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1.
EBioMedicine ; 50: 395-407, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31735552

RESUMO

BACKGROUND: Epigenetic mechanisms have been reported to play key roles in osteoarthritis (OA) development. P300/CBP-associated factor (PCAF) is a member of the histone acetyltransferases, which exhibits a strong relationship with endoplasmic reticulum (ER) stress and transcription factor nuclear factor kappa B (NF-κB) signals. Salidroside, a natural histone acetylation inhibitor, showed its anti-inflammatory and anti-apoptotic effects in lipopolysaccharide (LPS)-stimulated microglia cells in our previous study. However, whether Sal has a protective effect against OA remains unknown, and its relationships to PCAF, NF-κB, and the ER stress pathway should be explored further. METHODS: We identified the role of PCAF in the pathogenesis of OA and determined the chondroprotective effect of Sal on both tumor necrosis factor alpha (TNF-α)-treated human chondrocytes and a destabilized medial meniscus (DMM) mouse OA model. FINDINGS: We found increased PCAF expression in human OA cartilage and TNF-α-driven chondrocytes. Meanwhile, silencing of PCAF attenuated nuclear p65 and C/EBP homologous protein levels in chondrocytes upon TNF-α stimulation. Furthermore, Sal was found to specifically bind to the inhibitory site of the PCAF protein structure, which subsequently reversed the TNF-α-induced activation of NF-κB signal and ER stress-related apoptosis in chondrocytes. In addition, the protective effect of Sal and its inhibitory effects on PCAF as well as inflammatory- and ER stress-related markers were also observed in the mouse DMM model. INTERPRETATION: Pharmacological blockade of PCAF by Sal ameliorates OA development via inhibition of inflammation and ER stress, which makes Sal a promising therapeutic agents for the treatment of OA.

2.
Eur J Med Chem ; 182: 111633, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31461688

RESUMO

Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.


Assuntos
Azepinas/química , Descoberta de Drogas , Proteínas/antagonistas & inibidores , Pirazóis/química , Animais , Azepinas/síntese química , Azepinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Domínios Proteicos , Proteínas/metabolismo , Pirazóis/síntese química , Pirazóis/farmacologia , Relação Estrutura-Atividade
3.
Injury ; 50(3): 811-813, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30739761

RESUMO

Fractures of the medial comminuted clavicle are rare injuries but are associated with significant morbidity and mortality. Although rare, such injuries deserve rapid diagnosis and effective treatment to avoid future complications. An optimal, standardized operative treatment has not yet been established. We presented a medial-end comminuted clavicle fracture and demonstrated successful results using a bridging plate technique across the sternum maintaining reduction and achieving union. We aim to provide an alternative technique to fix a displaced periarticular medial clavicle fracture, which we believe is simple, safer and promising.


Assuntos
Clavícula/cirurgia , Fixação Interna de Fraturas/métodos , Consolidação da Fratura/fisiologia , Fraturas Ósseas/cirurgia , Fraturas Cominutivas/cirurgia , Acidentes por Quedas , Placas Ósseas , Clavícula/diagnóstico por imagem , Clavícula/lesões , Clavícula/fisiopatologia , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/fisiopatologia , Fraturas Cominutivas/diagnóstico por imagem , Fraturas Cominutivas/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
4.
EBioMedicine ; 41: 200-213, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30796006

RESUMO

BACKGROUND: LncRNAs have been found to be involved in various aspects of biological processes. In this study, we aimed to uncover the molecular mechanisms of lncRNA EPB41L4A-AS1 in regulating glycolysis and glutaminolysis in cancer cells. METHODS: The expression of EPB41L4A-AS1 in cancer patients was analyzed in TCGA and GEO datasets. The level of cellular metabolism was determined by extracellular flux analyzer. The relationship between p53 and EPB41L4A-AS1 was explored by qRT-PCR, luciferase assay and ChIP assay. The interactions between EPB41L4A-AS1 and HDAC2 or NPM1 were determined by RNA immunoprecipitation, RNA pull-down assay and RNA-FISH- immunofluorescence. FINDINGS: EPB41L4A-AS1 was a p53-regulated gene. Low expression and deletion of lncRNA EPB41L4A-AS1 were found in a variety of human cancers and associated with poor prognosis of cancer patients. Knock down EPB41L4A-AS1 expression triggered Warburg effect, demonstrated as increased aerobic glycolysis and glutaminolysis. EPB41L4A-AS1 interacted and colocalized with HDAC2 and NPM1 in nucleolus. Silencing EPB41L4A-AS1 reduced the interaction between HDAC2 and NPM1, released HDAC2 from nucleolus and increased its distribution in nucleoplasm, enhanced HDAC2 occupation on VHL and VDAC1 promoter regions, and finally accelerated glycolysis and glutaminolysis. Depletion of EPB41L4A-AS1 increased the sensitivity of tumor to glutaminase inhibitor in tumor therapy. INTERPRETATION: EPB41L4A-AS1 functions as a repressor of the Warburg effect and plays important roles in metabolic reprogramming of cancer.


Assuntos
Núcleo Celular/metabolismo , Glicólise , Histona Desacetilase 2/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Neoplasias/metabolismo , RNA Longo não Codificante/genética , Transporte Ativo do Núcleo Celular , Animais , Glutaminase/metabolismo , Células HeLa , Células Hep G2 , Humanos , Camundongos , Camundongos Nus , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , RNA Longo não Codificante/metabolismo
5.
Osteoarthritis Cartilage ; 27(2): 347-357, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30414849

RESUMO

OBJECTIVE: Excessive apoptosis and senescence of nucleus pulposus (NP) cells are major pathological changes in intervertebral disc degeneration (IVDD) development; previous studies demonstrated pharmacologically or genetically stimulation of autophagy may inhibit apoptosis and senescence in NP cells. Transcription factor EB (TFEB) is a master regulator of autophagic flux via initiating autophagy-related genes and lysosomal biogenesis. This study was performed to confirm whether TFEB was involved in IVDD development and its mechanism. METHODS: TFEB activity was detected in NP tissues in puncture-induced rat IVDD model by immunofluorescence as well as in tert-Butyl hydroperoxide (TBHP), the reactive oxygen species (ROS) donor to induce oxidative stress, treated NP cells by western blot. After TFEB overexpression in NP cells with lentivirus transfection, autophagic flux, apoptosis and senescence percentage were assessed. In in vivo study, the lentivirus-normal control (LV-NC) or lentivirus-TFEB (LV-TFEB) were injected into the center space of the NP tissue, after 4 or 8 weeks, Magnetic resonance imaging (MRI), X ray, Hematoxylin-Eosin (HE) and Safranin O staining were used to evaluate IVDD grades. RESULTS: The nuclear localization of TFEB declined in degenerated rat NP tissue as well as in TBHP treated NP cells. Applying lentivirus to transfect NP cells, TFEB overexpression restored the TBHP-induced autophagic flux blockage and protected NP cells against apoptosis and senescence; these protections of TFEB are diminished by chloroquine-medicated autophagy inhibition. Furthermore, TFEB overexpression ameliorates the puncture-induced IVDD development in rats. CONCLUSIONS: Experimental IVDD inhibited the TFEB activity. TFEB overexpression suppressed TBHP-induced apoptosis and senescence via autophagic flux stimulation in NP cell and alleviates puncture-induced IVDD development in vivo.

6.
Exp Mol Med ; 50(11): 146, 2018 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420619

RESUMO

Oxidative stress-induced mitochondrial dysfunction is implicated in the pathogenesis of intervertebral disc degeneration (IVDD). Sirtuin 3 (SIRT3), a sirtuin family protein located in mitochondria, is essential for mitochondrial homeostasis; however, the role of SIRT3 in the process of IVDD has remained elusive. Here, we explored the expression of SIRT3 in IVDD in vivo and in vitro; we also explored the role of SIRT3 in senescence, apoptosis, and mitochondrial homeostasis under oxidative stress. We subsequently activated SIRT3 using honokiol to evaluate its therapeutic potential for IVDD. We assessed SIRT3 expression in degenerative nucleus pulposus (NP) tissues and oxidative stress-induced nucleus pulposus cells (NPCs). SIRT3 was knocked down by lentivirus and activated by honokiol to determine its role in oxidative stress-induced NPCs. The mechanism by which honokiol affected SIRT3 regulation was investigated in vitro, and the therapeutic potential of honokiol was assessed in vitro and in vivo. We found that the expression of SIRT3 decreased with IVDD, and SIRT3 knockdown reduced the tolerance of NPCs to oxidative stress. Honokiol (10 µM) improved the viability of NPCs under oxidative stress and promoted their properties of anti-oxidation, mitochondrial dynamics and mitophagy in a SIRT3-dependent manner. Furthermore, honokiol activated SIRT3 through the AMPK-PGC-1α signaling pathway. Moreover, honokiol treatment ameliorated IVDD in rats. Our study indicated that SIRT3 is involved in IVDD and showed the potential of the SIRT3 agonist honokiol for the treatment of IVDD.


Assuntos
Antioxidantes/farmacologia , Compostos de Bifenilo/farmacologia , Degeneração do Disco Intervertebral/metabolismo , Lignanas/farmacologia , Sirtuína 3/genética , Animais , Antioxidantes/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Células Cultivadas , Feminino , Humanos , Degeneração do Disco Intervertebral/tratamento farmacológico , Lignanas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Dinâmica Mitocondrial/efeitos dos fármacos , Núcleo Pulposo/efeitos dos fármacos , Núcleo Pulposo/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Sirtuína 3/metabolismo
7.
Medchemcomm ; 9(2): 244-253, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108918

RESUMO

The success of acrylamide-containing drugs in treating cancers has spurred a passion to search for acrylamide bioisosteres. In our endeavour, we have identified that an allenamide group can be a reactive bioisostere of the acrylamide group. In our development of allenamide-containing compounds, we found that the most potent compound, 14, inhibited the kinase activities of both T790M/L858R double mutant and wild type EGFR in a low nM range. 14 also inhibited the growth of NCI-H1975 lung cancer cells at IC50 = 33 nM, which is comparable to that of acrylamide-containing osimertinib. The western blot analysis showed that the phosphorylation of EGFR, AKT, and ERK1/2 was simultaneously inhibited in a dose-dependent manner when NCI-H1975 cells were treated with 14. By measuring the conjugate addition product formed by 14 and GSH, we obtained a reaction rate constant of 302.5 × 10-3 min-1, which is about 30-fold higher than that of osimertinib. Taken together, our data suggest that the allenamide-containing compounds inhibited EGFR kinases through covalent modifications. Our study indicates that the allenamide group could serve as an alternative electrophilic warhead in the design of targeted covalent inhibitors, and this bioisostere replacement may have broad applications in medicinal chemistry.

8.
Oncotarget ; 8(37): 61440-61456, 2017 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-28977876

RESUMO

The inflammatory environment is correlated with extracellular matrix (ECM) degradation and chondrocyte hypertrophy in the development of osteoarthritis (OA). Previous studies have reported the anti-inflammatory effects of wogonoside in several diseases. In the present study, we investigated the protective effects of wogonoside in relation to the development of OA and delineated the potential mechanism. In vitro, wogonoside decreased the production of pro-inflammatory cytokines like Nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6). It also inhibited the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) both at gene and protein levels. Wogonoside also inhibited hypertrophy and the generation of vascular endothelial growth factor (VEGF) in interleukin-1ß (IL-1ß)-induced chondrocytes. Moreover, wogonoside promoted the expression of anabolic factors Sox-9, type two collagen and aggrecan while inhibiting the expression of catabolic factors such as matrix metalloproteinases (MMPs) and thrombospondin motifs 5 (ADAMTS-5) in mouse chondrocytes. Mechanistically, we found that wogonoside inhibited nuclear factor kappa B/ hypoxia-inducible factor two alpha (NF-κB/HIF-2α) activation via the phosphatidylinositol 3 kinase (PI3K) /AKT pathway. The protective effects of wogonoside were also observed in vivo and the pharmacokinetic results of wogonoside indicated that good systemic exposure was achievable after oral administration of wogonoside. In conclusion, our stduy demonstrates that wogonoside attenuates IL-1ß-induced ECM degradation and hypertrophy in mouse chondrocytes via suppressing the activation of NF-κB/HIF-2α by the PI3K/AKT pathway. Moreover, wogonoside ameliorates OA progression in vivo, indicating that wogonoside may serve as a promising therapeutic agent for the treatment of OA.

9.
World Neurosurg ; 104: 545-553, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28526640

RESUMO

BACKGROUND: Anterior cervical diskectomy and fusion with plate-screw construct has been gradually applied for multilevel cervical spondylotic myelopathy in recent years. However, long cervical plate was associated with complications including breakage or loosening of plate and screws, trachea-esophageal injury, neurovascular injury, and postoperative dysphagia. To reduce these complications, the zero-profile spacer has been introduced. This meta-analysis was performed to compare the clinical and radiologic outcomes of zero-profile spacer versus cage-plate construct for the treatment of multilevel cervical spondylotic myelopathy. METHODS: We systematically searched MEDLINE, Springer, and Web of Science databases for relevant studies that compared the clinical and radiologic outcomes of zero-profile spacer versus cage and plate for multilevel cervical spondylotic myelopathy. Risk of bias in included studies was assessed. Pooled estimates and corresponding 95% confidence intervals were calculated. RESULTS: On the basis of predefined inclusion criteria, 7 studies with a total of 409 patients were included in this analysis. The pooled data revealed that zero-profile spacer was associated with a decreased dysphagia rate at 2, 3, and 6 months postoperatively when compared with the cage-plate group. Both techniques had similar perioperative outcomes, functional outcome, radiologic outcome, and dysphagia rate immediately and at >1-year after operation. CONCLUSIONS: On the basis of available evidence, zero-profile spacer was more effective in reducing postoperative dysphagia rate for multilevel cervical spondylotic myelopathy. Both devices were safe in anterior cervical surgeries, and they had similar efficacy in improving the functional and radiologic outcomes. More randomized controlled trials are needed to compare these 2 devices.


Assuntos
Discotomia/instrumentação , Desenho de Equipamento , Próteses e Implantes , Fusão Vertebral/instrumentação , Espondilose/cirurgia , Vértebras Cervicais/cirurgia , Falha de Equipamento , Seguimentos , Humanos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle
10.
Pharmacol Res ; 117: 357-369, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28087442

RESUMO

It has been suggested that excessive apoptosis in intervertebral disc cells induced by inflammatory cytokines, such as interleukin (IL)-1ß, is related to the process of intervertebral disc degeneration (IVDD). Hydrogen sulfide (H2S), a gaseous signaling molecule, has drawn attention for its anti-apoptosis role in various pathophysiological processes in degenerative diseases. To date, there has been no investigation of the correlation of H2S production and IVDD or of the effects of H2S on IL-1ß-induced apoptosis in nucleus pulposus (NP) cells. Here, we found that the expression levels of cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE), two key enzymes in the generation of H2S, were significantly decreased in human degenerate NP tissues as well as in IL-1ß-treated NP cells. NaHS (H2S donor) administration showed a protective effect by inhibiting the endoplasmic reticulum (ER) stress response and mitochondrial dysfunction induced by IL-1ß stimulation in vitro, the effect was related to activation of the PI3K/Akt and ERK1/2 signaling pathways. Suppression of these pathways by specific inhibitors, LY294002 and PD98059, partially reduced the protective effect of NaHS. Moreover, in the percutaneous needle puncture disc degeneration rat tail model, disc degeneration was partially reversed by NaHS administration. Taken together, our results suggest that H2S plays a protective role in IVDD and the underlying mechanism involves PI3K/Akt and ERK1/2 signaling pathways-mediated suppression of ER stress and mitochondrial dysfunction in IL-1ß-induced NP cells.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Degeneração do Disco Intervertebral/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Núcleo Pulposo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Adolescente , Adulto , Idoso , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Criança , Citocinas/metabolismo , Feminino , Humanos , Degeneração do Disco Intervertebral/metabolismo , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Núcleo Pulposo/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
11.
In Vitro Cell Dev Biol Anim ; 53(2): 124-131, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27709418

RESUMO

Chondrocyte plays a critical role in endochondral ossification and cartilage repair by maintaining the cartilaginous matrix. Statins have been widely used to lower the cholesterol level in patients with cardiovascular disorders. Previous research has demonstrated potential role of statins in chondrocyte proliferation. This study addresses the proliferation-regulatory effect of lovastatin in rabbit chondrocytes as well as the underlying signaling mechanisms, thereby exploring its potential application in chondrocyte-related disorders, such as cartilage damage and osteoarthritis. Rabbit chondrocytes were treated with lovastatin at multiple concentrations, and the proliferation rate was measured by CCK-8 test. The results showed significant increase in chondrocyte proliferation under lovastatin treatment. Using real-time quantitative PCR, it was observed that the expression levels of COL2A1, SOX-9, Caspase-3, and MMP-3 genes were significantly changed by lovastatin treatment. Western blotting analysis showed that the abundance of COL2A1, SOX-9, MEK1/2, p-MEK1/2, ERK1/2, p-ERK1/2, Caspase-3, and MMP-3 proteins was also significantly influenced by lovastatin treatment. Interleukine-1 beta (IL-1ß) is involved in the progression of osteoarthritis (OA) by inducing articular cartilage and chondrocyte aging and senescence. In this study, we observed that lovastatin treatment inhibited IL-1ß-induced chondrocyte apoptosis, while the combined treatment of lovastatin and U0126 evidently offset the apoptosis-inhibiting effect of lovastatin in chondrocyte proliferation. The expressional level and protein abundance of COL2A1, SOX-9, MEK1/2, p-MEK1/2, ERK1/2, p-ERK1/2, caspase-3, and MMP-3 genes showed significant alterations under the combined treatment. Together, our results suggested that lovastatin significantly promoted proliferation and inhibited the IL-1ß-induced apoptosis in rabbit chondrocytes, which was mediated by the MEK/ERK signaling.


Assuntos
Apoptose/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/enzimologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Interleucina-1beta/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Animais , Biomarcadores/metabolismo , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Lovastatina/farmacologia , Coelhos
12.
FASEB J ; 31(2): 711-718, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27871061

RESUMO

Potent and selective chemical probes are valuable tools for discovery of novel treatments for human diseases. NF-κB-inducing kinase (NIK) is a key trigger in the development of liver injury and fibrosis. Whether inhibition of NIK activity by chemical probes ameliorates liver inflammation and injury is largely unknown. In this study, a small-molecule inhibitor of NIK, B022, was found to be a potent and selective chemical probe for liver inflammation and injury. B022 inhibited the NIK signaling pathway, including NIK-induced p100-to-p52 processing and inflammatory gene expression, both in vitro and in vivo Furthermore, in vivo administration of B022 protected against not only NIK but also CCl4-induced liver inflammation and injury. Our data suggest that inhibition of NIK is a novel strategy for treatment of liver inflammation, oxidative stress, and injury.-Ren, X., Li, X., Jia, L., Chen, D., Hou, H., Rui, L., Zhao, Y., Chen, Z. A small-molecule inhibitor of NF-κB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Intoxicação por Tetracloreto de Carbono , Linhagem Celular , Humanos , Masculino , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Células RAW 264.7 , RNA Mensageiro , Espécies Reativas de Oxigênio
13.
Cell Death Dis ; 7(10): e2441, 2016 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-27787519

RESUMO

Intervertebral disc degeneration (IDD) is a complicated process that involves both cellular apoptosis and senescence. Metformin has been reported to stimulate autophagy, whereas autophagy is shown to protect against apoptosis and senescence. Therefore, we hypothesize that metformin may have therapeutic effect on IDD through autophagy stimulation. The effect of metformin on IDD was investigated both in vitro and in vivo. Our study showed that metformin attenuated cellular apoptosis and senescence induced by tert-butyl hydroperoxide in nucleus pulposus cells. Autophagy, as well as its upstream regulator AMPK, was activated by metformin in nucleus pulposus cells in a dose- and time-dependent manner. Inhibition of autophagy by 3-MA partially abolished the protective effect of metformin against nucleus pulposus cells' apoptosis and senescence, indicating that autophagy was involved in the protective effect of metformin on IDD. In addition, metformin was shown to promote the expression of anabolic genes such as Col2a1 and Acan expression while inhibiting the expression of catabolic genes such as Mmp3 and Adamts5 in nucleus pulposus cells. In vivo study illustrated that metformin treatment could ameliorate IDD in a puncture-induced rat model. Thus, our study showed that metformin could protect nucleus pulposus cells against apoptosis and senescence via autophagy stimulation and ameliorate disc degeneration in vivo, revealing its potential to be a therapeutic agent for IDD.


Assuntos
Apoptose/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Degeneração do Disco Intervertebral/tratamento farmacológico , Degeneração do Disco Intervertebral/patologia , Metformina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Núcleo Pulposo/patologia , Adenina/análogos & derivados , Adenina/farmacologia , Adenilato Quinase/metabolismo , Animais , Apoptose/genética , Autofagia/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Degeneração do Disco Intervertebral/genética , Masculino , Metformina/farmacologia , Fármacos Neuroprotetores/farmacologia , Núcleo Pulposo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley , terc-Butil Hidroperóxido
14.
Menopause ; 23(11): 1239-1246, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27326816

RESUMO

OBJECTIVE: The purpose of this study was to investigate the association between menopause and severity of knee joint cartilage degeneration using a magnetic resonance imaging-based six-level grading system, with six cartilage surfaces, the medial and lateral femoral condyle, the femoral trochlea, the medial and lateral tibia plateau, and the patella. METHODS: The study cohort comprised 860 healthy women (age 36-83 y), and 5,160 cartilage surfaces were analyzed. Age, weight, height, age at natural menopause, and years since menopause (YSM) were obtained. Cartilage degeneration was assessed using a magnetic resonance imaging-based six-level grading system. RESULTS: After removing the age, height, and weight effects, postmenopausal women had more severe cartilage degeneration than pre- and perimenopausal women (P < 0.001). A positive trend was observed between YSM and severity of cartilage degeneration (P < 0.05). Postmenopausal women were divided into seven subgroups by every five YSM. When YSM was less than 25 years, the analysis of covariance indicated a significant difference in medial tibia plateau, medial femoral condyle, trochlea, patella, and total surfaces (P < 0.05 or 0.01) between every two groups. When YSM was more than 25 years, the significant difference, however, disappeared in these four surfaces (P > 0.05). No significant difference was observed in lateral tibia plateau and lateral femoral condyle in postmenopausal women. CONCLUSIONS: Menopause is associated with cartilage degeneration of knee joint. After menopause, cartilage showed progressive severe degeneration that occurred in the first 25 YSM, suggesting estrogen deficiency might be a risk factor of cartilage degeneration of the knee joint. Further studies are needed to investigate whether age or menopause plays a more important role in the progression of cartilage degeneration in the knee joint.


Assuntos
Doenças das Cartilagens/patologia , Cartilagem Articular/patologia , Artropatias/patologia , Articulação do Joelho/patologia , Menopausa/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Pós-Menopausa/fisiologia
15.
Brain Res ; 1632: 19-26, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26707978

RESUMO

Previous studies have shown that inhibition of prolyl hydroxylase(PHD) stabilizes Hypoxia-inducible factor 1, alpha subunit(HIF-1α), increases tolerance to hypoxia, and improves the prognosis of many diseases. However, the role of PHD inhibitor (PHDI) in the recovery of spinal cord injury remains controversial. In this study, we investigated the protective role of a novel PHDI FG-4592 both in vivo and in vitro. FG-4592 treatment stabilized HIF1α expression both in PC12 cells and in spinal cord. FG-4592 treatment significantly inhibited tert-Butyl hydroperoxide(TBHP)-induced apoptosis and increases the survival of neuronal PC-12 cells. FG-4592 administration also improved recovery and increased the survival of neurons in spinal cord lesions in the mice model. Combination therapy including the specific HIF-1α blocker YC-1 down-regulated the HIF-1α expression and partially abolished the protective effect of FG-4592. Taken together, our results revealed that the role of FG-4592 in SCI recovery is related to the stabilization of HIF-1α and inhibition of apoptosis. Overall, our study suggests that PHDIs may be feasible candidates for therapeutic intervention after SCI and central nervous system disorders in humans.


Assuntos
Glicina/análogos & derivados , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isoquinolinas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Feminino , Glicina/farmacologia , Glicina/uso terapêutico , Isoquinolinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Células PC12 , Ratos , Recuperação de Função Fisiológica/efeitos dos fármacos
16.
Sci Rep ; 5: 17130, 2015 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-26597839

RESUMO

In this study we examined the relationship between autophagy and apoptosis in diabetic rats after spinal cord injury (SCI), also we determined the role of autophagy in diabetes-aggravated neurological injury in vivo and in vitro. Our results showed that diabetes decreased the survival of neurons, promoted astrocytes proliferation, increased inflammatory cells infiltration and inhibited functional recovery after SCI. Diabetes was shown to confer increased activation of apoptotic pathways, along with an increase in autophagy; similar effects were also observed in vitro in neuronal PC12 cells. Treatment with rapamycin, an autophagy activator, partially abolished the adverse effect of diabetes, suggesting that diabetes may enhance neurological damage and suppress locomotor recovery after SCI, in addition to its effects on apoptosis and autophagy. In contrast, further stimulation of autophagy improved neurological function via inhibition of apoptosis. These results explained how diabetes exacerbates SCI in cellular level and suggested autophagy stimulation to be a new therapeutic strategy for diabetic SCI.


Assuntos
Autofagia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/patologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Apoptose , Astrócitos/fisiologia , Proliferação de Células , Sobrevivência Celular , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Locomoção , Neurônios/fisiologia , Células PC12 , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Sirolimo/farmacologia , Traumatismos da Medula Espinal/patologia
17.
Mol Med Rep ; 10(4): 2210-6, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25198465

RESUMO

Rejection is still a major obstacle in long-term allograft survival of renal transplant recipients. Long non­coding RNAs (lncRNAs) are an important class of pervasive RNAs involved in a variety of biological functions, and which are often found to be differentially expressed between healthy and pathological conditions. The aim of this study was to compare the expression profiles of lncRNAs between samples from acute rejection following kidney transplantation and control samples. Three patients were enrolled, diagnosed by renal biopsy with acute rejection upon kidney transplantation. We used lncRNA microarrays to study the lncRNA expression profiles in the kidney biopsies of these patients and in kidneys from healthy donors. Reverse transcription­quantitative polymerase chain reaction (RT-qPCR) was used to validate the microarray results. In addition, potential functions of the identified lncRNAs were further explored by searching the UCSC, RNAdb, RefSeq and NRED databases. Five candidate lncRNAs displaying differential expression in acute rejection samples were validated by RT-qPCR. The results were in agreement with the microarray data. Among the identified lncRNAs, certain have been previously identified in relevant conditions, thereby supporting previous evidence, but certain may constitute novel biomarker candidates. This is the first report to date using lncRNA microarrays to identify unique expression signatures of acute rejection in transplant biopsies. Our data indicate that lncRNAs are potentially involved in the pathogenesis of acute rejection. Our results may have important implications in the identification of diagnostic biomarkers, as well as in the understanding and treatment of acute rejection following renal transplantation.


Assuntos
Rejeição de Enxerto/patologia , Transplante de Rim , Rim/patologia , RNA Longo não Codificante/metabolismo , Regulação para Baixo , Rejeição de Enxerto/metabolismo , Humanos , Rim/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Homólogo , Regulação para Cima
18.
Integr Biol (Camb) ; 6(12): 1141-52, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25222482

RESUMO

The regulation of gene expression by microRNAs (miRNAs) is complex due to a number of variables involved. The potential for one miRNA to target many genes, the presence of multiple miRNA response elements (MREs) in one mRNA molecule and the interplay between RNAs that share common MREs each add a layer of complexity to the process; making it difficult to determine how regulation of gene expression by miRNAs works within the context of the system as a whole. In this study, we used luciferase report vectors inserted with different 3'UTR fragments as probes to detect the repressive effect of the miRNA pool on gene expression and uncovered some essential characteristics of gene regulation mediated by the miRNA pool, such as the nonlinear correlative relationship between the regulatory potential of a miRNA pool and the number of potential MREs, the buffering effect and the saturating effect of the miRNA pool, and the restrictive effect caused by the density of MREs. Through expressing gradient concentration of 3'UTR fragments, we indirectly detected the regulatory potential of the competing endogenous RNA (ceRNA) pool and analysed its effect on the regulatory potential of the miRNA pool. Our results provide some new insights into miRNA pool mediated gene regulation.


Assuntos
Regiões 3' não Traduzidas/genética , Regulação da Expressão Gênica/genética , Pool Gênico , MicroRNAs/genética , Modelos Genéticos , Proteoma/genética , Elementos de Resposta/genética , Sequência de Bases , Humanos , Dados de Sequência Molecular
19.
Int J Oncol ; 45(2): 619-28, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24819045

RESUMO

Long non-coding RNAs (lncRNAs) have been shown to play a critical role in cancer biology and are frequently aberrantly expressed. Despite their important role in pathology, little is known mechanistically regarding their role in gastric cancer (GC) pathogenesis. To characterize the role of lncRNAs in GC pathogenesis, 8 paired human GC tissue samples and matched adjacent normal tissue were examined. Large scale expression profiling of lncRNA and mRNA was performed utilizing microarray technology and validated by qPCR. Differentially expressed lncRNAs were subjected to bioinformatic analysis to predict target genes, followed by the integration of differentially expressed mRNA data and GO and network analysis to further characterize potential interactions. In our study, 2,621 lncRNAs and 3,121 mRNAs were identified to be differentially expressed (≥2.0-fold change) in GC samples relative to their matched counterparts. lncRNA target prediction revealed the presence of 221 potential lncRNA-mRNA target pairs for the 75 differentially expressed lncRNAs and 60 differentially expressed genes. KEGG pathway analysis showed that these target genes were significantly enriched in 7 different pathways, of which the p53 signaling pathway was the most significant and has been previously implicated in GC pathogenesis. Construction of a lncRNA-mRNA correlation network revealed 10 differentially expressed lncRNAs potentially regulating the p53 signaling pathway. Overall, this is the first study perform global expression profiling of lncRNAs and mRNAs relating to GC. These results may provide important information for further insights into the pathogenesis of GC and provide potential targets for future therapeutics.


Assuntos
Adenocarcinoma/genética , RNA Longo não Codificante/análise , RNA Mensageiro/análise , Neoplasias Gástricas/genética , Transcriptoma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real
20.
Connect Tissue Res ; 55(3): 187-96, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24645875

RESUMO

OBJECTIVES: Our aim in this study was to identify and examine the differential expression of microRNAs in patients with systemic lupus erythematosus (SLE). METHODS: We employed high-quality, high-throughput Solexa sequencing to clone and identify microRNAs in SLE patients and a control group. RESULTS: From the sequencing data, we identified numerous microRNAs displaying significantly different levels of expression in patients with SLE and in healthy controls. The 212 and 199 microRNAs were upregulated and downregulated, respectively. Only 61 novel microRNAs exhibited significantly different levels of expression in the two groups. The target genes of the novel microRNAs identified in the SLE group were found to have cell metabolism functions. We also analyzed the chromosomal locations of the microRNAs with high level of expression between the two groups. A profile comparison revealed that the majority of transcripts were expressed at a similar level. The functional classes of the most abundant microRNAs were equally represented on each chromosome. CONCLUSION: We identified novel and known microRNAs significantly enhancing our understanding of the microRNA expression profiles of SLE patients. These data also provide insight into the function of microRNAs in SLE and provide new strategies for future therapies.


Assuntos
Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação para Baixo/genética , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Valor Preditivo dos Testes , Regulação para Cima/genética
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