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1.
Biomaterials ; 246: 119971, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32247202

RESUMO

Photodynamic therapy (PDT) is an effective and noninvasive therapeutic strategy employing light-triggered singlet oxygen (SO) and reactive oxygen species (ROS) to kill lesional cells. However, for effective in vivo delivery of PDT agent into the cancer cells, various biological obstacles including blood circulation and condense extracellular matrix (ECM) in the tumor microenvironment (TME) need to be overcome. Furthermore, the enormous challenge in design of smart drug delivery systems is meeting the difference, even contradictory required functions, in different steps of the complicated delivery process. To this end, we present that TME-activatable circular pyrochlorophyll A (PA)-aptamer-PEG (PA-Apt-CHO-PEG) nanostructures, which combine the advantages of PEG and aptamer, would be able to realize efficient in vivo imaging and PDT. Upon intravenous (i.v.) injection, PA-Apt-CHO-PEG shows "stealth-like" long circulation in blood compartments without specific recognition capacity, but once inside solid tumor, PA-Apt-CHO-PEG nanostructures are cleaved and then form PA-Apt Aptamer-drug conjugations (ApDCs) in situ, allowing deep penetration into the solid tumor and specific recognition of cancer cells, both merits, considering anticipated future clinical translation of ApDCs.

2.
Theranostics ; 10(9): 4030-4041, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226537

RESUMO

Rationale: A cascade, or domino, reaction consists of two, or more, consecutive reactions such that subsequent reactions occur only if some chemical functionality has first been established in the prior step. However, while construction of predesigned and desired molecular domino reactors in a tailored manner is a valuable endeavor, it is still challenging. Methods: To address this challenge, we herein report an aptamer-based photodynamic domino reactor built through automated modular synthesis. The engineering of this reactor takes advantage of the well-established solid-phase synthesis platform to incorporate a photosensitizer into G-quadruplex/ hemin DNAzyme at the molecular level. Results: As a proof of concept, our photodynamic domino reactor, termed AS1411/hemin- pyrochlorophyll A, achieves in vivo photodynamic domino reaction for efficient cancer treatment by using a high concentration of hydrogen peroxide (H2O2) in the tumor microenvironment (TME) to produce O2, followed by consecutive generation of singlet oxygen (1O2) using the pre-produced O2. More specifically, phosphoramidite PA (pyrochlorophyll A) is coupled to aptamer AS1411 to form AS1411-PA ApDC able to simultaneously perform in vivo targeted imaging and photodynamic therapy (PDT). The insertion of hemin into the AS1411 G-quadruplex was demonstrated to alleviate tumor hypoxia by decomposition of H2O2 to produce O2. This was followed by the generation of 1O2 by PA to trigger cascading amplified PDT. Conclusion: Therefore, this study provides a general strategy for building an aptamer-based molecular domino reactor through automated modular synthesis. By proof of concept, we further demonstrate a novel method of achieving enhanced PDT, as well as alleviating TME hypoxia at the molecular level.

3.
J Am Chem Soc ; 142(5): 2532-2540, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31910340

RESUMO

Mitomycin C (MMC) has been using for the treatment of a variety of digestive tract cancers. However, its nonspecific DNA-alkylating ability usually causes severe side effects, thus largely limiting its clinical applications. The utilization of an efficient active targeted drug delivery technique would address this issue. Accordingly, we report the design and development of aptamer-mitomycin C conjugates that use different cross-linking chemistry. The targeted delivery ability and cytotoxicity of these conjugates were carefully studied. It is worth noting that a linker-dependent cytotoxicity effect was observed for these conjugates. The use of a reductant-sensitive disulfide bond cross-linking strategy resulted in significantly enhanced cytotoxicity of MMC against the target cancer cell lines. Importantly, this cytotoxicity enhancement was suited to different types of aptamers, demonstrating the success of our design. Mechanistic studies of the enhanced cytotoxicity effect indicated that the target recognition, specific binding, and receptor-mediated internalization of aptamer were also critical for the observed effect.

4.
J Am Chem Soc ; 142(6): 2699-2703, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31910009

RESUMO

Triple-negative breast cancer (TNBC) lacks three important receptors, ER, PR, and HER2. It is more aggressive and more likely to relapse after treatment, thus has been identified as one of the most malignant breast cancer types. The development of efficient targeted TNBC therapy is an important research topic in TNBC treatment. We report the development of a new aptamer-drug conjugate (ApDC), AS1411-triptolide conjugate (ATC), as targeted therapy for the treatment of TNBC with high efficacy. The conjugate possesses excellent specificity and high cytotoxicity against the MDA-MB-231 cell line. The advantages of our newly invented ATC are further highlighted by its excellent in vivo anti-TNBC efficacy and negligible side effects toward healthy organs.

5.
Bioconjug Chem ; 31(1): 37-42, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31815437

RESUMO

Nucleic acid aptamers, also known as "chemical antibodies", have been widely employed in targeted cancer therapy and diagnosis. For example, aptamer-drug conjugates (ApDCs), through covalent conjugation of cytotoxic warheads to aptamers, have demonstrated anticancer efficacy both in vitro and in vivo. However, a general strategy to endow ApDCs with enhanced biostability, prolonged circulation half-life, and high drug loading content remained elusive. Herein, we present a polymeric approach to engineer ApDCs via conjugation of cell-targeting aptamers with water-soluble polyprodrugs containing a reductive environmentally sensitive prodrug and biocompatible brush-like backbone. The resultant high-drug loading Aptamer-PolyproDrug Conjugates (ApPDCs) exhibited high nuclease resistance, extended in vivo circulation time, specific recognition, and cellular uptake to target cells, reduction-triggered and fluorescent-reporting drug release, and effective cytotoxicity. We could also further expand this design principle toward combination therapy by using two kinds of therapeutic drugs with distinct pharmacological mechanisms.

6.
Nat Commun ; 10(1): 2704, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221964

RESUMO

Attachment of lipid tails to oligonucleotides has emerged as a powerful technology in constructing cell membrane-anchorable nucleic acid-based probes. In practice, however, conventional lipid-conjugated oligonucleotides fail to distinguish among different cell membranes. Herein, a phosphorylated lipid-conjugated oligonucleotide (DNA-lipid-P) is reported for alkaline phosphatase (ALP)-dependent cell membrane adhesion. In the absence of ALP, DNA-lipid-P with its poor hydrophobicity shows only weak interaction with cell membrane. However, in the presence of the highly expressed plasma membrane-associated ALP, DNA-lipid-P is converted to lipid-conjugated oligonucleotide (DNA-lipid) by enzymatic dephosphorylation. As a result of such conversion, the generated DNA-lipid has greater hydrophobicity than DNA-lipid-P and is thus able to insert into cell membranes in situ. Accordingly, DNA-lipid-P enables selective anchoring on cell membranes with elevated ALP level. Since elevated ALP level is a critical index of some diseases and even cancers, DNA-lipid-P holds promise for cell membrane engineering and disease diagnostics at the molecular level.


Assuntos
Fosfatase Alcalina/metabolismo , Membrana Celular/metabolismo , Sondas Moleculares/metabolismo , Oligonucleotídeos/metabolismo , Linhagem Celular Tumoral , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lipídeos/química , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Imagem Molecular/métodos , Sondas Moleculares/química , Oligonucleotídeos/química , Compostos Organofosforados/química , Fosforilação
7.
Mol Med Rep ; 18(6): 5353-5360, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30365108

RESUMO

Pilose antler polypeptide (PAP) is an active substance isolated from the traditional Chinese medicine pilose antler, which possesses multiple biological activities. In the present study, the role and mechanism of PAP in sevoflurane (SEV)­induced neurocyte injury was explored. Cell viability was determined by Cell Counting kit­8 assay. Cell proliferation and apoptosis were analyzed by flow cytometry. Western blotting and reverse transcription­quantitative polymerase chain reaction analysis were used to evaluate the protein and mRNA expression levels, respectively. The results revealed that PAP enhanced the cell viability of SEV­treated nerve cells. In addition, through modulation of apoptosis­associated protein expression, PAP suppressed SEV­induced nerve cell apoptosis. Furthermore, PAP activated the p38 mitogen­activated protein kinase (p38)/c­Jun N­terminal kinase (JNK) pathway in the neurocyte injury model, whereas inhibition of the p38/JNK pathway reversed the beneficial effects produced by PAP. In conclusion, PAP protected against SEV­mediated neurocyte injury via upregulation of the p38/JNK pathway. The present findings suggested that PAP may be an effective agent for neurocyte injury.


Assuntos
Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Peptídeos/farmacologia , Sevoflurano/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Expressão Gênica , Masculino , Neurônios/patologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Ratos
8.
J Cell Biochem ; 2018 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-30246300

RESUMO

BACKGROUND AND OBJECTIVES: In this study, we aimed to study the molecular mechanisms underlying the symptoms of hyperresponsiveness during intubation. METHOD: The value of circulating long noncoding RNA (lncRNA)-prognosis-associated gallbladder cancer (PAGBC) in the prediction of hyperresponsiveness upon intubation during general anesthesia was evaluated via the receiver operating characteristic analyses of serum miR-511, serum PAGBC, and serum nitric oxide (NO). In addition, the possible association between lncRNA-PAGBC/NOS1 messenger RNA (mRNA) and miR-511 was further validated via real-time quantitative polymerase chain reaction, immunohistochemistry assay, computational analysis, and luciferase assay. Enzyme-linked immunosorbent assay and Western blot analysis were also conducted to establish the regulatory relationship among PAGBC, miR-511, and NO synthase 1 (NOS1). RESULTS: Compared with circulating miR-511 and serum NO, circulating PAGBC was associated with a higher predictive value. In addition, a negative correlation was found between serum miR-511 and serum PAGBC (multicorrelation coefficient: -0.5) as well as between serum miR-511 and serum NO (multicorrelation coefficient: -0.6). In addition, both lncRNA-PAGBC and NO were decreased in patients with hyperresponsiveness, whereas the levels of miR-511 and NOS1 in these patients were similar to those in normal patients. Furthermore, our computational analyses and luciferase assays validated the direct binding between miR-511 and lncRNA-PAGBC, whereas NOS1 mRNA was identified as a virtual target gene of miR-511. Moreover, in the presence of lncRNA-PAGBC, we also observed an evident increase in the levels of NOS1 and NO accompanied by an obvious decrease of miR-511 expression. CONCLUSION: LncRNA-PAGBC downregulated the expression of miR-511, which in turn upregulated the expression of NOS1 mRNA and led to the increase in NOS1 expression, thus leading to the inhibited responsiveness (normal-responsiveness rather than hyperresponsiveness) to intubation in patients.

9.
Biomaterials ; 182: 216-226, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30138784

RESUMO

Aptamers are often compared with antibodies since both types of molecules function as targeting ligands for specific cancer cell recognition. However, aptamers offer several advantages, including small size, facile chemical modification, high chemical stability, low immunogenicity, rapid tissue penetration, and engineering simplicity. Despite these advantages, several crucial factors have delayed their clinical translation, such as concerns over inherent physicochemical stability and safety. Meanwhile, steps have been taken to make aptamer-drug conjugates, or ApDCs, a clinically practical tool. In this review, we highlight the development of ApDCs and discuss how researchers are solving some problems associated with their clinical application for targeted therapy.


Assuntos
Aptâmeros de Nucleotídeos/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Preparações Farmacêuticas/administração & dosagem , Técnica de Seleção de Aptâmeros/métodos , Animais , Humanos , Preparações Farmacêuticas/química
10.
BMC Genet ; 19(1): 46, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-30029590

RESUMO

BACKGROUND: This study aimed to explore the molecular mechanism of estrogen-mediated neuroprotection in the relief of cerebral ischemic injury. The gene expression profiles were downloaded from Gene Expression Omnibus database, and differentially expressed genes (DEGs) were identified using limma package in R software. Further, DEGs were subjected to Gene Ontology (GO) cluster analysis using online Gene Ontology Enrichment Analysis Software Toolkit and to GO functional enrichment analysis using DAVID software. Using the Gene Set Analysis Toolkit V2, enrichment analysis of Kyoto Encyclopedia of Genes and Genomes pathways was performed. In addition, protein-protein interaction (PPI) network was constructed using STRING database, and submodule analysis of PPI network. Lastly, the significant potential target sites of microRNAs (miRNAs) were predicted using Molecular Signatures Database, and the function analysis of targets of predicted miRNA was also performed using DAVID software. RESULTS: In total, 321 DEGs were screened in the estrogen-treated sample. The DEGs were mainly associated with intracellular signaling and metabolic pathways, such as calcium channel, calcineurin complex, insulin secretion, low-density lipoprotein reconstruction, and starch or sugar metabolism. In addition, GO enrichment analysis indicated an altered expression of the genes related to starch and sucrose metabolism, retinol metabolism, anti-apoptosis (eg., BDNF and ADAM17) and response to endogenous stimulus. The constructed PPI network comprised of 243 nodes and 590 interaction pairs, and four submodules were obtained from PPI network. Among the module d, four glutamate receptors as Gria4, Gria3, Grin3a and Grik4 were highlighted. Further, 5 novel potential regulatory miRNAs were also predicted. MIR-338 and MIR520D were closely associated with cell cycle, while the targets of MIR-376A and MIR-376B were only involved in cell soma. CONCLUSIONS: The DEGs in estrogen-treated samples are closely associated with calcium channel, glutamate induced excitotoxicity and anti-apoptotic activity. In addition, some functionally significant DEGs such as BDNF, ADAM17, Gria4, Gria3, Grin3a, Grik4, Gys2 and Ugtla2, and new miRNAs like MIR-338 and MIR-376A were identified, which may serve as potential therapeutic targets for the effective treatment of cerebral ischemic injury.


Assuntos
Isquemia Encefálica/patologia , Estrogênios/farmacologia , Neuroproteção/genética , Proteína ADAM17/genética , Animais , Apoptose/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Canais de Cálcio/metabolismo , Bases de Dados Genéticas , Ácido Glutâmico/toxicidade , Glicoproteínas de Membrana/genética , MicroRNAs/genética , Ratos , Receptores de AMPA/genética , Transcriptoma
11.
Med Sci Monit ; 24: 4982-4991, 2018 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-30018280

RESUMO

BACKGROUND Collapsin response mediator protein-2 (CRMP-2) is the first member of the CRMP family that has been identified in primary neuronal cells; it was originally found and identified in the regulation of microtubule dimerization into microtubules. MATERIAL AND METHODS In the present study, we aimed to investigate the roles and mechanisms of CRMP-2 in sevoflurane-induced neurocyte injury. Cell viability, proliferation, and apoptosis were measured by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. Colorimetry was performed to measure the activity of caspase-3. Western blot and quantitative real-time reverse transcription assays were used to evaluate the related mRNAs and proteins expression. RESULTS We found that CRMP-2 reversed the inhibitory effect of sevoflurane on the viability of nerve cells. Moreover, CRMP-2 accelerated the proliferation and suppressed the apoptosis of sevoflurane-induced nerve cells. CRMP-2 modulated the expression levels of apoptosis-associated protein in sevoflurane-induced nerve cells. Furthermore, it was demonstrated that CRMP-2 impacted the PI3K-mTOR-S6K pathway. CONCLUSIONS CRMP2 ameliorated sevoflurane-mediated neurocyte injury by targeting the PI3K-mTOR-S6K pathway. Thus, CRMP2 might be an effective target for sevoflurane-induced neurocyte injury therapies.


Assuntos
Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Traumatismos dos Nervos Cranianos/tratamento farmacológico , Feminino , Hipocampo/efeitos dos fármacos , Éteres Metílicos/farmacologia , Proteínas do Tecido Nervoso/farmacologia , Neurônios/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Gravidez , Ratos , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas/metabolismo , Sevoflurano , Serina-Treonina Quinases TOR/metabolismo
12.
Biochem Biophys Res Commun ; 502(3): 409-414, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-29852169

RESUMO

Hepatic ischemia and reperfusion (I/R) injury is a major cause of liver damage during liver transplantation, resection surgery, shock, and trauma. It has been reported that TXNIP expression was upregulated in a rat model of hepatic I/R injury. However, the role of TXNIP in the hepatic I/R injury is little known. In our study, we investigated the biological role of TXNIP and its potential molecular mechanism in the human hepatic cell line (HL7702 cells). Using oxygen-glucose deprivation and reoxygenation (OGD/R) to create a cell model of hepatic I/R injury, we found that the mRNA and protein expression levels of TXNIP were upregulated in HL7702 cells exposed to OGD/R. TXNIP overexpression remarkably promoted OGD/R-induced cell apoptosis and lactate dehydrogenase (LDH) release, both of which were significantly decreased by TXNIP knockdown. The production of malondialdehyde (MDA) was also increased by TXNIP overexpression, but was reduced by TXNIP knockdown. Moreover, TXNIP overexpression significantly upregulated the phosphorylation of p38 and JNK, which was remarkably inhibited by TXNIP knockdown. Additionally, p38-specific inhibitor SB203580 abrogated the effect of TXNIP overexpression on OGD/R-induced cell injury. Taken together, these results indicated that TXNIP knockdown alleviated hepatocyte I/R injury through preventing p38/JNK pathway activation. Thus, TXNIP might offer a novel potential therapeutic target for the treatment of hepatic I/R injury.


Assuntos
Proteínas de Transporte/metabolismo , Hepatócitos/metabolismo , Sistema de Sinalização das MAP Quinases , Traumatismo por Reperfusão/metabolismo , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Linhagem Celular , Técnicas de Silenciamento de Genes , Hepatócitos/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Malondialdeído/metabolismo , Modelos Biológicos , Piridinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/terapia , Regulação para Cima
13.
Mol Med Rep ; 18(1): 333-341, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29749511

RESUMO

Brain ischemia leads to energy depletion, mitochondrial dysfunction and neuronal cell death. The present study was designed to identify key genes and pathways associated with brain ischemia. The gene expression profile GSE52001, including 3 normal brain samples and 3 cerebral ischemia samples, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified using the limma package. Then functional and pathway enrichment analyses were performed by the MATHT tool. Protein­protein interaction (PPI) network, module selection and microRNA (miRNA)­target gene network were constructed utilizing Cytoscape software. A total of 488 DEGs were identified (including 281 upregulated and 207 downregulated genes). In the PPI network, Rac family small GTPase 2 (RAC2) had higher degrees. RAC2 was significantly enriched in the FcγR­mediated phagocytosis pathway. miR­29A/B/C had a higher degree in the miRNA­target gene network. Insulin like growth factor 1 (Igf1) was identified as the target gene for miR­29A/B/C. RAC2 may function in brain ischemia through mediating the FcγR­mediated phagocytosis pathway. Meanwhile, miR­29A/B/C and their targets gene Igf1 may serve important roles in the development and progression of brain ischemia.


Assuntos
Isquemia Encefálica/metabolismo , Biologia Computacional , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Análise de Sequência com Séries de Oligonucleotídeos , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , MicroRNAs/biossíntese , MicroRNAs/genética , Ratos , Ratos Sprague-Dawley , Proteínas rac de Ligação ao GTP/biossíntese , Proteínas rac de Ligação ao GTP/genética
14.
Mol Med Rep ; 15(4): 2120-2128, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28260076

RESUMO

Previous gene expression profiling studies of neuropathic pain (NP) following spinal cord injury (SCI) have predominantly been performed in animal models. The present study aimed to investigate gene alterations in patients with spinal cord injury and to further examine the mechanisms underlying NP following SCI. The GSE69901 gene expression profile was downloaded from the public Gene Expression Omnibus database. Samples of peripheral blood mononuclear cells (PBMCs) derived from 12 patients with intractable NP and 13 control patients without pain were analyzed to identify the differentially expressed genes (DEGs), followed by functional enrichment analysis and protein­protein interaction (PPI) network construction. In addition, a transcriptional regulation network was constructed and functional gene clustering was performed. A total of 70 upregulated and 61 downregulated DEGs were identified in the PBMC samples from patients with NP. The upregulated and downregulated genes were significantly involved in different Gene Ontology terms and pathways, including focal adhesion, T cell receptor signaling pathway and mitochondrial function. Glycogen synthase kinase 3 ß (GSK3B) was identified as a hub protein in the PPI network. In addition, ornithine decarboxylase 1 (ODC1) and ornithine aminotransferase (OAT) were regulated by additional transcription factors in the regulation network. GSK3B, OAT and ODC1 were significantly enriched in two functional gene clusters, the function of mitochondrial membrane and DNA binding. Focal adhesion and the T cell receptor signaling pathway may be significantly linked with NP, and GSK3B, OAT and ODC1 may be potential targets for the treatment of NP.


Assuntos
Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Neuralgia/complicações , Neuralgia/genética , Mapas de Interação de Proteínas , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/genética , Biologia Computacional , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Família Multigênica , Neuralgia/metabolismo , Mapeamento de Interação de Proteínas , Transdução de Sinais , Traumatismos da Medula Espinal/metabolismo
15.
Dalton Trans ; 45(26): 10807-20, 2016 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-27294827

RESUMO

Reactions of amine-bridged bis(phenolate) protio-ligands N,N-bis(3,5-di-tert-butyl-2-hydroxybenzyl)aminoacetic acid (L(1)-H3) and N,N-bis[3,5-bis(α,α'-dimethylbenzyl)-2-hydroxybenzyl]aminoacetic acid (L(2)-H3), with 1 equiv. M[N(SiMe3)2]3 (M = La, Nd, Sm, Gd, Y) in THF at room temperature yielded the neutral rare-earth complexes [M2(L)2(THF)4] (L = L(1), M = La (), Nd (), Sm (), Gd (), Y (); L = L(2), M = La (), Nd (), Sm (), Gd (), Y ()). All of these complexes were characterized by single-crystal X-ray diffraction, elemental analysis and in the case of yttrium and lanthanum complexes, (1)H NMR spectroscopy. The molecular structure of revealed dinuclear species in which the eight-coordinate lanthanum centers were bonded to two oxygen atoms of two THF molecules, to three oxygen atoms and one nitrogen atom of one L(1) ligand, and two oxygen atoms of the carboxyl group of another. Complexes were also dinuclear species containing seven-coordinate metal centers similar to , albeit with bonding to one rather than two carboxyl group oxygens of another ligand. Further treatment of with excess benzyl alcohol provided dinuclear complex [La2(L(1))2(BnOH)6] (), in which each lanthanum ion is eight-coordinate, bonded to three oxygen atoms and one nitrogen atom of one ligand, three oxygen atoms of three BnOH molecules, as well as one oxygen atom of bridging carboxyl group of the other ligand. In the presence of BnOH, complexes efficiently catalyzed the ring-opening polymerization of l-lactide in a controlled manner and gave polymers with relatively narrow molecular weight distributions. The kinetic and mechanistic studies associated with the ROP of l-lactide using /BnOH initiating system have been performed.


Assuntos
Aminas/química , Complexos de Coordenação/química , Dioxanos/química , Metais Terras Raras/química , Fenóis/química , Polimerização , Aminas/síntese química , Catálise , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Ligantes , Metais Terras Raras/síntese química , Modelos Moleculares , Fenóis/síntese química , Poliésteres/síntese química
16.
Nutr Neurosci ; 19(2): 63-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25411761

RESUMO

BACKGROUND/AIMS: Global cerebral ischemia/reperfusion (GCIR) may incur neurocognitive impairment. Tea polyphenols (TP) have strong anti-oxidant capacity. This study planned to investigate the protective effect of TP against the neurocognitive impairment caused by GCIR and its mechanism. METHODS: One-stage anterior approach for cerebral four-vessel occlusion (4VO) was used to construct the GCIR model. Sprague Dawley rats were randomly classified into Sham group, GCIR group, and TP group (n = 50 per group). Besides receiving the same 4VO, the rats in TP group were treated with TP (6.4%) injection from the tail vein 30 minutes before cerebral ischemia. Morris water-maze test was used to evaluate the changes in space recognition and memory and open field activity test to assess the activity and motor function of rats. The cell apoptotic study in hippocampal CA1 region at specified time points (12, 24, 48, and 72 hours after surgery) was carried out by the flow cytometry, histology (hematoxylin and eosin staining), and immunohistochemical (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining) examinations. One-way analysis of variance and least significant difference t-test were used and statistical significance considered at P < 0.05. RESULTS: Compared with the GCIR group, the TP group was significantly attenuated in the impairment of space recognition and memory caused by GCIR and so was the neuronal apoptosis in the hippocampal CA1 region (P < 0.05). CONCLUSION: TP may attenuate the impairment of space recognition and memory caused by GCIR via anti-apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Isquemia Encefálica/fisiopatologia , Transtornos Neurocognitivos/tratamento farmacológico , Polifenóis/farmacologia , Chá/química , Animais , Antioxidantes/farmacologia , Isquemia Encefálica/tratamento farmacológico , Região CA1 Hipocampal/efeitos dos fármacos , Modelos Animais de Doenças , Marcação In Situ das Extremidades Cortadas , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
17.
Int J Mol Med ; 36(6): 1593-600, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26498025

RESUMO

The present study aimed to explore potential molecular targets and gain further insights into the mechanism of intervertebral disc degeneration (IDD) progression. Microarray datasets of GSE19943, GSE15227 and GSE34095 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) in 3 IDD specimens compared with 3 controls in GSE34095, DEGs in 7 grade III and 3 grade IV samples compared with 5 grade II samples in GSE19943, and differentially expressed miRNAs in 3 degenerated samples compared with 3 controls in GSE15227 were screened. Grade III­ and IV­specific networks were constructed and grade­specific genes were extracted. The network features were analyzed, followed by Gene Ontology (GO) enrichment analysis and pathway enrichment analysis of grade­specific genes and DEGs identified in GSE34095. Furthermore, miRNA­pathway interactions were analyzed using Fisher's exact test. Tumor protein p53 (TP53) was a hub gene in the grade III­specific network and ubiquitin C (UBC) was identified to be a hub gene in the grade IV­specific network. Six significant features were identified by grade­specific network topology analysis. Grade­specific genes and DEGs were involved in different GO terms and pathways. Differentially expressed miRNAs were identified to participate in 35 pathways, among which 6 pathways were significantly enriched by DEGs, including apoptosis. The present study identified that key genes (TP53 and UBC) and miR­129­5p may participate in the mechanism of IDD progression. Thus, they may be potential therapeutic targets for IDD.


Assuntos
Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Predisposição Genética para Doença/genética , Degeneração do Disco Intervertebral/genética , Análise por Conglomerados , Bases de Dados Genéticas , Ontologia Genética , Redes Reguladoras de Genes/genética , Humanos , Modelos Logísticos , MicroRNAs/genética , Transdução de Sinais/genética
18.
J Pharm Pharm Sci ; 18(2): 199-206, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26158285

RESUMO

PURPOSE: To compare the effect of desflurane versus sevoflurane in pediatric anesthesia by conducting meta-analysis. METHODS: Studies were searched from PubMed, Medline, Springer, Elsevier Science Direct, Cochrane Library and Google Scholar up to July 2014. Weighted mean difference (WMD) or risk ratio (RR) and 95% confidence intervals (CIs) were considered as effect sizes. Heterogeneity across studies was assessed by Cochran Q test and I2 statistic. The random effects model was performed in the meta-analysis when heterogeneity was observed, or the fixed effect model was used. Review Manager 5.1 software was applied for the meta-analysis. RESULTS: A total of 11 studies (13 comparisons) involving 1,273 objects were included in this meta-analysis. No heterogeneity was observed between studies for any comparison but for postoperative extubation time. The results showed significant differences between desflurane and sevoflurane groups for postoperative extubation time (WMD = -3.87, 95%CI = -6.14 to -1.60, P < 0.01), eye opening time (WMD = -1.11, 95%CI = -1.49 to -0.72, P < 0.01), awakening time (WMD = -4.27, 95%CI = -5.28 to -3.26, P < 0.01) and agitation (RR = 1.44, 95%CI = 1.05 to 1.96, P = 0.02). No significant differences (P > 0.05) were detected for discharge from the recovery room, oculocardiac reflex, nausea and vomiting and severe pain. CONCLUSIONS: Desflurane may have less adverse effects than sevoflurane when used in pediatric anesthesia with significantly shorter postoperative extubation time, eye opening time and awakening time as well as slighter agitation.


Assuntos
Anestesia , Isoflurano/análogos & derivados , Éteres Metílicos/efeitos adversos , Anestésicos Inalatórios/efeitos adversos , Criança , Desflurano , Humanos , Isoflurano/efeitos adversos , Sevoflurano
19.
Neurosci Bull ; 25(3): 115-21, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19448685

RESUMO

OBJECTIVE: To investigate the protein levels of phospho-ERK and phospho-APE/Ref-1 in hippocampal neurons after global cerebral ischemia reperfusion in rats, and observe the relationship between transmembrane signal transduction and repair of DNA damage. The role of ERK signal transduction pathway following global cerebral ischemia reperfusion in rats is further discussed. METHODS: Ninety healthy male SD rats were divided into 3 groups randomly: Sham group (S group), Ischemia reperfusion group (IR group) and Pd98059 pretreatment/ischemia reperfusion group (PD group). Global cerebral ischemia reperfusion model was established by four-vessel occlusion (4-VO) method, and reperfusion was performed 5 minutes following ischemia. Protein levels of phospho-ERK and phospho-APE/Ref-1 were detected using immunohistochemical method at 2 h, 6 h, 12 h, 24 h, 48 h and 72 h after reperfusion, and neuron apoptosis was observed by HE and TUNEL staining. RESULTS: In CA1 region of IR group, TUNEL positive cells began to appear at 6 h after IR, and reached the apex during 24 h to 48 h. However, TUNEL positive was most strongly exhibited in PD group. In IR group, phospho-ERK was obviously detected in CA3 region at 2 h after IR, and its level was gradually decreased from 6 h until totally absent at 48 h. Besides, phospho-ERK expression in PD group was weaker than that in IR group. For phospho-APE/Ref-1, its expression began to appear in CA1 region in IR group at 2 h after IR, with no obvious changes during 2 h to 12 h. Phospho-APE/Ref-1 expression began to decrease at 24 h and this decrease continued thereafter. Expression level of phospho-APE/Ref-1 in PD group was lower than that in IR group. Results showed the concurrence of decreased phospho-ERK expression level and increased neuron apoptosis after cerebral ischemia reperfusion, the former of which was consistent with the decrease of phospho-APE/Ref-1 expression. Also, the greater the inhibition of ERK phosphorylation was, the greater decrease of APE/Ref-1 expression occurred. CONCLUSION: Activation of ERK signal transduction pathway increased the expression of phospho-APE/Ref-1, and thus faciliated the repair of DNA damage. So, activation of ERK signal transduction pathway may protect neurons from apoptosis after cerebral ischemia reperfusion.


Assuntos
Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Reparo do DNA/fisiologia , Reperfusão/efeitos adversos , Transdução de Sinais/fisiologia , Animais , Isquemia Encefálica/prevenção & controle , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Flavonoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Marcação In Situ das Extremidades Cortadas/métodos , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
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