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1.
Lab Invest ; 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201368

RESUMO

Microvascularity is highly correlated with the grading and subtyping of gliomas, making this one of its most important histological features. Accurate quantitative analysis of microvessels is helpful for the development of a targeted therapy for antiangiogenesis. The deep-learning algorithm is by far the most effective segmentation and detection model and enables location and recognition of complex microvascular networks in large images obtained from hematoxylin and eosin (H&E) stained specimens. We proposed an automated deep-learning-based method to detect and quantify the microvascularity in glioma and applied it to comprehensive clinical analyses. A total of 350 glioma patients were enrolled in our study, for which digitalized imaging of H&E stained slides were reviewed, molecular diagnosis was performed and follow-up was investigated. The microvascular features were compared according to their histologic types, molecular types, and patients' prognosis. The results show that the proposed method can quantify microvascular characteristics automatically and effectively. Significant increases of microvascular density and microvascular area were observed in glioblastomas (95% p < 0.001 in density, 170% p < 0.001 in area) in comparison with other histologic types; increases were also observed in cases with TERT-mut only (68% p < 0.001 in density, 54% p < 0.001 in area) compared with other molecular types. Survival analysis showed that microvascular features can be used to cluster cases into two groups with different survival periods (hazard ratio [HR] 2.843, log-rank <0.001), which indicates the quantified microvascular features may potentially be alternative signatures for revealing patients' prognosis. This deep-learning-based method may be a useful tool in routine clinical practice for precise diagnosis and antiangiogenic treatment.

2.
Int Immunopharmacol ; 72: 48-54, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30959371

RESUMO

Oxidative stress is considered as major culprit for neurodegenerative diseases and triggers cognitive and memory impairments. The present study mainly aimed to study the protective effects and underlying mechanisms of aloin on d-galactose (d-gal) induced ageing mice. Our results demonstrated that chronic administration of d-gal (150 mg kg-1) in mice caused spontaneous and cognitive impairments, as determined by open-field test and Morris water-maze test. Aloin treatment significantly ameliorated histopathological damage, attenuated the microglia activation and reduced levels of inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 in the hippocampus. Moreover, it effectively suppressed the level of reactive oxygen species (ROS) and increased antioxidant enzymes activities. Further data showed that these protective effects were accompanied by inhibition of the activation of nuclear factor kappa B and the phosphorylation of p38 and ERK. In conclusion, the present study suggests that aloin can ameliorate d-gal induced oxidative stress, cognitive impairment and inflammation, possibly via mediating the ERK, p38 and NF-κB signaling pathways.

3.
Brain Pathol ; 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30861589

RESUMO

Giant cell glioblastoma (gcGBM) is a rare histological variant of GBM, accounting for about 1% of all GBM. The prognosis is poor generally though gcGBM does slightly better than the other IDH-wild-type GBM. Because of the rarity of the cases, there has been no comprehensive molecular analysis of gcGBM. Previously, single-gene study identified genetic changes in TP53, PTEN and TERT promoter mutation in gcGBM. In this report, we performed whole-exome sequencing (WES) to identify somatically acquired mutations and copy number variations (CNVs) in 10 gcGBM genomes. We also examined TERT promoter mutation and MGMT methylation in our cohort. On top of the reported mutations, WES revealed ATRX, PIK3R1, RB1 and SETD2 as the recurrent mutations in gcGBM. Notably, one tumor harbored a mutation in MutS homolog 6 (MSH6) that is a key mismatch repair (MMR) gene. This tumor demonstrated hypermutation phenotype and showed an increased number of somatic mutations. TERT promoter mutation and MGMT methylation were observed in 20% and 40% of our samples, respectively. In conclusion, we described relevant mutation profiling for developing future targeted therapies in gcGBM.

4.
Front Psychiatry ; 9: 483, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386260

RESUMO

Post-stroke depression (PSD) is one of the most frequent complications of stroke. The Yi-nao-jie-yu prescription (YNJYP) is an herbal prescription widely used as a therapeutic agent against PSD in traditional Chinese medicine. Disruption of adult neurogenesis has attracted attention as a potential cause of cognitive pathophysiology in neurological and psychiatric disorders. The Notch signaling pathway plays an important role in neurogenesis. This study investigated the effects of YNJYP on adult neurogenesis and explored its underlying molecular mechanism in a rat model of PSD that is established by middle cerebral artery occlusion and accompanied by chronic immobilization stress for 1 week. At 2, 4, and 8 weeks, depression-like behavior was evaluated by a forced swim test (FST) and sucrose consumption test (SCT). Neurogenesis was observed by double immunofluorescence staining. Notch signals were detected by real-time polymerase chain reaction. The results show that, at 4 weeks, the immobility time in the FST for rats in the PSD group increased and the sucrose preference in the SCT decreased compared with that in the stroke group. Therefore, YNJYP decreased the immobility time and increased the sucrose preference of the PSD rats. Further, PSD interfered with neurogenesis and decreased the differentiation toward neurons of newly born cells in the hippocampal dentate gyrus, and increased the differentiation toward astrocytes, effects that were reversed by YNJYP, particularly at 4 weeks. At 2 weeks, compared with the stroke group, expression of target gene Hes5 mRNA transcripts in the PSD group decreased, but increased after treatment with YNJYP. At 4 weeks, compared with the stroke group, the expression of Notch receptor Notch1 mRNA transcripts in the PSD group decreased, but also increased after treatment with YNJYP. Overall, this study indicated that disturbed nerve regeneration, including the increased numbers of astrocytes and decrease numbers of neurons, is a mechanism of PSD, and Notch signaling genes dynamically regulate neurogenesis. Moreover, YNJYP can relieve depressive behavior in PSD rats, and exerts a positive effect on neurogenesis by dynamically regulating the expression of Notch signaling genes.

5.
Bioconjug Chem ; 29(11): 3561-3570, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30371055

RESUMO

Neural stem cells (NSCs) have been attractive donor sources for cell therapy in traumatic brain injuries (TBI). Monitoring the fate of transplanted cells, including the survival and differentiation, will provide vital information to assess the outcome during the therapy time course. However, the current labeling methods are based on the principles of cell endocytosis, demanding relatively high fluorescent probes concentration and long incubation time, which may affect the proliferation and differentiation of transplanted cells. In our study, an efficient and relatively fast labeling strategy for NSCs with Cy3 based on DNA hybridization was proposed for monitoring the fate of transplanted cells. The oligo[dA]20 conjugated with Cy3 was anchored on NSCs which had modified with oligo[dT]20 via the oligo[dT]20-oligo[dA]20 hybridization. This labeling system did not affect the viability of labeled NSCs. After implantation of labeled NSCs into the brain, immunohistology demonstrated implanted cells were able to survive and differentiate into mature neural cells as long as one month. In conclusion, the DNA hybridization system can be used as an efficient cell labeling method in cell therapy.

6.
Oncol Rep ; 40(2): 579-588, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29901146

RESUMO

Radiosensitivity of prostate cancer (PCa) cells promotes the curative treatment for PCa. The present study was designed to investigate the synergistic effect of genistein and AG1024 on the radiosensitivity of PCa cells. The optimal X­irradiation dose (4 Gy) and genistein concentration (30 µM) were selected by using the CCK­8 assay. Before X­irradiation (4 Gy), PC3 and DU145 cells were treated with genistein (30 µM), AG1024 (10 µM) and their combination. All treatments significantly reduced cell proliferation and enhanced cell apoptosis. Using flow cytometric analysis, we found that genistein arrested the cell cycle at S phase and AG1024 arrested the cell cycle at G2/M phase. Genistein treatment suppressed the homologous recombination (HRR) and the non­homologous end joining (NHEJ) pathways by inhibiting the expression of Rad51 and Ku70, and AG1024 treatment only inhibited the NHEJ pathway via the inactivation of Ku70 as detected by western blot analysis. Moreover, the combination treatment with genistein and AG1024 more effectively radiosensitized PCa cells than single treatments by suppressing cell proliferation, enhancing cell apoptosis and inactivating the HRR and NHEJ pathways. In vivo experiments demonstrated that animals receiving the combination treatment with genistein and AG1024 displayed obviously decreased tumor volume compared with animals treated with single treatment with either genistein or AG1024. We conclude that the combination of genistein (30 µM) and AG1024 (10 µM) exhibited a synergistic effect on the radiosensitivity of PCa cells by suppressing the HRR and NHEJ pathways.


Assuntos
Genisteína/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Tirfostinas/farmacologia , Animais , Anticarcinógenos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , Sinergismo Farmacológico , Recombinação Homóloga/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos
7.
J Nanobiotechnology ; 16(1): 25, 2018 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-29592798

RESUMO

BACKGROUND: The size and receptor-binding abilities of plasma lipoproteins are closely related with their structure/functions. Presently, the sizes of native lipoproteins have been measured by various methods including atomic force microscopy (AFM) whereas the sizes of modified lipoproteins are poorly determined and the receptor-binding ability of lipoproteins is less detected and compared at the nanoscale. METHODS: Here, AFM was utilized to detect/compare the size and scavenger receptor-binding properties of three native human lipoproteins including high-density lipoprotein, low-density lipoprotein (LDL), and very low-density lipoprotein, and two modified human lipoproteins including oxidized and acetylated LDL, as well as bovine serum albumin and their antibodies as negative and positive controls, respectively. RESULTS: AFM detected that the sizes of these lipoproteins are close to the commonly known values and the previously-reported AFM-detected sizes and that native and modified LDL have different height/size. AFM also revealed that the CD36-binding abilities of the five lipoproteins are different from one another and from their SR-B1-binding abilities and that the anti-CD36/SR-B1 antibodies as positive controls have strong CD36/SR-B1-binding abilities. CONCLUSIONS: The data provide important information on lipoproteins for better understanding their structures/functions. Moreover, the data certify that besides size measurement AFM also can visualize receptor-lipoprotein binding at the nanoscale, as well as antigen-antibody (scavenger receptors and their antibodies) binding.


Assuntos
Lipoproteínas LDL/metabolismo , Microscopia de Força Atômica , Tamanho da Partícula , Receptores Depuradores/metabolismo , Antígenos CD36/metabolismo , Humanos , Nanopartículas/química , Ligação Proteica , Soroalbumina Bovina/metabolismo
8.
Acta Biomater ; 69: 146-155, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29330037

RESUMO

Facial nerve injury caused by traffic accidents or operations may reduce the quality of life in patients, and recovery following the injury presents unique clinical challenges. Glial cell-derived neurotrophic factor (GDNF) is important in nerve regeneration; however, soluble GDNF rapidly diffuses into body fluids, making it difficult to achieve therapeutic efficacy. In this work, we developed a rat tail derived collagen conduit to connect nerve defects in a simple and safe manner. GDNF was immobilized in the collagen conduits via chemical conjugation to enable controlled release of GDNF. The GDNF delivery system prevented rapid diffusion from the site without impacting bioactivity of GDNF; degradation of the collagen conduit was inhibited owing to the chemical conjugation. The artificial nerve conduit was then used to examine facial nerve regeneration across a facial nerve defect. Following transplantation, the artificial nerve conduits degraded gradually without causing dislocations and serious inflammation, with good integration into the host tissue. Functional and histological tests indicated that the artificial nerve conduits were able to guide the axons to grow through the defect, reaching the distal stumps. The degree of nerve regeneration in the group that was treated with the artificial nerve conduit approached that of the autograft group, and exceeded that of the other conduit grafted groups. STATEMENT OF SIGNIFICANCE: In this study, we developed artificial nerve conduits consisting of GDNF immobilized on collagen, with the aim of providing an environment for nerve regeneration. Our results show that the artificial nerve conduits guided the regeneration of axons to the distal nerve segment. GDNF was immobilized stably in the artificial nerve conduits, and therefore retained a sufficient concentration at the target site to effectively promote the regeneration process. The artificial nerve conduits exhibited good biocompatibility and facilitated nerve regeneration and functional recovery with an efficacy that was close to that of an autograft, and better than that of the other conduit grafted groups. Our approach provides an effective delivery system that overcomes the rapid diffusion of GDNF in body fluids, promoting peripheral nerve regeneration. The artificial nerve conduit therefore qualifies as a putative candidate material for the fabrication of peripheral nerve reconstruction devices.

9.
Biomed Pharmacother ; 97: 616-623, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29101805

RESUMO

MicroRNA-543 (miR-543) has been suggested as an important regulator of the development and progression of various cancer types. However, the role and biological function of miR-543 in clear cell renal cell carcinoma (ccRCC) remains unclear. Here, we found that miR-543 expression was significantly increased in tumor tissues from ccRCC patients and ccRCC cell lines. We found that overexpression of miR-543 markedly promoted the proliferation and invasion of ccRCC cells, whereas suppression of miR-543 had the opposite effects. Krüppel-like factor 6 (KLF6) was identified as a target gene of miR-543. Furthermore, we found that miR-543 negatively regulates the expression of KLF6 and p21 in ccRCC cells. Overexpression of KLF6 markedly attenuated the oncogenic effect of miR-543 overexpression. Moreover, knockdown of KLF6 significantly reversed the antitumor effect of miR-543 inhibition. Overall, our results demonstrate that miR-543 promotes the proliferation and invasion of ccRCC cells by targeting KLF6 and suggest that miR-543 may serve as a potential therapeutic target for treatment of ccRCC.


Assuntos
Carcinoma de Células Renais/metabolismo , Proliferação de Células/fisiologia , Neoplasias Renais/metabolismo , Fator 6 Semelhante a Kruppel/biossíntese , MicroRNAs/biossíntese , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Renais/patologia , Fator 6 Semelhante a Kruppel/antagonistas & inibidores , Invasividade Neoplásica/patologia
10.
BMC Neurol ; 17(1): 183, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28915860

RESUMO

BACKGROUND: Tumor location served as an important prognostic factor in glioma patients was considered to postulate molecular features according to cell origin theory. However, anatomic distribution of unique molecular subtypes was not widely investigated. The relationship between molecular phenotype and histological subgroup were also vague based on tumor location. Our group focuses on the study of glioma anatomic location of distinctive molecular subgroups and histology subtypes, and explores the possibility of their consistency based on clinical background. METHODS: We retrospectively reviewed 143 cases with both molecular information (IDH1/TERT/1p19q) and MRI images diagnosed as cerebral diffuse gliomas. The anatomic distribution was analyzed between distinctive molecular subgroups and its relationship with histological subtypes. The influence of tumor location, molecular stratification and histology diagnosis on survival outcome was investigated as well. RESULTS: Anatomic locations of cerebral diffuse glioma indicate varied clinical outcome. Based on that, it can be stratified into five principal molecular subgroups according to IDH1/TERT/1p19q status. Triple-positive (IDH1 and TERT mutation with 1p19q codeletion) glioma tended to be oligodendroglioma present with much better clinical outcome compared to TERT mutation only group who is glioblastoma inclined (median overall survival 39 months VS 18 months). Five molecular subgroups were demonstrated with distinctive locational distribution. This kind of anatomic feature is consistent with its corresponding histological subtypes. DISCUSSION: Each molecular subgroup in glioma has unique anatomic location which indicates distinctive clinical outcome. Molecular diagnosis can be served as perfect complementary tool for the precise diagnosis. Integration of histomolecular diagnosis will be much more helpful in routine clinical practice in the future.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Glioma/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Estudos Retrospectivos , Adulto Jovem
11.
Biochim Biophys Acta Biomembr ; 1859(5): 756-766, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28088446

RESUMO

In contrast to the released/circulating membrane vesicles (extracellular vesicles), cell-bound membrane vesicles are poorly identified and characterized. In this study, cell-bound membrane vesicles on human umbilical vein endothelial cells (HUVECs) and human hepatoma HepG-2 cells were investigated. We identified that cell-bound membrane vesicles are not co-localized with the major markers for extracellular vesicles (e.g. phosphatidylserine, CD63, CD107α, CD31, and DNA fragments for the three well-known types of extracellular vesicles) and for intracellular organelles with similar sizes (e.g. MitoTracker and LAMP1/LAMP3 for mitochondria and multivesicular bodies or lysosomes, respectively). The data imply that cell-bound membrane vesicles are neither the precursors of extracellular vesicles nor a false structure pushed up by an intracellular organelle but probably a novel unknown structure in the plasma membrane. Moreover, we revealed that cell-bound membrane vesicles are resistant to various detergents including but probably not limited to Triton X-100, SDS, and saponin. We further characterized that these unique vesicles are soluble in organic solvents (e.g. chloroform-methanol mixture and ethanol) which can be prevented by a lipid-stabilizing fixative (e.g. OsO4) and that they are co-localized with, but do not monopolize, the major markers (e.g. caveolin-1 and GM1) for lipid rafts (a nano-sized detergent-resistant domains in the plasma membrane). The data imply that cell-bound membrane vesicles contain the lipid component and lipid rafts. Involvement of other specific unknown components might explain the detergent resistance of cell-bound membrane vesicles. Further research will mainly depend on the establishment of an effective approach for isolation/purification of these vesicles from the plasma membrane.


Assuntos
Membrana Celular/ultraestrutura , Vesículas Extracelulares/química , Detergentes/farmacologia , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Microdomínios da Membrana/química , Organelas/química , Solubilidade
12.
Acta Biomater ; 50: 188-197, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-27940160

RESUMO

Introducing neural stem/progenitor cells (NS/PCs) for repairing facial nerve injuries could be an alternative strategy for nerve gap reconstruction. However, the lack of success associated with current methods of applying NS/PCs to neurological disease is due to poor engraftment following transplantation into the host tissue. In this work, we developed rat-tail collagen-based nerve conduits to repair lengthy facial nerve defects, promoting NS/PC proliferation in the natural nerve conduits with anchored bFGF to improve the therapeutic effects of cell transplantation. In vitro studies showed that heparinized collagen prevented leakage of bFGF and NS/PCs expended in the rat-tail collagen gel with the anchored bFGF. The natural nerve conduits were implanted to connect 8-mm facial nerve defects in rats. The repair outcomes including vibrissae movements, electrophysiological tests, immunohistochemistry and remyelination analysis of regenerated nerve were evaluated. At 12weeks after implantation, only natural nerve conduits treated group showed Hoechst labeled NS/PCs. Besides, the natural nerve conduit significantly promoted functional recovery and nerve growth, which was similar to those of the gold standard, an autograft. The animal experiment results suggesting that the natural nerve conduits were valuable for facial nerve reconstruction. STATEMENT OF SIGNIFICANCE: Neural stem/progenitor cells (NS/PCs) were beneficial for the treatment of nervous system diseases. However, after transplantation, the beneficial was limited because the number of living NS/PCs decreased rapidly due to insufficient signaling molecules, such as growth factors, in the microenvironments surrounding transplanted cells. In the present study, we constructed collagen-based nerve conduit with anchored bFGF to achieve higher numbers of NS/PCs for repairing facial nerve injury. Compared with other methods involving neutral salt treatment or dialysis, the fabrication method of collagen scaffolds was simple, low-cost and safe, requiring a relatively short time to prepare. At 12weeks after transplantation, the functional and histological results of natural nerve conduits treated group showed significant similarities to the gold standard method of nerve autografting.


Assuntos
Colágeno , Traumatismos do Nervo Facial/terapia , Nervo Facial/fisiologia , Fator 2 de Crescimento de Fibroblastos , Regeneração Nervosa/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Animais , Colágeno/química , Colágeno/farmacologia , Traumatismos do Nervo Facial/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/química , Fator 2 de Crescimento de Fibroblastos/farmacologia , Ratos , Ratos Sprague-Dawley
13.
Neuropsychiatr Dis Treat ; 12: 2827-2837, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27843317

RESUMO

BACKGROUND: The Yi-nao-jie-yu decoction (YNJYD) is a herbal preparation widely used in the clinics of traditional Chinese medicine and has been recently used as an important new therapeutic agent in poststroke anxiety (PSA). The neuroendocrine-immune system plays an important role in PSA mechanisms, although the modulating effects of YNJYD remain unknown. This study investigated the potential effects of YNJYD on the neuroendocrine-immune system in a rat model of PSA. MATERIALS AND METHODS: The PSA model was induced by injecting collagenase (type VII) into the right globus pallidus, accompanied by empty water bottle stimulation for 2 weeks. The sham group and the PSA model group were gavaged with saline, while the treatment groups received buspirone (BuSpar) or YNJYD. Behavior was evaluated with the open field test and elevated plus maze once a week. Pathological changes were observed by hematoxylin and eosin staining. Serum levels of tumor necrosis factor, interleukin (IL)-6, adrenocorticotropic hormone, thyroid stimulating hormone, free triiodothyronine, free thyroxine, IL-1α, and cortisol were detected by radioimmunoassay. Expression of the γ-aminobutyric acid type A receptor (GABAAR) α2 subunit was examined by Western blot and real-time polymerase chain reaction. RESULTS: YNJYD-treated rats exhibited significantly better recovery than BuSpar-treated rats at 21 days and 28 days in the open field test and elevated plus maze. Hematoxylin and eosin staining revealed neural repair in the hippocampus in the treatment groups. Serum levels of IL-1α in the YNJYD group were significantly less than those in the model group and the BuSpar group. GABAAR protein and mRNA expressions were higher in the PSA model group than in the sham group, and YNJYD reversed these effects. CONCLUSION: YNJYD alleviated the symptoms of PSA mainly by decreasing IL-1α levels and downregulating GABAAR expression in the hippocampus to maintain a neuroendocrine-mmune system balance.

14.
Oncol Rep ; 36(6): 3707-3715, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27748848

RESUMO

MicroRNAs (miRNAs) have emerged as important regulators in cancer that are implicated in regulation of various cellular processes. miR-382 has been proposed as a tumor suppressor by several recent studies. However, the function of miR-382 in prostate cancer remains unknown. In this study, we aimed to investigate the potential function of miR-382 in prostate cancer. We found that miR-382 was significantly decreased in prostate cancer specimens and cancer cell lines. The overexpression of miR-382 in prostate cancer cells markedly inhibited cell proliferation, migration, and invasion. In contrast, miR-382 suppression exhibited an opposite effect. Target analysis predicted that chicken ovalbumin upstream promoter transcription factor II (COUP­TFII) was a direct target of miR-382. This prediction was experimentally confirmed by dual-luciferase reporter assay, real-time quantitative polymerase chain reaction, and western blot analysis. Our results further demonstrated that miR-382 inhibited the downstream genes of COUP­TFII, including Snail and matrix metalloproteinase 2 (MMP2). Moreover, the restoration of COUP­TFII expression significantly blocked the inhibitory effect of miR-382 on cell proliferation, migration, and invasion, and Snail expression. Taken together, this study suggests that miR-382 inhibits prostate cancer cell proliferation and metastasis through inhibiting COUP­TFII, representing an important new mechanism for understanding prostate cancer pathogenesis and providing a novel therapeutic candidate target for prostate cancer therapy.


Assuntos
Fator II de Transcrição COUP/genética , Proliferação de Células , MicroRNAs/fisiologia , Neoplasias da Próstata/genética , Interferência de RNA , Regiões 3' não Traduzidas , Sequência de Bases , Sítios de Ligação , Fator II de Transcrição COUP/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metástase Neoplásica , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo
15.
Oncotarget ; 7(40): 64615-64630, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27556304

RESUMO

Although 1p/19q codeletion is the genetic hallmark defining oligodendrogliomas, approximately 30-40% of oligodendroglial tumors have intact 1p/19q in the literature and they demonstrate a worse prognosis. This group of 1p/19q intact oligodendroglial tumors is frequently suggested to be astrocytic in nature with TP53 and ATRX mutations but actually remains under-investigated. In the present study, we provided evidence that not all 1p/19q intact oligodendroglial tumors are astrocytic through histologic and molecular approaches. We examined 1p/19q status by FISH in a large cohort of 337 oligodendroglial tumors and identified 39.8% lacking 1p/19q codeletion which was independently associated with poor prognosis. Among this 1p/19q intact oligodendroglial tumor cohort, 58 cases demonstrated classic oligodendroglial histology which showed older patient age, better prognosis, association with grade III histology, PDGFRA expression, TERTp mutation, as well as frequent IDH mutation. More than half of the 1p/19q intact oligodendroglial tumors showed lack of astrocytic defining markers, p53 expression and ATRX loss. TP53 mutational analysis was additionally conducted in 45 cases of the 1p/19q intact oligodendroglial tumors. Wild-type TP53 was detected in 71.1% of cases which was associated with classic oligodendroglial histology. Importantly, IDH and TERTp co-occurred in 75% of 1p/19q intact, TP53 wild-type oligodendrogliomas, highlighting the potential of the co-mutations in assisting diagnosis of oligodendrogliomas in tumors with clear cell morphology and non-codeleted 1p/19q status. In summary, our study demonstrated that not all 1p/19q intact oligodendroglial tumors are astrocytic and co-evaluation of IDH and TERTp mutation could potentially serve as an adjunct for diagnosing 1p/19q intact oligodendrogliomas.


Assuntos
Astrócitos/fisiologia , Neoplasias Encefálicas/patologia , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 1/genética , Mutação/genética , Oligodendroglioma/patologia , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Deleção Cromossômica , Estudos de Coortes , Feminino , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Oligodendroglioma/genética , Oligodendroglioma/mortalidade , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Análise de Sobrevida , Telomerase/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Nuclear Ligada ao X/genética , Adulto Jovem
16.
Am J Transl Res ; 8(2): 705-18, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27158363

RESUMO

Stem cell-based reparative approaches have been applied to cerebellum-related disorders during the last two decades. Direct lineage reprogramming of human fibroblasts into functional granular neurons holds great promise for biomedical applications such as cerebellum regeneration and cellbased disease modeling. In the present study, we showed that a combination of Ascl1, Sox2 and OCT4, in a culture subsequently treated with secreted factors (BMP4, Wnt3a and FGF8b), was capable of converting human fibroblasts from the scalp tissue of patients with traumatic brain injury (TBI) into functional human induced cerebellar granular-like cells (hiCGCs). Morphological analysis, immunocytochemistry, gene expression and electrophysiological analysis were performed to identify the similarity of induced neuronal cells to human cerebellum granular cells. Our strategy improved the efficiency for hiCGCs induction, which gave the highest conversion efficiency 12.30±0.88%, and Ath1(+)/Tuj1(+) double positive cells to 5.56±0.80%. We transplanted hiCGCs into the cerebellum of Nmyc(TRE/TRE): tTS mice, a novel mouse model of cerebellar ataxia, and demonstrated that the hiCGCs were able to survive, migrate, proliferate and promote mild functional recovery after been grafted into cerebellum.

17.
Neuropsychiatr Dis Treat ; 12: 883-96, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27143890

RESUMO

BACKGROUND: Shen-Qi-Jie-Yu-Fang (SJF) is composed of eight Chinese medicinal herbs. It is widely used in traditional Chinese medicine for treating postpartum depression (PPD). Previous studies have shown that SJF treats PPD through the neuroendocrine mechanism. AIM: To further investigate the effect of SJF on the immune system, including the inflammatory response system and CD4(+)CD25(+) regulatory T (Treg) cells. MATERIALS AND METHODS: Sprague Dawley rats were used to create an animal model of PPD by inducing hormone-simulated pregnancy followed by hormone withdrawal. After hormone withdrawal, the PPD rats were treated with SJF or fluoxetine for 1, 2, and 4 weeks. Levels of Treg cells in peripheral blood were measured by flow cytometry analysis. Serum interleukin (IL)-1ß and IL-6 were evaluated by enzyme-linked immunosorbent assay, and gene and protein expressions of IL-1RI, IL-6Rα, and gp130 in the hippocampus were observed by reverse-transcription polymerase chain reaction and Western blot. RESULTS: Serum IL-1ß in PPD rats increased at 2 weeks and declined from then on, while serum IL-6 increased at 1, 2, and 4 weeks. Both IL-1ß and IL-6 were downregulated by SJF and fluoxetine. Changes in gene and protein expressions of IL-1RI and gp130 in PPD rats were consistent with changes in serum IL-1ß, and were able to be regulated by SJF and fluoxetine. The levels of Treg cells were negatively correlated with serum IL-1ß and IL-6, and were decreased in PPD rats. The levels of Treg cells were increased by SJF and fluoxetine. CONCLUSION: Dysfunction of proinflammatory cytokines and Tregs in different stages of PPD was attenuated by SJF and fluoxetine through the modulation of serum concentrations of IL-1ß and IL-6, expressions of IL-1RI, and gp130 in the hippocampus, and CD4(+)CD25(+) Treg cells in peripheral blood.

18.
Tumour Biol ; 37(3): 3765-74, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26468019

RESUMO

The initiation and formation of haemangioblastoma (HB) neovascularisation remain unknown, with concomitant controversy on its cytological origin. We detected HB-derived specific haematopoietic progenitors identified by surface expression of CD41 and CD45, which are similar to human embryonic vasculogenesis. CD41/CD45 cells expressed mesodermal markers, including SCL, Flk1 and c-kit. CD41 also seemed to appear before CD45 on haematopoietic progenitors. In vitro analysis showed that the CD41(+)/CD45 subpopulation gave rise to occasional primitive erythroid activity and endothelial marker expression. Meanwhile, kinetic investigation of the CD41(+)/CD45(+) subpopulation showed that some molecules, including SCL, Flk1 and c-kit, were involved in vascular formation. The CD45(+)/c-kit(+) population that lacked primitive haematopoiesis came from CD41(+) cells. Acquisition of CD45 expression by the haematopoietic progenitors was associated with advanced differentiation towards the vascular cell lineage. Taken together, the present data suggested that CD41 and CD45 expression marked the onset of HB neovascularisation and the stepwise development of the angioformative period. Our findings provide new insights into the mechanisms of HB neovascularisation and the underlying therapeutic targets of anti-vascular treatment.


Assuntos
Neoplasias Cerebelares/metabolismo , Hemangioblastoma/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Neovascularização Patológica/metabolismo , Glicoproteína IIb da Membrana de Plaquetas/metabolismo , Adolescente , Adulto , Idoso , Diferenciação Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Neoplasias Cerebelares/irrigação sanguínea , Neoplasias Cerebelares/genética , Feminino , Hemangioblastoma/irrigação sanguínea , Hemangioblastoma/genética , Células-Tronco Hematopoéticas/metabolismo , Humanos , Immunoblotting , Imuno-Histoquímica , Antígenos Comuns de Leucócito/genética , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Neovascularização Patológica/genética , Glicoproteína IIb da Membrana de Plaquetas/genética , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
19.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 35(8): 988-92, 2015 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-26485916

RESUMO

OBJECTIVE: To observe the evolutionary tendency of brain derived neurotrophic factor (BDNF) of the limbic system in post-stroke model rats and the intervention effect of Yinao Jieyu Recipe (YJR). METHODS: Male Wistar rats were randomly divided into the normal control group (n =6), the sham-operation group (n =7), the multiple cerebral infarction (MCI) group (n =10), the post-stroke depression (PSD) group (n =10), the Chinese medicine (CM) treatment group (n =10), and the Western medicine (WM) treatment group (n =10) according to random digit table after open-field testing. Rats in the normal control group were routinely fed. 0. 3 mL normal saline was intravenously pushing from the external carotid artery to rats in the sham-operation group, and distilled water administered to them by gastrogavage. Each dose allogenic microthrombi were in vitro pushed to rats in the rest groups from the external carotid artery. The PSD model was duplicated by 21-day chronic unpredictable mild stress (CUMS) and single cage feeding in the PSD group 7 days after surgery. After preparing models rats in the CM group and the WM group were administered with YJR and Nimodipine respectively for 4 successive weeks. Changes of BDNF and the intervention effect of YJR were observed at week 1, 2, and 4 after intervention. RESULTS: Immunohistochemical results of BDNF showed, compared with the normal control group, expression levels of BDNF in the hippocampus, hypothalamus, and amygdala decreased in the MCI group at week 2 and 4 (P <0. 01 , P <0. 05) ; expression levels of BDNF in each part decreased in the PSD group at week 1-4 (P <0.01). Compared with the MCI group, expression levels of BDNF in each part decreased in the PSD group at week 1-4 (P <0. 01). Compared with the PSD group, expression levels of BDNF in each part increased in the CM group at week 1-4 (P <0. 01). CONCLUSION: BDNF changes existed in post-stroke model rats, and YJR could slow down this progress.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Tonsila do Cerebelo , Animais , Depressão , Transtorno Depressivo , Medicamentos de Ervas Chinesas/uso terapêutico , Hipocampo , Masculino , Modelos Animais , Ratos , Ratos Wistar , Acidente Vascular Cerebral/tratamento farmacológico
20.
Biochim Biophys Acta ; 1848(10 Pt A): 2225-32, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26141051

RESUMO

While circulating/plasma membrane vesicles have been extensively characterized, due to the lack of effective methods cell-bound membrane vesicles are poorly understood including their shape and correlation with the intracellular cytoskeleton. In this study, we focused on cell-bound membrane vesicles and individual vesicle-derived pits on endothelial cells by using confocal microscopy and atomic force microscopy (AFM). For the first time, we found that cell-bound membrane vesicles are hemisphere-shaped and that the actin cortical filaments/network lies at the cytosolic opening of a vesicle instead of being closely attached to the inner side of the vesicle membrane. This structure of cell-bound membrane vesicles may be beneficial to their movement in, or release from, the plasma membrane of cells due to less membrane-cytoskeleton coupling to be broken therefore probably minimizing energy consumption and time usage. Further study indicates that TNF-α activation induced a significant increase in average number/size of cell-bound vesicles and the local disruption of the actin network at the cytosolic opening of cell-bound vesicles.


Assuntos
Citoesqueleto de Actina/ultraestrutura , Membrana Celular/ultraestrutura , Células Endoteliais/ultraestrutura , Microscopia de Força Atômica/métodos , Vesículas Transportadoras/ultraestrutura , Citoesqueleto de Actina/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Humanos , Fluidez de Membrana/efeitos dos fármacos , Vesículas Transportadoras/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia
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