogeneous contrast agents are urgently needed for imminent biomedical and clinical applications. Given that a material meets the basic criteria of efficient photoacoustic conversion, high biocompatibility, and fast excretion, great effort has been devoted to evaluating various materials for developing advantageous contrast agents to explore the full potentials of PAI. One focus is through modification of the current agents to boost their PA performance; whilst the other focus is to develop novel agents. Antimonene (AM) has emerged as a promising candidate for next generation of electronics among 2D materials due to its outstanding properties. Herein, it is reported that liquid-phase exfoliated antimonene exhibits extraordinary photoacoustic performance, which is not only more advantageous than other 2D materials, such as black phosphorus, graphene oxide, and transition metal dichalcogenides, but also superior to the commonly used PA contrast agents, such as ICG and gold nanorods. An insight analysis reveals that the unique thermal property of AM, including intrinsic low thermal conductivity and the morphology-related high interfacial thermal conductivity, might interpret the high photothermal conversion efficiency, and thus the excellent photoacoustic performance. The prodigious performance allows sensitive monitoring of intracellular events and high-quality in vivo tumor imaging.

6.
BMC Bioinformatics ; 20(1): 396, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31315558

RESUMO

BACKGROUND: Since the number of known lncRNA-disease associations verified by biological experiments is quite limited, it has been a challenging task to uncover human disease-related lncRNAs in recent years. Moreover, considering the fact that biological experiments are very expensive and time-consuming, it is important to develop efficient computational models to discover potential lncRNA-disease associations. RESULTS: In this manuscript, a novel Collaborative Filtering model called CFNBC for inferring potential lncRNA-disease associations is proposed based on Naïve Bayesian Classifier. In CFNBC, an original lncRNA-miRNA-disease tripartite network is constructed first by integrating known miRNA-lncRNA associations, miRNA-disease associations and lncRNA-disease associations, and then, an updated lncRNA-miRNA-disease tripartite network is further constructed through applying the item-based collaborative filtering algorithm on the original tripartite network. Finally, based on the updated tripartite network, a novel approach based on the Naïve Bayesian Classifier is proposed to predict potential associations between lncRNAs and diseases. The novelty of CFNBC lies in the construction of the updated lncRNA-miRNA-disease tripartite network and the introduction of the item-based collaborative filtering algorithm and Naïve Bayesian Classifier, which guarantee that CFNBC can be applied to predict potential lncRNA-disease associations efficiently without entirely relying on known miRNA-disease associations. Simulation results show that CFNBC can achieve a reliable AUC of 0.8576 in the Leave-One-Out Cross Validation (LOOCV), which is considerably better than previous state-of-the-art results. Moreover, case studies of glioma, colorectal cancer and gastric cancer demonstrate the excellent prediction performance of CFNBC as well. CONCLUSIONS: According to simulation results, due to the satisfactory prediction performance, CFNBC may be an excellent addition to biomedical researches in the future.


Assuntos
Doença/genética , RNA Longo não Codificante/metabolismo , Algoritmos , Teorema de Bayes , Neoplasias Colorretais/genética , Simulação por Computador , Glioma/genética , Humanos , MicroRNAs/metabolismo , Neoplasias Gástricas/genética
7.
Plant J ; 100(4): 784-800, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31349367

RESUMO

Plants endure challenging environments in which they are constantly threatened by diverse pathogens. The soil-borne fungus Verticillium dahliae is a devastating pathogen affecting many plant species including cotton, in which it significantly reduces crop yield and fiber quality. Melatonin involvement in plant immunity to pathogens has been reported, but the mechanisms of melatonin-induced plant resistance are unclear. In this study, the role of melatonin in enhancing cotton resistance to V. dahliae was investigated. At the transcriptome level, exogenous melatonin increased the expression of genes in phenylpropanoid, mevalonate (MVA), and gossypol pathways after V. dahliae inoculation. As a result, lignin and gossypol, the products of these metabolic pathways, significantly increased. Silencing the serotonin N-acetyltransferase 1 (GhSNAT1) and caffeic acid O-methyltransferase (GhCOMT) melatonin biosynthesis genes compromised cotton resistance, with reduced lignin and gossypol levels after V. dahliae inoculation. Exogenous melatonin pre-treatment prior to V. dahliae inoculation restored the level of cotton resistance reduced by the above gene silencing effects. Melatonin levels were higher in resistant cotton cultivars than in susceptible cultivars after V. dahliae inoculation. The findings indicate that melatonin affects lignin and gossypol synthesis genes in phenylpropanoid, MVA, and gossypol pathways, thereby enhancing cotton resistance to V. dahliae.

8.
Ocul Surf ; 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31201956

RESUMO

PURPOSE: To investigate the pathological changes of the meibomian gland (MG) and ocular surface in Apolipoprotein E knockout (ApoE-/-) mice and to investigate the association of meibomian gland dysfunction (MGD) with hyperlipidemia. METHODS: Total plasma cholesterol was measured in different ages of ApoE-/- and wild type (WT) mice, whilst the ocular surfaces were observed by slit-lamp biomicroscopy. MG sections were subjected to H&E staining, Oil Red O staining, TUNEL assay and immunostaining. Quantitate RT-PCR and Western blot analyses were performed to detect the relative gene expression in MGs. The 5-month-old ApoE-/- mice were administered with rosiglitazone or GW9662 + rosiglitazone via oral gavage for 2 months to determine their effect on MG pathological change. RESULTS: We found eyelid abnormality, MG dropout, abnormal MG acinar morphology, dilated MG duct and plugging of the MG orifice in ApoE-/- mice. MG acini in ApoE-/- mice showed exaggerated lipid accumulation. Abnormal keratinization increased in MG duct, accompanied with decreased proliferation and increased apoptosis in ApoE-/- mice. Inflammatory cells infiltrated into the surrounding microenvironment of MG acini, and the NF-κB signaling pathway was activated in MG acinar cells. Oxidative stress was evident in MG acinar cells of ApoE-/- mice. Further investigation showed downregulation of PPAR-γ in MG acinar cells of ApoE-/- mice. PPAR-γ agonist rosiglitazone treatment reduced the morbidity of eyelid, as well as corneal pathological changes and MG inflammation in ApoE-/- mice. CONCLUSION: MGD and hyperlipidemia are closely associated in ApoE-/- mice, which represent a new model to study the pathophysiology of MGD related to dyslipidemia.

9.
Comput Math Methods Med ; 2019: 7614850, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191710

RESUMO

A lot of research studies have shown that many complex human diseases are associated not only with microRNAs (miRNAs) but also with long noncoding RNAs (lncRNAs). However, most of the current existing studies focus on the prediction of disease-related miRNAs or lncRNAs, and to our knowledge, until now, there are few literature studies reported to pay attention to the study of impact of miRNA-lncRNA pairs on diseases, although more and more studies have shown that both lncRNAs and miRNAs play important roles in cell proliferation and differentiation during the recent years. The identification of disease-related genes provides great insight into the underlying pathogenesis of diseases at a system level. In this study, a novel model called PADLMHOOI was proposed to predict potential associations between diseases and lncRNA-miRNA pairs based on the higher-order orthogonal iteration, and in order to evaluate its prediction performance, the global and local LOOCV were implemented, respectively, and simulation results demonstrated that PADLMHOOI could achieve reliable AUCs of 0.9545 and 0.8874 in global and local LOOCV separately. Moreover, case studies further demonstrated the effectiveness of PADLMHOOI to infer unknown disease-related lncRNA-miRNA pairs.

10.
Environ Toxicol ; 34(8): 912-920, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31074208

RESUMO

Drinking water with high levels of iodine has been identified as the key contributor to iodine excess, but the mechanisms of neurotoxicity induced by excessive iodine remain elusive. The present study aimed to explore the role of autophagy in the neurotoxic effect induced by excessive iodine in vivo. The Morris water maze test results demonstrated that excessive iodine impaired the learning and memory capabilities of rats, which were associated with marked body weight and brain weight abnormalities. In addition, iodine treatment increased malondialdehyde accumulation, decreased superoxide dismutase activity and glutathione (GSH) level, and enhanced levels of autophagy markers in the hippocampus. Notably, inhibition of autophagy with 3-methyladenine (3-MA) could significantly alleviate excessive iodine-induced cognitive impairment. These data imply that autophagy is involved in the cognitive impairment elicited by excessive iodine as a pathway of cell death, and inhibition of autophagy via 3-MA may significantly alleviate the above damage.


Assuntos
Adenina/análogos & derivados , Autofagia/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Iodo/toxicidade , Aprendizagem em Labirinto/efeitos dos fármacos , Adenina/farmacologia , Animais , Disfunção Cognitiva/induzido quimicamente , Feminino , Hipocampo/metabolismo , Masculino , Malondialdeído/metabolismo , Ratos
11.
CNS Neurosci Ther ; 25(6): 783-795, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30779332

RESUMO

AIM: Multiple sclerosis (MS) is a relapsing-remitting inflammatory demyelinating disease that requires long-term treatment. Although Rho kinase inhibitor Fasudil shows good therapeutic effect in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, certain side effects may limit its clinical use. This study aimed at observing the therapeutic potential of Fasudil-modified encephalitogenic mononuclear cells (MNCs) via nasal delivery in EAE and exploring possible mechanisms of action. METHODS: Experimental autoimmune encephalomyelitis was induced with myelin oligodendrocyte glycoprotein 35-55 in C57BL/6 mice, and encephalitogenic MNCs were treated with Fasudil in vitro. Mice received 3 × 106  cells/10 µL per nasal cavity on day 3 and 11 postimmunization, respectively. RESULTS: Fasudil-modified MNCs reduced clinical severity of EAE, improved demyelination, and decreased inflammatory cells in spinal cords. Immunohistochemical results indicated that CD4+ T cells and CD68+ macrophages were barely detected in Fasudil-MNCs group. Fasudil-modified MNCs decreased CD4+ IFN-γ+ and CD4+ IL-17+ T cells, increased CD4+ IL-10+ T cells, restrained M1 markers CD16/32, CCR7, IL-12, CD8a, enhanced M2 markers CD206, CD200, CD14 in spleen. Fasudil-modified MNCs inhibited the activation of inflammatory signaling p-NF-kB/P38, accompanied by the decrease of COX-2 and the increase of Arg-1 in spinal cord, as well as the reduction of IL-17, TNF-α, IL-6 and the elevation of IL-10 in cultured supernatant of splenocytes. Fasudil-modified MNCs enhanced the levels of neurotrophic factors BDNF and NT-3 in spinal cord. CONCLUSION: Our results indicate that intranasal delivery of Fasudil-modified MNCs have therapeutic potential in EAE, providing a safe and effective cell therapeutic strategy to MS and/or other related disorders.

12.
Med Sci Monit ; 25: 1204-1213, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30762028

RESUMO

BACKGROUND The POU domain class 5 transcription factor 1B (POU5F1B), is a pseudogene that is homologous to octamer-binding transcription factor 4 (OCT4), and is located adjacent to the MYC gene on human chromosome 8q24. POU5F1B has been reported to be transcribed in several types of cancer, but its role in cervical cancer remains unclear. This study aimed to investigate the expression and function of POU5F1B in tissue samples of human cervical cancer and in cervical cancer cell lines in vitro. MATERIAL AND METHODS Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to quantify POU5F1B expression in cervical cancer tissues and in SiHa, HeLa, CaSki, and C33A human cervical cancer cell lines. Functional in vitro studies included analysis of the effects of POU5F1B expression on cervical cancer cell proliferation, migration, and apoptosis using a Cell Counting Kit-8 (CCK-8) assay, cell migration assays, and flow cytometry. Luciferase activity assays, qRT-PCR, and Western blot were performed to confirm the expression of POU5F1B. RESULTS POU5F1B was significantly upregulated in cervical cancer tissues and cell lines. Interference with the expression of POU5F1B significantly inhibited cell proliferation, apoptosis, migration and invasion, and induced apoptosis in vitro. Western blot demonstrated that POU5F1B could modulate the expression of the OCT4 protein. CONCLUSIONS POU5F1B was upregulated in cervical cancer and down-regulation inhibited cell proliferation and migration and induced apoptosis in cervical cancer cell lines by modulating OCT4. Further studies are required to determine whether POU5F1B might be a diagnostic or prognostic biomarker or therapeutic target in cervical cancer.


Assuntos
Proteínas de Homeodomínio/genética , Fator 3 de Transcrição de Octâmero/genética , Neoplasias do Colo do Útero/genética , Adulto , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular , Técnicas de Silenciamento de Genes , Genes myc , Células HeLa , Xenoenxertos , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator 3 de Transcrição de Octâmero/biossíntese , Fator 3 de Transcrição de Octâmero/metabolismo , Pseudogenes , Regulação para Cima , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
13.
Brain Behav Immun ; 80: 73-87, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30807841

RESUMO

NADPH oxidase (NOX2) is an enzyme that induces reactive oxygen species (ROS) and serves as a switch between the pro-inflammatory and neurorestorative microglial/macrophage phenotypes; such changes play an important role in neuropathic pain and motor dysfunction. Increased NOX2 expression after spinal cord injury (SCI) has been reported, and inhibition of NOX2 improves motor function. However, the underlying mechanisms of NOX2 in post-traumatic pain and motor deficit remain unexplored. In the present study, we report that depletion of NOX2 (NOX2-/-) or inhibition of NOX2 using NOX2ds-tat significantly reduced mechanical/thermal cutaneous hypersensitivity and motor dysfunction after moderate contusion SCI at T10 in male mice. Western blot (WB, 3 mm lesion area) and immunohistochemistry (IHC) showed that SCI elevates NOX2 expression predominantly in microglia/macrophages up to 8 weeks post-injury. Deletion of NOX2 significantly reduced CD11b+/CD45hiF4/80+ macrophage infiltration at 24 h post-injury detected by flow cytometry and 8-OHG+ ROS production at 8 weeks post-injury by IHC in both lesion area and lumbar enlargement. NOX2 deficiency also altered microglial/macrophage pro-inflammatory and anti-inflammatory balance towards the neurorestorative response. WB analysis showed robust increase of Arginase-1 and YM1 proteins in NOX2-/- mice. Furthermore, qPCR analysis showed significant up-regulation of anti-inflammatory cytokine IL-10 levels in NOX2-/- mice, associated with reduced microRNA-155 expression. These findings were confirmed in CD11b+ microglia/macrophages isolated from spinal cord at 3 days post-injury. Taken together, our data suggest an important role for IL-10/miR-155 pathway in regulating NOX2-mediated SCI-dysfunction. Thus, specific targeting of NOX2 may provide an effective strategy for treating neurological dysfunction in SCI patients.

14.
Invest Ophthalmol Vis Sci ; 60(2): 517-527, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30707753

RESUMO

Purpose: To investigate a novel strategy in constructing tissue-engineered corneal stromal equivalent based on amniotic membrane and keratocytes. Methods: The ultrathin amniotic membrane (UAM) was laminated, with corneal stromal cells (CSCs) distributed between the space of the layered UAMs. Calcein AM staining was used to evaluate cellular viability, morphology, and arrangement. Immunostaining, qRT-PCR, and Western blot were performed to detect gene and protein expression in keratocytes. Optical coherence tomography visualized the cross sections and thickness of the UAM construction. The microstructure of the CSC-secreted extracellular matrix (ECM) was investigated by scanning electron microscopy and transmission electron microscopy (TEM). To evaluate the feasibility of the multilayer UAM-CSC lamination for surgery, the corneal substitute was used to perform lamellar keratoplasty. Slit lamp microscopy and corneal fluorescein staining were performed in postsurgery observation. Results: The CSCs maintained their keratocyte phenotype and secreted well-organized ECM on the aligned UAM surface. The four-layer UAM-CSC lamination attained half thickness of the human cornea (250 ± 18 µm) after 8 weeks' culture, which also showed promising optimal transparency. In TEM images, the CSC-generated ECM displayed stratified, multilayered lamellae with orthogonal fibril arrangement, which was similar to the human cornea microstructure. Furthermore, the stromal equivalent was successfully preformed in lamellar keratoplasty. Four weeks post surgery, the substitute was well integrated into the recipient cornea and completely epithelialized without myofibroblast differentiation. Conclusions: Our study established a novel 3D biomimetic corneal model to replicate the corneal stromal organization with multilayer UAM, which was capable of promoting the development of corneal stroma-like tissues in vitro, establishing a new avenue for basic research and therapeutic potential.


Assuntos
Âmnio/citologia , Ceratócitos da Córnea/citologia , Substância Própria/citologia , Engenharia Tecidual/métodos , Tecidos Suporte , Animais , Western Blotting , Sobrevivência Celular , Células Cultivadas , Substância Própria/metabolismo , Transplante de Córnea , Matriz Extracelular/ultraestrutura , Regulação da Expressão Gênica/fisiologia , Humanos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , RNA Mensageiro/genética , Coelhos , Reação em Cadeia da Polimerase em Tempo Real , Microscopia com Lâmpada de Fenda , Tomografia de Coerência Óptica
15.
Genes (Basel) ; 10(2)2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30744078

RESUMO

Recently, an increasing number of studies have indicated that long-non-coding RNAs (lncRNAs) can participate in various crucial biological processes and can also be used as the most promising biomarkers for the treatment of certain diseases such as coronary artery disease and various cancers. Due to costs and time complexity, the number of possible disease-related lncRNAs that can be verified by traditional biological experiments is very limited. Therefore, in recent years, it has been very popular to use computational models to predict potential disease-lncRNA associations. In this study, we constructed three kinds of association networks, namely the lncRNA-miRNA association network, the miRNA-disease association network, and the lncRNA-disease correlation network firstly. Then, through integrating these three newly constructed association networks, we constructed an lncRNA-disease weighted association network, which would be further updated by adopting the KNN algorithm based on the semantic similarity of diseases and the similarity of lncRNA functions. Thereafter, according to the updated lncRNA-disease weighted association network, a novel computational model called PMFILDA was proposed to infer potential lncRNA-disease associations based on the probability matrix decomposition. Finally, to evaluate the superiority of the new prediction model PMFILDA, we performed Leave One Out Cross-Validation (LOOCV) based on strongly validated data filtered from MNDR and the simulation results indicated that the performance of PMFILDA was better than some state-of-the-art methods. Moreover, case studies of breast cancer, lung cancer, and colorectal cancer were implemented to further estimate the performance of PMFILDA, and simulation results illustrated that PMFILDA could achieve satisfying prediction performance as well.

16.
Metab Brain Dis ; 34(2): 377-384, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30552558

RESUMO

Multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), and other neurodegenerative diseases of central nervous system (CNS) disorders are serious human health problems. Rho-kinase (ROCK) is emerging as a potentially important therapeutic target relevant to inflammatory neurodegeneration diseases. This is supported by studies showing the beneficial effects of fasudil, a ROCK inhibitor, in inflammatory neurodegeneration diseases. MS is an autoimmune disease resulting from inflammation and demyelination in the white matter of the CNS. It has been postulated that activation of Rho/ROCK causes neuropathological changes accompanied with related clinical symptoms, which are improved by treatment with ROCK inhibitors. Therefore, inhibition of abnormal activation of the Rho/ROCK signaling pathway appears to be a new mechanism for treating CNS diseases. In this review, we extensively discussed the role of ROCK inhibitors, summarized the efficacy of fasudil in the MS conventional animal model of experimental autoimmune encephalomyelitis (EAE), both in vivo and in vitro, and highlighted the mechanism involved. Overall, the findings collected in this review support the role of the ROCK signaling pathway in neurodegenerative diseases. Hence, ROCK inhibitors such as fasudil can be novel, and efficacious treatment for inflammatory neurodegenerative diseases.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Animais , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/diagnóstico , Humanos , Inflamação/tratamento farmacológico , Esclerose Múltipla/diagnóstico
17.
PLoS Biol ; 16(12): e2006613, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30566428

RESUMO

Mutations of WD repeat domain 62 (WDR62) lead to autosomal recessive primary microcephaly (MCPH), and down-regulation of WDR62 expression causes the loss of neural progenitor cells (NPCs). However, how WDR62 is regulated and hence controls neurogenesis and brain size remains elusive. Here, we demonstrate that mitogen-activated protein kinase kinase kinase 3 (MEKK3) forms a complex with WDR62 to promote c-Jun N-terminal kinase (JNK) signaling synergistically in the control of neurogenesis. The deletion of Mekk3, Wdr62, or Jnk1 resulted in phenocopied defects, including premature NPC differentiation. We further showed that WDR62 protein is positively regulated by MEKK3 and JNK1 in the developing brain and that the defects of wdr62 deficiency can be rescued by the transgenic expression of JNK1. Meanwhile, WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. Our findings demonstrate that the coordinated reciprocal and bidirectional regulation among MEKK3, FBW7, WDR62, and JNK1, is required for fine-tuned JNK signaling for the control of balanced NPC self-renewal and differentiation during cortical development.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteína 7 com Repetições F-Box-WD/fisiologia , MAP Quinase Quinase Quinase 3/fisiologia , Proteínas Associadas aos Microtúbulos/metabolismo , Animais , Diferenciação Celular , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Células HEK293 , Humanos , MAP Quinase Quinase Quinase 3/genética , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microcefalia/genética , Microcefalia/fisiopatologia , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Fosforilação , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
18.
Int Immunopharmacol ; 66: 69-81, 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30445309

RESUMO

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system characterized by recurrent and progressive demyelination, neuroinflammation and oligodendrocyte loss. The cuprizone (CPZ) model is characterized by primary and reversible demyelination, accompanied by oligodendrocyte loss and neuroinflammation. In the current study, we explored the efficiency of Bilobalide in the demyelination and remyelination. The results demonstrate that Bilobalide improved behavioral abnormality and promoted remyelination in the corpus callosum by using Luxol Fast Blue, Black Gold II and myelin basic protein (MBP) staining. We for the first time found that CPZ caused the splenic atrophy and induced the formation of myelin oligodendrocyte glycoprotein (MOG) antibody, which was attenuated by Bilobalide. Thus, Bilobalide decreased the loss of O4+ oligodendrocytes possibly through MOG antibody-dependent cell cytotoxicity. Bilobalide also prevented the infiltration of CD4+ T cells, CD68+ macrophages and B220+ B cells within the brain, and reduced the inflammatory microenvironment mediated with Iba1+iNOS+ and Iba1+NF-kB+ microglia after CPZ challenge, accompanied by the inhibition of IL-1ß and IL-6 in the brain. These results identify a potent therapeutic efficiency for Bilobalide and highlight clear pleiotropic effects of the compound beyond specific autoantibody and inflammatory microenvironment in CPZ-mediated demyelination.

19.
Gene ; 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30453073

RESUMO

The cellulose synthase gene superfamily, which includes the cellulose synthase (CesA) and cellulose synthase-like (Csl) gene families, plays a vital role in the biosynthesis of cellulose and hemicellulose in plants. However, these genes have not been extensively studied in tomato (Solanum lycopersicum), a model for Solanaceae plants and for fleshy fruit development. Here, we identified and systematically analyzed 38 CesA/Csl family members that contained cellulose synthase domain regions, and categorized their encoded proteins into 6 subfamilies (CesA, CslA, CslB, CslD, CslE, and CslG) based on phylogenetic analysis. Most CesA/Csl genes from tomato are closely related to those from Arabidopsis, but the families have distinct features regarding gene structure, chromosome distribution and localization, phylogeny, and deduced protein sequence, indicating that they arose via different evolutionary process. Furthermore, expression analysis of CesA/Csl genes in different tissues at various developmental stages showed that most CesAs were constitutively expressed with differential expression levels in various organs; three CslD genes were expressed specifically in flowers, and four CesA and five Csl putative genes were preferentially expressed in fruits. Our results provide insight into the general characteristics of the CesA/Csl genes in tomato, and lay the foundation for further functional studies of CesA/Csl genes in tomato and other Solanaceae species.

20.
Artigo em Inglês | MEDLINE | ID: mdl-30421488

RESUMO

We report the rational design of coordination-driven self-assembly metal-organic nanostructures for multifunctional nanotheranostics. Zinc(II) coordination-based nano-formulations capable of loading indocyanine green (ICG) and therapeutic genes were prepared to achieve a fluorescence/photoacoustic imaging-guided combination photo/gene therapy strategy. We showed the enhanced theranostic capability of zinc(II)-dipicolylamine-assisted assembly of ICG, as well as simultaneous targeted gene delivery in an experimental mouse model of cancer. Such a co-assembly strategy provides a facile way to achieve combined therapeutic functions for personalized nanomedicine.

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