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1.
Colloids Surf B Biointerfaces ; 209(Pt 1): 112145, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34637957

RESUMO

Poor healing ability and adhesion formation greatly hinder the recovery of injured tendon function. Previously, our local sustained gene delivery system by using cyclooxygenases (COX-1 and COX-2)-engineered miRNA plasmid/nanoparticles loaded hydrogel significantly inhibited adhesion formation and promoted tendon healing. The present study aims to study morphological changes of the macrophages in the healing tendons after above treatment with the hydrogel. Firstly, we assessed the therapeutic effect of localized delivery of the hydrogel on cyclooxygenases in the injured rat Achilles tendon model. We found ultimate strengths of the healing tendons were significantly increased at week 2 and 3. We then studied the distribution of macrophages before and after tendon injury, and found macrophages were rapidly recruited into injured sites of tendons. After being isolated and cultured, macrophages were transfected with 6-Carboxyfluorescein (FAM) labeled siRNA/nanoparticles and presented a high transfection efficiency (>70%). We further compared the change of iNOS/CD206 in macrophages between negative control siRNA/nanoparticle group and COX siRNA/nanoparticle group. The major finding is that the morphology of the macrophages changed from type I macrophages to type II macrophages after transfection of COX siRNA/nanoparticles in vitro. Subsequently, rat Achilles tendon cells were cultured with supernatant collected from macrophages transfected with negative control siRNA/nanoparticles and COX siRNA/nanoparticles, and the proliferation of tendon cells was significantly increased in COX siRNA/nanoparticle supernatant group. Because type II macrophages are responsible for tissue repair, the changes in macrophage polarization from M1 to M2 may be one of the important events in promoting the tendon healing.

2.
Zool Res ; 42(5): 637-649, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34472225

RESUMO

The insect brain is the central part of the neurosecretory system, which controls morphology, physiology, and behavior during the insect's lifecycle. Lepidoptera are holometabolous insects, and their brains develop during the larval period and metamorphosis into the adult form. As the only fully domesticated insect, the Lepidoptera silkworm Bombyx mori experienced changes in larval brain morphology and certain behaviors during the domestication process. Hormonal regulation in insects is a key factor in multiple processes. However, how juvenile hormone (JH) signals regulate brain development in Lepidoptera species, especially in the larval stage, remains elusive. We recently identified the JH receptor Methoprene tolerant 1 ( Met1) as a putative domestication gene. How artificial selection on Met1 impacts brain and behavioral domestication is another important issue addressing Darwin's theory on domestication. Here, CRISPR/Cas9-mediated knockout of Bombyx Met1 caused developmental retardation in the brain, unlike precocious pupation of the cuticle. At the whole transcriptome level, the ecdysteroid (20-hydroxyecdysone, 20E) signaling and downstream pathways were overactivated in the mutant cuticle but not in the brain. Pathways related to cell proliferation and specialization processes, such as extracellular matrix (ECM)-receptor interaction and tyrosine metabolism pathways, were suppressed in the brain. Molecular evolutionary analysis and in vitro assay identified an amino acid replacement located in a novel motif under positive selection in B. mori, which decreased transcriptional binding activity. The B. mori MET1 protein showed a changed structure and dynamic features, as well as a weakened co-expression gene network, compared with B. mandarina. Based on comparative transcriptomic analyses, we proposed a pathway downstream of JH signaling (i.e., tyrosine metabolism pathway) that likely contributed to silkworm larval brain development and domestication and highlighted the importance of the biogenic amine system in larval evolution during silkworm domestication.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Bombyx/metabolismo , Proteínas de Insetos/metabolismo , Hormônios Juvenis/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Bombyx/crescimento & desenvolvimento , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Sistemas CRISPR-Cas , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Genótipo , Proteínas de Insetos/genética , Tegumento Comum/fisiologia , Larva/crescimento & desenvolvimento , Larva/metabolismo , Filogenia , Conformação Proteica
3.
J Mol Neurosci ; 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471984

RESUMO

Polo-like kinase 4 (PLK4) is one of the key regulators of centrosomal replication. However, its role and mechanism in spinal cord injury (SCI) are still unclear. The SCI model on rats was constructed and the expression and localization of PLK4 in the spinal cord are analyzed with Western blot and immunofluorescence, respectively. Then the specific siRNAs were encapsulated in nanoparticles for the inhibition of PLK4 expression. Afterward, the role of PLK4 on astrocytes was investigated by knocking down its expression in the primary astrocytes. Moreover, siRNA-loaded nanoparticles were injected into the injured spinal cord of rats, and the motor function recovery of rats after SCI was assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor scale method. Notably, the siRNA-loaded nanoparticles effectively transfect primary astrocytes and significantly inhibit PLK4 expression, together with the expression of PCNA with significance. After treatment, restoration of the motor function following SCI was significantly improved in the PLK4 knockdown group compared with the control group. Therefore, we speculate that inhibition of Plk4 may inhibit the proliferation of astrocytes and decrease the inflammatory response mediated by astrocytes, so as to promote the functional recovery of SCI. In conclusion, inhibition of PLK4 expression via siRNA-loaded nanoparticles may be a potential treatment for SCI.

4.
Colloids Surf B Biointerfaces ; 205: 111876, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34087778

RESUMO

During the injured flexor tendon healing process, tendon tissue is easy to form extremely dense adhesion with the surrounding tissue, which causes the serious influence of hand function recovery. Uncaria is widely used in clinic and its main composition, Rhynchophylline (Rhy), has been reported on its good therapeutic effect, which could effectively inhibit the intra-abdominal adhesion formation. However, the therapeutic effect of Rhy on tendon healing and adhesion formation is still unclear. Due to the short half-life of Rhy, hyaluronic acid (HA) sustained-release system for Rhy delivery was constructed and it could also avoid drug from the undesired loss during the transit. After Rhy delivery system was applied around the injured tendons, adhesion formation, gliding function and healing strength of tendons were evaluated. Our results showed that the gliding excursion and healing strength of repaired tendons were both significantly increased, as well as the adhesion was inhibited. From in vivo experiments, Rhy could be able to increase the expression of Col Ⅰ/Col Ⅲ and helped fibroblasts to ordered organization for tendon tissues. But for adhesion tissues, Rhy promoted the apoptosis and accelerated the degradation of extracellular matrix. In vitro study showed Rhy could help tenocytes stimulated with TGF-ß1 to recover to normal cell functions involving cell proliferation and apoptosis level. Through high-throughput sequencing, we found that Rhy was involved in the regulation of Extracellular Matrix (ECM) signaling pathway. We draw a conclusion that Rhy enhanced the tendon healing and prevented adhesion formation through inhibiting the phosphorylation of Smad2. In a word, this sustained release system of Rhy may be a promising strategy for the treatment of injured tendons.


Assuntos
Hidrogéis , Tendões , Preparações de Ação Retardada , Humanos , Oxindóis , Tendões/patologia , Aderências Teciduais/tratamento farmacológico , Aderências Teciduais/patologia
5.
Insect Sci ; 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34018323

RESUMO

Periodic post-embryonic changes in insects, including growth, development and metamorphosis, are strictly controlled by many compounds, including steroid hormones. The biosynthesis and clearance of 20-hydroxyecdysone (20E), the major active form of the insect steroid hormone ecdysone, result in titer fluctuations that help control insect development. The inactivation of 20E in the silkworm Bombyx mori is highly tissue-specific, with CYP18A1 and ecdysone oxidase controlling 20E inactivation specifically in the mid-silk gland and midgut, respectively. Here, we characterized silkworm 3-dehydroecdysone 3α reductase (Bm3DE3α) and 3-dehydroecdysone 3ß reductase (Bm3DE3ß), two enzymes involved predominantly in the C-3-mediated catalysis of 20E in fat bodies. The ubiquitous and silk gland-specific overexpression of Bm3DE3α decreased the 20E titer, resulting in larval lethality and larval-pupal transition failure, respectively. In contrast, the ubiquitous and mid-silk gland-specific overexpression of Bm3DE3ß increased the 20E titer, resulting in larval growth delays and lethality at the mid-fifth larval stage, respectively. Thus, Bm3DE3α and Bm3DE3ß mediate fat body-specific steroid hormone metabolism in B. mori, indicating that highly diversified 20E metabolism-related mechanisms exist in different insect species.

6.
Nano Lett ; 21(7): 3007-3015, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33797927

RESUMO

Brain injuries are devastating central nervous system diseases, resulting in cognitive, motor, and sensory dysfunctions. However, clinical therapeutic options are still limited for brain injuries, indicating an urgent need to investigate new therapies. Furthermore, the efficient delivery of therapeutics across the blood-brain barrier (BBB) to the brain is a serious problem. In this study, a facile strategy of dual site-selective functionalized (DSSF) poly(ß-amino esters) was developed using bio-orthogonal chemistry for promoting brain nerve regeneration. Fluorescence colocalization studies demonstrated that these proton-sponge DSSF poly(ß-amino esters) targeted mitochondria through electrostatic interactions. More importantly, this delivery system could effectively accumulate in the injured brain sites and accelerate the recovery of the injured brain. Finally, this DSSF poly(ß-amino esters) platform may provide a new methodology for the construction of dual regioselective carriers in protein/peptide delivery and tissue engineering.


Assuntos
Ésteres , Regeneração Nervosa , Barreira Hematoencefálica , Encéfalo , Engenharia Tecidual
7.
Antonie Van Leeuwenhoek ; 114(4): 479-486, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33646472

RESUMO

A short-rod-shaped, non-spore-forming endophytic actinobacterium, was isolated from a surface-sterilized leaf of Acrostichum aureum in Fangchenggang, Guangxi Zhuang Autonomous Region, China, designated strain CBS4Y-1T and examined by a polyphasic approach to determine its taxonomic position. This actinobacterium was Gram-staining-positive and aerobic. Substrate mycelia and aerial mycelia were not observed, and no diffusible pigments were observed on the media tested. Strain CBS4Y-1T grew optimally with 0-1.0% (w/v) NaCl at 30 °C, pH 7.0-8.0. Comparative analysis of 16S rRNA genes showed that strain CBS4Y-1T shared the highest 16S rRNA gene sequence similarities with Nocardioides marinus CL-DD14T (96.7%) and Nocardioides terrae BX5-10T (96.7%). Phylogenetic analyses based on 16S rRNA gene sequence and phylogenomic analysis based on core proteomes alignment revealed that strain CBS4Y-1T belonged to the genus Nocardioides and formed a distinct cluster within the genus Nocardioides. The DNA G + C content of strain CBS4Y-1T was 71.1 mol%. The cell-wall peptidoglycan contained LL-diaminopimelic acid and MK-8(H4) was the predominant menaquinone. Phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), phosphatidylinositol (PI) were detected in the polar lipid extracts. The major fatty acids were iso-C16:0, C18:1ω9c and iso-C17:0. On the basis of phylogenetic analysis, phenotypic and chemotaxonomic characteristics, strain CBS4Y-1T represents a novel species of the genus Nocardioides, for which the name Nocardioides acrostichi sp. nov. is proposed. The type strain is CBS4Y-1T (= KCTC 49238T = CGMCC 4.7548T).


Assuntos
Nocardioides , Fosfolipídeos , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácidos Graxos , Filogenia , Folhas de Planta , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Vitamina K 2
8.
Acta Biomater ; 124: 301-314, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33444793

RESUMO

Tendon injuries are common diseases. The healing capacity of tendon is limited due to its special composition of extra-cellular matrix and hypocellularity and hypovascularity. The purpose of this study was to evaluate the effectiveness of nanoparticle-coated sutures carrying growth factors for accelerating tendon repair. A variety of experimental methods had been used to investigate the characteristics and therapeutic effects of the modified sutures. Nanoparticles could adhere uniformly to the surface of the suture through polydopamine. Even sutured in the tendon, most of nanoparticles were still remained on the surface of suture, and the loaded proteins could spread into the tendon tissues. In vivo study, the ultimate strength of repaired tendons treated with bFGF and VEGFA-releasing sutures was significantly greater than the tendons repaired with control sutures at multiple time-points, whether in the chicken model of flexor tendon injury or the rat model of Achilles tendon injury. At week 6, the adhesion score in the bFGF and VEGFA-releasing suture group was significantly lower than those of the control suture group. Tendon gliding excursion was significantly longer in the bFGF and VEGFA-releasing suture group than that in the control bare sutures. Work of digital flexion was significantly decreased in the bFGF and VEGFA-releasing suture group. In a word, we developed a platform for local and continuous delivery of growth factors based on the nanoparticle-coated sutures, which could effectively deliver growth factors to tissues and control the release of growth factors. This growth factors delivery system is an attractive therapeutic tool to repair injured tendons. STATEMENT OF SIGNIFICANCE: Tendon rupture is a common clinical injury, due to the special character of the tendon with mainly extra cellular matrix and hypocellularity and hypovascularity, the healing capacity of the injured tendon is limited. In this study, nanoparticle-coated surgical sutures carrying growth factors were prepared to accelerate tendon repair. After treatment, bFGF and VEGFA loaded nanoparticle-coated sutures can significantly enhance tendon healing, and significantly improve tendon gliding function and effectively inhibit the formation of adhesion. Moreover, these nanoparticle-coated sutures have good biocompatibility and no obvious tissue reaction, which provides more guarantee for further clinical application. This is an attractive and promising approach that uses surgical suture as a growth factor delivery tool to repair tendon injury, which can simplify the treatment. And this kind of bioactive sutures may be applied to other tissue repair, such as muscle, nerve, intestinal canal, blood vessel, skin, and so on.


Assuntos
Nanopartículas , Cicatrização , Animais , Fenômenos Biomecânicos , Peptídeos e Proteínas de Sinalização Intercelular , Ratos , Técnicas de Sutura , Suturas , Tendões/cirurgia , Resistência à Tração
9.
Biomater Sci ; 8(23): 6611-6624, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33231577

RESUMO

The tendon-to-bone healing after trauma is usually slow and weak, and the repair site is easily disrupted during early mobilization exercise. bFGF and VEGFA gene therapy may hold promise in augmenting the tendon-to-bone healing process through enhancing cell proliferation and angiogenesis. This study is conducted to determine the effects of nanoparticle-mediated co-delivery of bFGF and VEGFA genes to the tendon-to-bone repair interface on the healing strength and biological responses in a chicken model. The PLGA nanoparticle/pEGFP-bFGF + pEGFP-VEGFA plasmid complexes were prepared and were characterized in vitro and in vivo. The nanoparticle/plasmid complexes can effectively transfer bFGF and VEGFA genes to the tendon-to-bone interface. Nanoparticle-mediated co-delivery of bFGF and VEGFA genes significantly improved the tendon-to-bone healing in terms of healing strengths and histology in a chicken flexor tendon repair model. Our results suggest a new biological approach to accelerate the tendon-to-bone healing.


Assuntos
Nanopartículas , Traumatismos dos Tendões , Cicatrização , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Tendões
10.
Int Immunopharmacol ; 83: 106477, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32278127

RESUMO

BACKGROUND: Although multiple key molecules in lung adenocarcinoma (LUAD) have been identified in recent years, the overall tumor microenvironment (TME) immune cell infiltration characterizations mediated by multiple key molecules remain little known. This study aimed to integrate the roles of multiple key molecules to evaluate patient prognosis and TME cell infiltration characterization as well as responses to immunotherapy. METHODS: Using combined LUAD cancer cohorts with 228 normal samples and 913 tumor samples, we comprehensively dissected the differences of genomic and TME cell infiltration landscapes between normal lung tissues and tumor tissues. The single-sample gene-set enrichment analysis (ssGSEA) was used to quantify the relative abundance of 24 cell infiltration. The riskScore signature was constructed using a least absolute shrinkage and selection operator (LASSO) Cox regression mode. RESULTS: Seven novel key molecules with significantly up-regulated expression in LUAD were determined. Survival analyses revealed their important prognostic values. LUAD microenvironment presented a markedly decreased infiltration of immune cells compared to normal lung tissues. We found tumors with up-regulated expression of these key molecules exhibited a significantly decreased TME cell infiltration and increased immune checkpoint molecule expression. The high riskScore subtype was characterized by decreased innate and adaptive immune cell infiltration. Activation of p53 signaling pathway and regulator T cells were observed in the high riskScore subtype, which were regarded as T-cell suppressive and could be responsible for poorer prognosis in this subtype (HR 1.83(1.27-2.63)). Multivariate analyses demonstrated the riskScore was a robust and independent prognostic biomarker, and its value in predicting immunotherapeutic outcomes was also confirmed (HR 1.70(1.22-2.37)). CONCLUSIONS: This study reveal a novel gene signature significantly related to patient prognosis and TME cell infiltration in LUAD. We demonstrated the integrated roles of multiple key molecules played a crucial role in shaping TME cell infiltration diversity and complexity. Evaluating the integrated characterization of multiple key molecules could contribute to predicting patients' response to immunotherapy and guiding more effective immunotherapy strategies.


Assuntos
Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Pulmão/fisiologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Reguladores/imunologia , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Anotação de Sequência Molecular , Prognóstico , Risco , Transdução de Sinais , Análise de Sobrevida , Transcriptoma , Microambiente Tumoral , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
11.
Mol Cancer ; 19(1): 53, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164750

RESUMO

BACKGROUND: The epigenetic regulation of immune response has been demonstrated in recent studies. Nonetheless, potential roles of RNA N6-methyladenosine (m6A) modification in tumor microenvironment (TME) cell infiltration remain unknown. METHODS: We comprehensively evaluated the m6A modification patterns of 1938 gastric cancer samples based on 21 m6A regulators, and systematically correlated these modification patterns with TME cell-infiltrating characteristics. The m6Ascore was constructed to quantify m6A modification patterns of individual tumors using principal component analysis algorithms. RESULTS: Three distinct m6A modification patterns were determined. The TME cell-infiltrating characteristics under these three patterns were highly consistent with the three immune phenotypes of tumors including immune-excluded, immune-inflamed and immune-desert phenotypes. We demonstrated the evaluation of m6A modification patterns within individual tumors could predict stages of tumor inflammation, subtypes, TME stromal activity, genetic variation, and patient prognosis. Low m6Ascore, characterized by increased mutation burden and activation of immunity, indicated an inflamed TME phenotype, with 69.4% 5-year survival. Activation of stroma and lack of effective immune infiltration were observed in the high m6Ascore subtype, indicating a non-inflamed and immune-exclusion TME phenotype, with poorer survival. Low m6Ascore was also linked to increased neoantigen load and enhanced response to anti-PD-1/L1 immunotherapy. Two immunotherapy cohorts confirmed patients with lower m6Ascore demonstrated significant therapeutic advantages and clinical benefits. CONCLUSIONS: This work revealed the m6A modification played a nonnegligible role in formation of TME diversity and complexity. Evaluating the m6A modification pattern of individual tumor will contribute to enhancing our cognition of TME infiltration characterization and guiding more effective immunotherapy strategies.


Assuntos
Adenosina/análogos & derivados , Linfócitos T CD8-Positivos/imunologia , Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas/imunologia , Microambiente Tumoral/imunologia , Adenosina/química , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Humanos , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Células Tumorais Cultivadas
12.
Pain ; 161(5): 989-1004, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31895269

RESUMO

Functional dyspepsia is a common functional gastrointestinal disorder. Gastric hypersensitivity (GHS) is a hallmark of this disorder, but the cellular mechanisms remain largely unknown. Stressors during gestational period could have effects on the offspring's tissue structure and function, which may predispose to gastrointestinal diseases. The aim of this study was to test whether prenatal maternal stress (PMS) induces GHS and to investigate role of acid-sensing ion channel (ASIC)/nuclear factor-κB (NF-κB) signaling by examining Asic1 methylation status in adult offspring rats. Gastric hypersensitivity in response to gastric distension was examined by electromyography recordings. Changes in neuronal excitability were determined by whole-cell patch-clamp recording techniques. Demethylation of CpG islands of Asic1 was determined by methylation-specific PCR and bisulfite sequencing assay. Prenatal maternal stress produced GHS in adult offspring rats. Treatment with amiloride, an inhibitor of ASICs, significantly attenuated GHS and reversed hyperexcitability of gastric-specific dorsal root ganglion (DRG) neurons labeled by the dye DiI. Expression of ASIC1 and NF-κBp65 was markedly enhanced in T7 to T10 DRGs. Furthermore, PMS led to a significant demethylation of CpG islands in the Asic1 promoter. A chromatin immunoprecipitation assay showed that PMS also enhanced the ability of NF-κBp65 to bind the promoter of Asic1 gene. Blockade of NF-κB using lentiviral-p65shRNA reversed upregulation of ASIC1 expression, GHS, and the hyperexcitability of DRG neurons. These data suggest that upregulation of ASIC1 expression is attributed to Asic1 promoter DNA demethylation and NF-κB activation, and that the enhanced interaction of the Asic1 and NF-κBp65 contributes to GHS induced by PMS.


Assuntos
Epigênese Genética , Estômago , Estresse Fisiológico , Canais Iônicos Sensíveis a Ácido/genética , Animais , Feminino , Gânglios Espinais , Técnicas de Patch-Clamp , Gravidez , Ratos , Regulação para Cima
13.
Mol Ther ; 27(9): 1534-1546, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31278034

RESUMO

How to accelerate tendon healing remains a clinical challenge. In this study, a suture carrying nanoparticle/pEGFP-basic fibroblast growth factor (bFGF) and pEGFP-vascular endothelial growth factor A (VEGFA) complexes was developed to transfer the growth factor genes into injured tendon tissues to promote healing. Polydopamine-modified sutures can uniformly and tightly absorb nanoparticle/plasmid complexes. After tendon tissues were sutured, the nanoparticle/plasmid complexes still existed on the suture surface. Further, we found that the nanoparticle/plasmid complexes delivered into tendon tissues could diffuse from sutures to tendon tissues and effectively transfect genes into tendon cells, significantly increasing the expression of growth factors in tendon tissues. Finally, biomechanical tests showed that nanoparticle/pEGFP-bFGF and pEGFP-VEGFA complex-coated sutures could significantly increase the ultimate strengths of repaired tendons, especially at 4 weeks after operation. Two kinds of nanoparticle/plasmid complex-coated sutures significantly increased flexor tendon healing strength by 3.7 times for Ethilon and 5.8 times for PDS II, respectively, compared with the corresponding unmodified sutures. In the flexor tendon injury model, at 6 weeks after surgery, compared with the control suture, the nanoparticle/plasmid complex-coated sutures can significantly increase the gliding excursions of the tendon and inhibit the formation of adhesion. These results indicate that this nanoparticle/plasmid complex-coated suture is a promising tool for the treatment of injured tendons.


Assuntos
Materiais Revestidos Biocompatíveis , Técnicas de Transferência de Genes , Nanopartículas , Suturas , Traumatismos dos Tendões/genética , Traumatismos dos Tendões/terapia , Transgenes , Cicatrização , Animais , Sobrevivência Celular , Materiais Revestidos Biocompatíveis/química , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Expressão Gênica , Terapia Genética , Cinética , Nanopartículas/química , Nanopartículas/ultraestrutura , Plasmídeos/genética , Transgenes/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/genética
14.
Pathol Res Pract ; 215(5): 1038-1048, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30975489

RESUMO

BACKGROUND AND OBJECTIVE: The underlying molecular mechanisms of gastric cancer (GC) have yet not been investigated clearly. In this study, we aimed to identify hub genes involved in the pathogenesis and prognosis of GC. METHODS: We integrated five microarray datasets from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between GC and normal samples were analyzed with limma package. Gene ontology (GO) and KEGG enrichment analysis were performed using DAVID. Then we established the protein-protein interaction (PPI) network of DEGs by the Search Tool for the Retrieval of Interacting Genes database (STRING). The prognostic analysis of hub genes were performed through Gene Expression Profiling Interactive Analysis (GEPIA). Additionally, we used real-time quantitative PCR to validate the expression of hub genes in 5 pairs of tumor tissues and corresponding adjacent tissues. Finally, the candidate small molecules as potential drugs to treat GC were predicted in CMap database. RESULTS: Through integrating five microarray datasets, a total of 172 overlap DEGs were detected including 79 up-regulated and 93 down-regulated genes. Biological process analysis of functional enrichment showed these DEGs were mainly enriched in digestion, collagen fibril organization and cell adhesion. Signaling pathway analysis indicated that these DEGs played an vital in ECM-receptor interaction, focal adhesion and metabolism of xenobiotics by cytochrome P450. Protein-protein interaction network among the overlap DEGs was established with 124 nodes and 365 interactions. Three DEGs with high degree of connectivity (NID2, COL4A1 and COL4A2) were selected as hub genes. The GEPIA database confirmed that overexpression levels of hub genes were significantly associated with worse survival of patients. Finally, the 20 most significant small molecules were obtained based on CMap database and spiradoline was the most promising small molecule to reverse the GC gene expression. CONCLUSIONS: Our results indicated that NID2, COL4A1 and COL4A2 could be the potential novel biomarkers for GC diagnosis prognosis and the promising therapeutic targets. The present study may be crucial to understanding the molecular mechanism of GC initiation and progression.


Assuntos
Biomarcadores Tumorais/análise , Moléculas de Adesão Celular/genética , Colágeno Tipo IV/genética , Neoplasias Gástricas/genética , Biomarcadores Tumorais/genética , Proteínas de Ligação ao Cálcio , Biologia Computacional/métodos , Conjuntos de Dados como Assunto , Progressão da Doença , Descoberta de Drogas/métodos , Perfilação da Expressão Gênica/métodos , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias Gástricas/patologia , Transcriptoma
15.
J Cell Biochem ; 120(9): 15106-15118, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31020692

RESUMO

Overall survival of patients with low-grade glioma (LGG) has shown no significant improvement over the past 30 years, with survival averaging approximately 7 years. This study aimed to identify novel promising biomarkers of LGG and reveal its potential molecular mechanisms by integrated bioinformatics analysis. The microarray datasets of GSE68848 and GSE4290 were selected from GEO database for integrated analysis. In total, 293 overlapping differentially expressed genes (DEGs) were detected using the limma package. One hundred and eighty-eight nodes with 603 interactions were obtained from the establishment of protein-protein interaction (PPI) network. Functional and signaling pathway enriched were significantly correlated with the synapse and calcium signaling pathway, respectively. Module analysis revealed eight hub genes with high connectivity, which included CHRM1, DLG2, GABRD, GRIN1, HTR2A, KCNJ3, KCNJ9, and NUSAP1, and they were markedly correlated with patients' prognosis. The mining of the Gene Expression Profiling Interactive Analysis database and qPCR further confirmed the abnormal expression of these key genes with their prognostic value in LGG. We eventually predicted the 20 most vital small molecule drugs, which potentially reverse the carcinogenic state of LGG, as per the CMap (connectivity map) database and these DEGs, and MS-275 (enrichment score = -0.939) was considered as the most promising small molecule to treat LGG. In conclusion, our study provided eight reliable novel molecular biomarkers for diagnosis, prognosis prediction, and treatment targets for LGG. These conclusions will contribute to a better comprehension of molecular mechanisms fundamental to LGG occurrence and progression, and providing new insights for future development of genomic individualized treatment in LGG.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Biologia Computacional , Glioma/tratamento farmacológico , Glioma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Bibliotecas de Moléculas Pequenas/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Humanos , Gradação de Tumores , Mapas de Interação de Proteínas/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Análise de Sobrevida
16.
Oncoimmunology ; 8(4): e1568810, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906662

RESUMO

Background: Although immunosenescence-induced difference on overall immune function and immune cell subsets between younger and older populations has been well characterized, the potential effect of patients' age on the efficacy of immune checkpoint inhibitors (ICIs) remains little known. We performed a meta-analysis to investigate whether age differences play a role in cancer immunotherapy efficacy based on a large amount of clinical data. Methods: We conducted a systematic search of PubMed, Embase and MEDLINE for relevant randomized controlled trials. The primary outcome was overall survival (OS) and progression-free survival (PFS) was secondary outcome. The interaction test was used to assess the heterogeneity of HR between younger and older groups. Results: In total, 19 clinical randomized trials involving 11157 patients were included. The pooled HR for OS was 0.73 (95% CI 0.69-0.78) and 0.63 (95% CI 0.52-0.73) for PFS in younger patients receiving ICIs treatments, when compared with younger patients treated with controls. For older patients treated with ICIs, the pooled HR for OS compared with controls was 0.64 (95% CI 0.59-0.69) and 0.66 (95% CI 0.58-0.74) for PFS. The difference on OS efficacy between younger and older patients treated with ICIs was significant (Pheterogeneity = 0.025). Conclusions: Immune checkpoint inhibitors significantly improved OS and PFS in both younger and older patients compared with controls, but the magnitude of benefit was clinically age-dependent. Patients ≥65 y can benefit more from immunotherapy than younger patients. Future research should take age difference into consideration in trials and focus on tolerance and toxicity of ICIs in older patients.

17.
Mol Genet Genomic Med ; 7(5): e607, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30793530

RESUMO

BACKGROUND: Kidney renal clear cell carcinoma (KIRC) is the most common subtype of renal tumor. However, the molecular mechanisms of KIRC pathogenesis remain little known. The purpose of our study was to identify potential key genes related to the occurrence and prognosis of KIRC, which could serve as novel diagnostic and prognostic biomarkers for KIRC. METHODS: Three gene expression profiles from gene expression omnibus database were integrated to identify differential expressed genes (DEGs) using limma package. Enrichment analysis and PPI construction for these DEGs were performed by bioinformatics tools. We used Gene Expression Profiling Interactive Analysis (GEPIA) database to further analyze the expression and prognostic values of hub genes. The GEPIA database was used to further validate the bioinformatics results. The Connectivity Map was used to identify candidate small molecules that could reverse the gene expression of KIRC. RESULTS: A total of 503 DEGs were obtained. The PPI network with 417 nodes and 1912 interactions was constructed. Go and KEGG pathway analysis revealed that these DEGs were most significantly enriched in excretion and valine, leucine, and isoleucine degradation, respectively. Six DEGs with high degree of connectivity (ACAA1, ACADSB, ALDH6A1, AUH, HADH, and PCCA) were selected as hub genes, which significantly associated with worse survival of patients. Finally, we identified the top 20 most significant small molecules and pipemidic acid was the most promising small molecule to reverse the KIRC gene expression. CONCLUSIONS: This study first uncovered six key genes in KIRC which contributed to improving our understanding of the molecular mechanisms of KIRC pathogenesis. ACAA1, ACADSB, ALDH6A1, AUH, HADH, and PCCA could serve as the promising novel biomarkers for KIRC diagnosis, prognosis, and treatment.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos
18.
Int Immunopharmacol ; 68: 131-136, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30622030

RESUMO

BACKGROUND: Although immune checkpoint inhibitor monotherapy has demonstrated significant efficacy in advanced melanoma, no study has systematically evaluated the efficacy and safety of the combination regimens. In this study, we conduct a comprehensive meta-analysis to explore the efficacy and safety of CTLA-4 inhibitors combined with PD-1 inhibitors or chemotherapy in advanced melanoma. METHODS: We performed a systematic search of Medline, PubMed, Embase and Web of Science for relevant clinical trials. The primary objective was to explore the efficacy and safety of combination regimens compared to monotherapy. The secondary objective was to compare the difference in efficacy between CTLA-4 inhibitors plus PD-1 inhibitors and CTLA-4 inhibitors plus chemotherapy. RESULTS: A total of 12 trials involving 3308 patients were included for our meta-analysis. For combination regimens compared to monotherapy, the pooled HR for overall survival (OS) was 0.67 (95%CI 0.53-0.81) and for progression-free survival (PFS) was 0.56 (95%CI 0.41-0.71). For CTLA-4 inhibitors plus PD-1 inhibitors, the combined one-year OS rate (OSR1y), six-month PFS rate (PFSR6m) and disease control rate (DCR) were 64.0% (95%CI: 49.6%-78.4%), 56.4% (95%CI: 50.1%-62.7%) and 69.9% (95%CI: 65.1%-74.7%), respectively. For CTLA-4 inhibitors plus chemotherapy, the combined OSR1y, PFSR6m and DCR were 35.2% (95%CI: 25.4%-45.0%), 54.6% (95%CI: 42.7%-66.60%) and 33.5% (95%CI: 28.0%-38.9%), respectively. CONCLUSIONS: Combination regimens significantly improved OS and PFS of advanced melanoma patients compared to monotherapy. An acceptable safety profile was observed in both CTLA-4 inhibitors plus PD-1 inhibitors and CTLA-4 inhibitors plus chemotherapy. A comparison of these two combination regimens showed that patients who received CTLA-4 inhibitors plus PD-1 inhibitors had a better therapeutic effect compared to those receiving CTLA-4 inhibitors plus chemotherapy. Further randomized clinical trials are urgently required to validate our results.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Humanos , Resultado do Tratamento
19.
Insect Sci ; 26(6): 1020-1028, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29938905

RESUMO

Ostrinia furnacalis (Lepidoptera: Pyralidae) is one of the most destructive agricultural pests in Asia. Traditional pest-management methods include sex pheromone capture, transgenic crops that produce Bacillus thuringiensis toxin, and pesticides. Although these strategies control pest populations effectively, they also cause negative side effects, including dramatically increased pesticide resistance, severe pollution, and hazards for human health. Recently developed genome editing tools provide new prospects for pest management and have been successfully used in several species. However, few examples have been reported in the agricultural pest O. furnacalis due to a lack in genomic information. In this report, we identified only one transcript of O. furnacalis Argonaute 1 (OfAgo1) gene from the genome and cloned the open reading frame. OfAgo1 presented the maximum expression at the embryo stage or in the fat body during the larval stages. To understand its function, an OfAgo1 mutant was constructed using the Clustered Regularly Interspaced Short Palindromic Repeat/RNA-guided Cas9 nuclease (CRISPR/Cas9). Mutagenesis of OfAgo1 disrupted cuticle pigmentation by down-regulating micro RNAs and pigmentation-related genes. This is the first report for the cloning and functional analysis of OfAgo1, revealing a role of OfAgo1 in cuticle pigmentation. The current report also established a CRISPR/Cas9 system in O. furnacalis, providing a new insight for pest management.


Assuntos
Proteínas Argonauta/genética , Mariposas/genética , Pigmentação/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Sistemas CRISPR-Cas , Clonagem Molecular , Mutação
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