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1.
Mol Med Rep ; 21(2): 649-658, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974626

RESUMO

Osteosarcoma (OS) is the most common type of primary malignant bone tumor, which has a high incidence rate in children and adolescents. This research aims to reveal the role of long intergenic non­protein coding RNA 00460 (LINC00460) in OS by the loss­of­function experiment. LINC00460 is involved in the development of multiple types of tumor, but the role of LINC00460 in OS is unclear. To discover more effective molecular targets for the treatment of OS, the association between LINC00460 and OS prognosis was analyzed using the Gene Expression Profiling Interactive Analysis database. Additionally, small interfering RNA was used to knockdown LINC00460 gene expression in vitro to verify its biological effects on the viability, invasive and migratory potential of OS cells. LINC00460 knockdown significantly reduced the viability of OS cells and initiated cell cycle arrest within the G0/G1 phase through the decreased expression of cyclin D1 and CDK4/CDK6. In addition, LINC00460 knockdown promoted apoptosis of OS cells, and inhibited the migratory and invasive abilities of OS cells through the inhibition of the epithelial­mesenchymal transition pathway. In conclusion, the present study reported that LINC00460 may predict OS prognosis, and may serve an important role in mediating the viability, invasive and migratory potential of OS cells. Based on these findings, LINC00460 demonstrated promising potential as a future therapeutic target for OS treatment.

2.
Diabetes Ther ; 11(1): 71-81, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31673971

RESUMO

INTRODUCTION: Small fiber neuropathy (SFN)-the early stage of diabetic peripheral neuropathy (DPN)-progresses gradually and is difficult to diagnose using neurophysiological tests. To facilitate the early diagnosis of SFN, biomarkers for SFN must be identified. The purpose of this study was to investigate the characteristics of SFN in prediabetic patients and the relationship between pNF-H and SFN. METHODS: 44 IGT patients (inpatients and outpatients) were selected at random. 33 healthy subjects served as controls. Data on clinical characteristics and laboratory parameters were collected. Quantitative sensory testing (QST), electromyography (EMG), and Sudoscan were performed, and pNF-H was measured by ELISA. RESULTS: 24 of the 44 patients with impaired glucose tolerance (IGT) were diagnosed with SFN according to the modified Toronto Diabetic Neuropathy Expert Group consensus criteria. The thermal sensory thresholds of the IGT-SFN group were significantly different from those of the CTRL group (p < 0.05), except for the heat pain threshold. The sensory nerve action potential (SNAP) of the sural nerve was 12.39 in the IGT-SFN group, which was significantly lower than those in the other groups. No significant difference in nerve conduction velocity (NCV) was observed among the three groups. The electrochemical skin conductance (ESC) in the IGT-SFN group was 69.78 ± 14.03uS, which was significantly lower than that in the CTRL group. The pNF-H in the IGT-SFN group was 170.6 (140.0, 223.6) pg/ml, which was significantly higher than those in the CTRL and IGT-non-SFN groups (76.55 and 64.7 pg/ml, respectively). Multivariate regression analysis demonstrated that pNF-H and 2h plasma glucose were independently correlated with SFN; the ORs (95% CI) were 1.429 (1.315, 1.924) and 2.375 (1.157, 4.837), respectively. CONCLUSIONS: Serum pNF-H may be associated with SFN in IGT patients, and serum pNF-H could therefore serve as a sensitive biomarker for the detection of SFN.

3.
Diabetes Ther ; 11(2): 569-570, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31865611

RESUMO

In the original article, there was some error in Table 2. The correct table is given below.

4.
Biomed Pharmacother ; 118: 109227, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351433

RESUMO

Endothelial-to-mesenchymal transition (EndMT) is closely related to the pathogenesis of various diseases, including cardiac fibrosis. Transforming growth factor (TGF)-ß1 strongly induces EndMT, and sirtuin 1 (SIRT1) may play vital roles in TGF-ß/Smad pathway inhibition. This study aimed to determine whether SIRT1 activation inhibits EndMT, thereby attenuating cardiac fibrosis. Cardiac fibrosis was induced in C57BL/6 mice by subcutaneously injecting isoproterenol. SIRT1 was activated and then suppressed by intraperitoneally injecting resveratrol (RSV) and EX527, respectively. EndMT was induced by adding TGF-ß1 to H5V cells and measured by immunofluorescence and western blot. The role of SIRT1 in EndMT was determined by lentivirus-mediated overexpression of SIRT1. Interactions between SIRT1 and Smad2/3 in the TGF-ß/Smad2/3 pathway were examined by immunoprecipitation. SIRT1 activation upregulated CD31 and vascular endothelial-cadherin, and downregulated α-smooth muscle actin, fibroblast-specific protein 1, and vimentin. SIRT1 upregulated and EX527 inhibited TGF-ß receptor 1 (TGF-ßR1) and P-Smad2/3 expression, respectively. SIRT1 activation and overexpression by RSV/SRT2104 and lentivirus transfection, respectively, reduced TGF-ß1-induced EndMT. SIRT1 and Smad2/3 interaction was shown by immunoprecipitation in vivo and in vitro. TGF-ßR1 and P-Smad2/3 expression was downregulated and Smad2/3 nuclear translocation was inhibited. In conclusion, SIRT1 activated by RSV attenuated isoproterenol-induced cardiac fibrosis by regulating EndMT via the TGF-ß/Smad2/3 pathway.


Assuntos
Endotélio/patologia , Mesoderma/patologia , Miocárdio/patologia , Sirtuína 1/metabolismo , Animais , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Colágeno/metabolismo , Regulação para Baixo/efeitos dos fármacos , Endotélio/efeitos dos fármacos , Fibrose , Isoproterenol , Masculino , Mesoderma/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo
5.
Basic Res Cardiol ; 114(4): 30, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31218471

RESUMO

Microvascular obstruction (MVO) and leakage (MVL) forms a pivotal part of microvascular damage following cardiac ischemia-reperfusion (IR). We tested the effect of relaxin therapy on MVO and MVL in mice following cardiac IR injury including severity of MVO and MVL, opening capillaries, infarct size, regional inflammation, cardiac function and remodelling, and permeability of cultured endothelial monolayer. Compared to vehicle group, relaxin treatment (50 µg/kg) reduced no-reflow area by 38% and the content of Evans blue as a permeability tracer by 56% in jeopardized myocardium (both P < 0.05), effects associated with increased opening capillaries. Relaxin also decreased leukocyte density, gene expression of cytokines, and mitigated IR-induced decrease in protein content of VE-cadherin and relaxin receptor. Infarct size was comparable between the two groups. At 2 weeks post-IR, relaxin treatment partially preserved cardiac contractile function and limited chamber dilatation versus untreated controls by echocardiography. Endothelial cell permeability assay demonstrated that relaxin attenuated leakage induced by hypoxia-reoxygenation, H2O2, or cytokines, action that was independent of nitric oxide but associated with the preservation of VE-cadherin. In conclusion, relaxin therapy attenuates IR-induced MVO and MVL and endothelial leakage. This protection was associated with reduced regional inflammatory responses and consequently led to alleviated adverse cardiac remodeling.


Assuntos
Anti-Inflamatórios/farmacologia , Vasos Coronários/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Relaxina/farmacologia , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Linhagem Celular , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Modelos Animais de Doenças , Fibrose , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Microvasos/metabolismo , Microvasos/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Receptores Acoplados a Proteínas-G/metabolismo , Remodelação Ventricular/efeitos dos fármacos
6.
J Diabetes Res ; 2019: 4650906, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179340

RESUMO

Background: Type 2 diabetes mellitus (T2DM) has become a chronic disease, serious harm to human health. Complications of the blood pipe are the main cause of disability and death in diabetic patients, including vascular lesions that directly affects the prognosis of patients with diabetes and survival. This study was to determine the influence of high glucose and related mechanism of vascular lesion of type 2 diabetes mellitus pathogenesis. Methods: In vivo aorta abdominalis of GK rats was observed with blood pressure, heart rate, hematoxylin and eosin (H&E), Masson, and Verhoeff staining. In vitro cells were cultured with 30 mM glucose for 24 h. RT-QPCR was used to detect the mRNA expression of endothelial markers PTEN, PI3K, Akt, and VEGF. Immunofluorescence staining was used to detect the expression of PTEN, PI3K, Akt, and VEGF. PI3K and Akt phosphorylation levels were detected by Western blot analysis. Results: Heart rate, systolic blood pressure, diastolic blood pressure, and mean blood pressure in the GK control group were higher compared with the Wistar control group and no difference compared with the GK experimental model group. Fluorescence intensity of VEGF, Akt, and PI3K in the high-sugar stimulus group was stronger than the control group; PTEN in the high-sugar stimulus group was weakening than the control group. VEGF, Akt, and PI3K mRNA in the high-sugar stimulus group were higher than the control group; protein expressions of VEGF, Akt, and PI3K in the high-sugar stimulus group were higher than the control group. PTEN mRNA in the high-sugar stimulus group was lower than the control group. Protein expression of PTEN in the high-sugar stimulus group was lower than the control group. Conclusions: Angiogenesis is an important pathogenesis of T2DM vascular disease, and PTEN plays a negative regulatory role in the development of new blood vessels and can inhibit the PI3K/Akt signaling pathway.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Aorta Abdominal/metabolismo , Glicemia/análise , Pressão Sanguínea , Doença Crônica , Diabetes Mellitus Tipo 2/mortalidade , Glicosilação , Frequência Cardíaca , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , NG-Nitroarginina Metil Éster/química , Neovascularização Patológica , Fosforilação , Prognóstico , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Resultado do Tratamento
7.
Med Sci (Paris) ; 34 Focus issue F1: 81-86, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30403180

RESUMO

Osteosarcoma is the most common malignant bone tumor with high incidence in adolescence and poor prognosis. RBM10, a member of RBPs, was reported to be a tumor suppressor in many kinds of cancers. However, the roles of RBM10 in osteosarcoma remain unknown. In this study, we found that overexpression of RBM10 decreased osteosarcoma cell proliferation and colony formation in soft agar, and inhibited osteosarcoma cell migration and invasion. Our results also revealed that RBM10 overexpression induced osteosarcoma cell apoptosis via the inhibition of Bcl-2, the activation of caspase-3, and the transcription and production of TNF-α. Our results indicated that RBM10 acts as a tumor suppressor in osteosarcoma. This could enable to define a new strategy for diagnosis and treatment of patients with osteosarcoma.


Assuntos
Apoptose/genética , Neoplasias Ósseas/patologia , Movimento Celular/genética , Proliferação de Células/genética , Osteossarcoma/patologia , Proteínas de Ligação a RNA/genética , Neoplasias Ósseas/genética , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Osteossarcoma/genética , Proteínas de Ligação a RNA/fisiologia , Células Tumorais Cultivadas , Regulação para Cima/genética
8.
Int J Mol Med ; 42(4): 2053-2061, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30015859

RESUMO

Toll­like receptor 4 (TLR4)­mediated immune and inflammatory signaling serves a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Our previous study demonstrated that celastrol treatment was able to improve hepatic steatosis and inhibit the TLR4 signaling cascade pathway in type 2 diabetic rats. The present study aimed to investigate the effects of celastrol on triglyceride accumulation and inflammation in steatotic HepG2 cells, and the possible mechanisms responsible for the regulation of cellular responses following TLR4 gene knockdown by small interfering RNA (siRNA) in vitro. A cell model of hepatic steatosis was prepared by exposing the HepG2 cells to free fatty acid (FFA) in the absence or presence of celastrol. Intracellular triglycerides were visualized by Oil red O staining, and the TLR4/myeloid differentiation primary response 88 (MyD88)/nuclear factor­κB (NF­κB) signaling cascade pathway were investigated. To directly elucidate whether TLR4 was the blocking target of celastrol upon FFA exposure, the cellular response to inflammation was determined upon transfection with TLR4 siRNA. The results revealed that celastrol significantly reduced triglyceride accumulation in the steatotic HepG2 cells, and downregulated the expression levels of TLR4, MyD88 and phospho­NF­κBp65, as well as of the downstream inflammatory cytokines interleukin­1ß and tumor necrosis factor α. Knockdown of TLR4 also alleviated FFA­induced inflammatory response. In addition, co­treatment with TLR4 siRNA and celastrol further attenuated the expression of inflammatory mediators. These results suggest that celastrol exerts its protective effect partly via inhibiting the TLR4­mediated immune and inflammatory response in steatotic HepG2 cells.


Assuntos
Ácidos Graxos não Esterificados/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/imunologia , Receptor 4 Toll-Like/imunologia , Triglicerídeos/imunologia , Triterpenos/farmacocinética , Animais , Ácidos Graxos não Esterificados/farmacologia , Células Hep G2 , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos , Receptor 4 Toll-Like/genética , Triglicerídeos/genética
9.
World J Gastroenterol ; 23(20): 3684-3689, 2017 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-28611521

RESUMO

AIM: To assess the feasibility and safety of a novel enteroscope, negative-pressure suction endoscope in examining the small intestine of a porcine model. METHODS: In vitro experiments in small intestinal loops from 20 pigs and in vivo experiments in 20 living pigs were conducted. RESULTS: In in vitro experiments, a negative pressure of > 0.06 MPa was necessary for optimal visualization of the intestine, and this pressure did not cause gross or histological damage to the mucosa. For satisfactory examination of the small intestine in vivo, higher negative pressure (> 1.00 MPa) was required. Despite this higher pressure, the small intestine did not show any gross or microscopic damage in the suctioned areas. The average time of examination in the living animals was 60 ± 7.67 min. The animals did not experience any apparent ill effects from the procedure. CONCLUSION: Small intestine endoscope was safely performed within a reasonable time period and enabled complete visualization of the intestine in most cases.


Assuntos
Endoscopia Gastrointestinal/instrumentação , Endoscopia Gastrointestinal/métodos , Intestino Delgado/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Estudos de Viabilidade , Técnicas In Vitro , Segurança do Paciente , Pressão , Suínos
10.
Am J Physiol Heart Circ Physiol ; 312(5): H1068-H1075, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28341632

RESUMO

Cardiac microvascular obstruction (MVO) after ischemia-reperfusion (I/R) has been well studied, but microvascular leakage (MVL) remains largely unexplored. We characterized MVL in the mouse I/R model by histology, biochemistry, and cardiac magnetic resonance (CMR) imaging. I/R was induced surgically in mice. MVL was determined by administrating the microvascular permeability tracer Evans blue (EB) and/or gadolinium-diethylenetriaminepentaacetic acid contrast. The size of MVL, infarction, and MVO in the heart was quantified histologically. Myocardial EB was extracted and quantified chromatographically. Serial CMR images were acquired from euthanized mice to determine late gadolinium enhancement (LGE) for comparison with MVL quantified by histology. I/R resulted in MVL with its severity dependent on the ischemic duration and reaching its maximum at 24-48 h after reperfusion. The size of MVL correlated with the degree of left ventricular dilatation and reduction in ejection fraction. Within the risk zone, the area of MVL (75 ± 2%) was greater than that of infarct (47 ± 4%, P < 0.01) or MVO (36 ± 4%, P < 0.01). Contour analysis of paired CMR-LGE by CMR and histological MVL images revealed a high degree of spatial colocalization (r = 0.959, P < 0.0001). These data indicate that microvascular barrier function is damaged after I/R leading to MVL. Histological and biochemical means are able to characterize MVL by size and severity while CMR-LGE is a potential diagnostic tool for MVL. The size of ischemic myocardium exhibiting MVL was greater than that of infarction and MVO, implying a role of MVL in postinfarct pathophysiology.NEW & NOTEWORTHY We characterized, for the first time, the features of microvascular leakage (MVL) as a consequence of reperfused myocardial infarction. The size of ischemic myocardium exhibiting MVL was significantly greater than that of infarction or no reflow. We made a proof-of-concept finding on the diagnostic potential of MVL by cardiac magnetic resonance imaging.


Assuntos
Hemorragia/diagnóstico por imagem , Hemorragia/patologia , Imagem Cinética por Ressonância Magnética/métodos , Microvasos/patologia , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/patologia , Animais , Permeabilidade Capilar , Hemorragia/etiologia , Masculino , Camundongos Endogâmicos C57BL , Microvasos/diagnóstico por imagem , Infarto do Miocárdio/complicações , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
11.
Cardiovasc Drugs Ther ; 31(2): 145-156, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28204966

RESUMO

PURPOSE: Inhibition of the renin-angiotensin system (RAS) is beneficial in patient management after myocardial infarction (MI). However, whether RAS inhibition also provides cardiac protection in the acute phase of MI is unclear. METHODS: Male 129sv mice underwent coronary artery occlusion to induce MI, followed by treatment with losartan (L, 20 and 60 mg/kg), perindopril (P, 2 and 6 mg/kg), amlodipine (20 mg/kg as a BP-lowering agent) or vehicle as control. Drug effects on hemodynamics were examined. Effects of treatments on incidence of cardiac rupture, haematological profile, monocyte and neutrophil population in the spleen and the heart, cardiac leukocyte density, expression of inflammatory genes and activity of MMPs were studied after MI. RESULTS: Incidence of cardiac rupture within 2 weeks was significantly and similarly reduced by both losartan (L) and perindopril (P) in a dose-dependent manner [75% (27/36) in vehicle, 40-45% in low-dose (L 10/22, P 8/20) and 16-20% (L 5/32, P 4/20) in high-dose groups, all P < 0.05]. This action was independent of their BP-lowering action, as amlodipine reduced BP to a similar degree without effect on rupture (70%, 21/30). Compared to the control group, high dose losartan and perindopril decreased counts of white blood cells, neutrophils and lymphocytes (all P < 0.05), and inhibited splenic monocyte and neutrophil release into the circulation. Consequently, monocyte, neutrophil and leukocyte infiltration, inflammatory gene expressions (IL-1ß, IL-6, MMP9, MCP-1, TNF-α and TGFß1) and activity of MMP2 and MMP9 in the infarct tissue were attenuated by losartan and/or perindopril treatment (all P < 0.05). CONCLUSIONS: RAS inhibition by losartan or perindopril prevented cardiac rupture at the acute phase of MI through blockade of splenic release of monocytes and neutrophils and consequently attenuation of systemic and regional inflammatory responses.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Inflamatórios/farmacologia , Ruptura Cardíaca Pós-Infarto/prevenção & controle , Inflamação/prevenção & controle , Losartan/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Perindopril/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Anlodipino/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ruptura Cardíaca Pós-Infarto/etiologia , Ruptura Cardíaca Pós-Infarto/metabolismo , Ruptura Cardíaca Pós-Infarto/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos da Linhagem 129 , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Infarto do Miocárdio/complicações , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/patologia , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Baço/efeitos dos fármacos , Baço/metabolismo , Fatores de Tempo
12.
Mol Biol Rep ; 43(11): 1285-1292, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27558092

RESUMO

Neuropathy target esterase (NTE) and NTE-related esterase (NRE) are endoplasmic reticulum (ER) membrane-anchored proteins belonging to the NTE protein family. NTE and NRE are degraded by macroautophagy and by the ubiquitin-proteasome pathway. However, the regulation of NTE and NRE by proteasome has not been well understood. Western blotting showed that the deletion of the regulatory region of NTE and NRE led to protein accumulation compared with that of the corresponding wild-type proteins. Further, deletion and site-directed mutagenesis experiments demonstrated that the destruction (D) box was required for the proteasomal degradation of NTE and NRE. However, unlike the deletion of the regulatory region, the deletion of the D box did not affect the subcellular localisation of NTE or NRE or disrupt the ER. Moreover, the deletion of the D box or the regulatory region of NTE has similar inhibitory effects on cell growth, which are greater than those produced by the full-length NTE. Here, for the first time, we show that the D box is involved in the regulation of NTE family proteins by the proteasome but not in their subcellular localisation. In addition, these results suggest that the NTE overexpression-mediated inhibition of cell growth is related to active protein levels but not to its ER disruption effect.


Assuntos
Hidrolases de Éster Carboxílico/química , Hidrolases de Éster Carboxílico/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Animais , Autofagia , Células COS , Hidrolases de Éster Carboxílico/genética , Análise Mutacional de DNA , Células HeLa , Humanos , Ligação Proteica , Proteólise
13.
Exp Ther Med ; 11(6): 2221-2224, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27284304

RESUMO

The aim of this study was to investigate the effect of erythropoietin (EPO) on the inflammatory response and the mechanism analysis of the Τoll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway of NEC. A total of 94 patients with necrotizing enterocolitis (NEC) were randomly divided into the control (42 cases) and observation (52 cases) groups, The control group received the standard medical treatment plan, whereas for the observation group this treatment plan was combined with the application of recombinant EPO for intramuscular injection treatment. The clinical effect was subsequently compared. The results showed that the complication and death rates in the observation group were significantly lower than those in the control group with statistically significant differences (P<0.05). Following treatments, the levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in the observation group were significantly lower than those in the control group. The expression levels of mRNA of TLR4 and NF-κB in the observation group were significantly lower than those in the control group, with statistically significant differences (P<0.05). In summary, EPO was able to reduce the levels of inflammatory response of TNF-α and IL-6 through the TLR4/NF-κB signaling pathway, and improve the NEC, thus providing a basis for the clinical treatment of NEC.

14.
Gene ; 591(2): 344-50, 2016 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-27267404

RESUMO

Patatin-like phospholipase domain containing protein 1 (PNPLA1) mutations have been identified to be associated with autosomal recessive congenital ichthyosis (ARCI) in recent years. However, its molecular characters have not been achieved until now. In the current study, the full length coding cDNA sequence of mouse PNPLA1 (mPNPLA1) was identified firstly. There were several putative transmembrane domains (TMDs) in mPNPLA1 by bioinformation analysis. mPNPLA1 was further found to be expressed exclusively in the membrane fraction in mammalian cells. However, it did not colocalized with the endoplasmic reticulum (ER) or lipid droplets (LDs). Moreover, the mRNA levels of mPNPLA1 was detected to be highly expressed in the skin, while very weak or even less in other mouse tissues by quantitative PCR. In addition, based on experiments with inhibitors and inducer of protein degradation pathways, mPNPLA1 was demonstrated to be degraded by macroautophagy, but not by the proteasome. These results indicated PNPLA1 was a skin-specific and membrane-associated protein for the first time, suggesting that it may mainly play a role in the skin.


Assuntos
Lipase/fisiologia , Proteínas de Membrana/fisiologia , Fosfolipases/fisiologia , Pele/metabolismo , Sequência de Aminoácidos , Animais , Células COS , Retículo Endoplasmático/metabolismo , Expressão Gênica , Humanos , Lipase/química , Lipase/genética , Gotículas Lipídicas/metabolismo , Proteínas de Membrana/biossíntese , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Mutação , Fosfolipases/biossíntese , Fosfolipases/química , Fosfolipases/genética , Domínios Proteicos , Alinhamento de Sequência , Análise de Sequência de DNA
15.
Int J Mol Med ; 37(5): 1229-38, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27049825

RESUMO

Oxidative stress plays a key role in the pathogenesis of diabetic myopathy. Celastrol provides a wide range of health benefits, including antioxidant, anti-inflammatory and antitumor effects. We hypothesized that celastrol may exert an antioxidant effect in the skeletal muscle of diabetic rats. In the present study, MnSOD activity was determined by spectrophotometry. The protein levels were evaluated by western blot analysis and mRNA content was quantified by RT­qPCR. We firstly found that the levels of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor coactivator 1α (PGC1α), silent mating-type information regulation 2 homolog 3 (Sirt3) and manganese superoxide dismutase (MnSOD) were all decreased in the skeletal muscle of diabetic patients. Male rats with diabetes were also treated with the vehicle or with celastrol at 1, 3 and 6 mg/kg/day for 8 weeks. The administration of celastrol at 3 and 6 mg/kg attenuated the deterioration of skeletal muscle, as shown by histological analysis, decreased the malondialdehyde (MDA) level and increased the glutathione (GSH) level assayed by enzyme-linked immunosorbent assay (ELISA) method. It also enhanced the enzyme activity and increased the expression of MnSOD, and increased the AMPK phosphorylation level, as well as PGC1α and Sirt3 expression. The findings of our study suggest that the expression of AMPK, PGC1α, Sirt3 and MnSOD are decreased in the skeletal muscle of diabetic patients. Celastrol exerted antioxidant effects on skeletal muscle partly by regulating the AMPK-PGC1α-Sirt3 signaling pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus/metabolismo , Músculo Esquelético/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 3/metabolismo , Triterpenos/farmacologia , Idoso , Animais , Biomarcadores , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Ratos , Superóxido Dismutase/metabolismo
16.
J Diabetes Res ; 2016: 2641248, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27057550

RESUMO

Immune and inflammatory pathways play a central role in the pathogenesis of diabetic liver injury. Celastrol is a potent immunosuppressive and anti-inflammatory agent. So far, there is no evidence regarding the mechanism of innate immune alterations of celastrol on diabetic liver injury in type 2 diabetic animal models. The present study was aimed at investigating protective effects of celastrol on the liver injury in diabetic rats and at elucidating the possible involved mechanisms. We analyzed the liver histopathological and biochemical changes and the expressions of TLR4 mediated signaling pathway. Compared to the normal control group, diabetic rats were found to have obvious steatohepatitis and proinflammatory cytokine activities were significantly upregulated. Celastrol-treated diabetic rats show reduced hepatic inflammation and macrophages infiltration. The expressions of TLR4, MyD88, NF-κB, and downstream inflammatory factors IL-1ß and TNFα in the hepatic tissue of treated rats were downregulated in a dose-dependent manner. We firstly found that celastrol treatment could delay the progression of diabetic liver disease in type 2 diabetic rats via inhibition of TLR4/MyD88/NF-κB signaling cascade pathways and its downstream inflammatory effectors.


Assuntos
Anti-Inflamatórios/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hepatopatias/prevenção & controle , Fígado/efeitos dos fármacos , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Triterpenos/farmacologia , Animais , Citoproteção , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Interleucina-1beta/sangue , Fígado/metabolismo , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/sangue
17.
Clin Sci (Lond) ; 130(13): 1089-104, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27129192

RESUMO

Acute myocardial infarction (AMI) is characterized by a rapid increase in circulating platelet size but the mechanism for this is unclear. Large platelets are hyperactive and associated with adverse clinical outcomes. We determined mean platelet volume (MPV) and platelet-monocyte conjugation (PMC) using blood samples from patients, and blood and the spleen from mice with AMI. We further measured changes in platelet size, PMC, cardiac and splenic contents of platelets and leucocyte infiltration into the mouse heart. In AMI patients, circulating MPV and PMC increased at 1-3 h post-MI and MPV returned to reference levels within 24 h after admission. In mice with MI, increases in platelet size and PMC became evident within 12 h and were sustained up to 72 h. Splenic platelets are bigger than circulating platelets in normal or infarct mice. At 24 h post-MI, splenic platelet storage was halved whereas cardiac platelets increased by 4-fold. Splenectomy attenuated all changes observed in the blood, reduced leucocyte and platelet accumulation in the infarct myocardium, limited infarct size and alleviated cardiac dilatation and dysfunction. AMI-induced elevated circulating levels of adenosine diphosphate and catecholamines in both human and the mouse, which may trigger splenic platelet release. Pharmacological inhibition of angiotensin-converting enzyme, ß1-adrenergic receptor or platelet P2Y12 receptor reduced platelet abundance in the murine infarct myocardium albeit having diverse effects on platelet size and PMC. In conclusion, AMI evokes release of splenic platelets, which contributes to the increase in platelet size and PMC and facilitates myocardial accumulation of platelets and leucocytes, thereby promoting post-infarct inflammation.


Assuntos
Plaquetas/fisiologia , Inflamação/metabolismo , Monócitos/citologia , Infarto do Miocárdio/sangue , Miocárdio/citologia , Contagem de Plaquetas , Animais , Tamanho Celular , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/fisiopatologia , Peptidil Dipeptidase A/metabolismo
18.
Tumour Biol ; 37(1): 291-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26201895

RESUMO

Previous studies demonstrate that microRNA-138 (miR-138) is critical in non-small cell lung cancer (NSCLC) regulation. We further explored the molecular mechanism of miR-138 in NSCLC. Lentivirus was used to upregulate miR-138 in NSCLC cell lines H460 and SPC-A1 cells. Previously known effects of miR-138 upregulation on NSCLC, proliferation, cell cycle division, and cisplatin sensitivity were examined in H460 and SPC-A1 cells. Moreover, previously unknown effect of miR-138 upregulation on NSCLC migration was also examined in H460 and SPC-A1 cells. A new miR-138 downstream target, cyclin D3 (CCND3), was assessed by dual-luciferase reporter assay and quantitative real-time PCR (qRT-PCR). CCND3 was then ectopically overexpressed in H460 and SPC-A1 cells. The effects of forced overexpression of CCND3 on miR-138-induced NSCLC regulations were further examined by proliferation, cell cycle, cisplatin sensitivity, and migration assays, respectively. Lentivirus-induced miR-138 upregulation inhibited NSCLC proliferation and cell cycle division, in line with previous findings. Moreover, we found that miR-138 upregulation had other anti-tumor effects, such as increasing cisplatin sensitivity and reducing cancer migration, in H460 and SPC-A1 cells. Luciferase assay and qRT-PCR showed that CCND3 was directly targeted by miR-138. Forced overexpression of CCND3 in H460 and SPC-A1 cells reversed the anti-tumor effects of miR-138 upregulation on cancer cell growth, cell cycle, cisplatin sensitivity, and migration. Our study revealed novel anti-cancer effects of miR-138 upregulation in NSCLC, as well as its new molecular target of CCND3.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ciclina D3/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Antineoplásicos/química , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Cisplatino/química , Perfilação da Expressão Gênica , Humanos , Lentivirus/genética , Lentivirus/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
19.
Am J Physiol Heart Circ Physiol ; 309(5): H946-57, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26116714

RESUMO

Myocardial fibrosis is regarded as a pivotal proarrhythmic substrate, but there have been no comprehensive studies showing a correlation between the severity of fibrosis and ventricular tachyarrhythmias (VTAs). Our purpose was to document this relationship in a transgenic (TG) strain of mice with fibrotic cardiomyopathy. TG mice with cardiac overexpression of ß2-adrenoceptors (ß2-AR mice) and non-TG (NTG) littermates were studied at 4-12 mo of age. VTA was quantified by ECG telemetry. The effect of pharmacological blockade of ß2-ARs on VTA was examined. Myocardial collagen content was determined by hydroxyproline assay. NTG and TG mice displayed circadian variation in heart rate, which was higher in TG mice than in NTG mice (P <0.05). Frequent spontaneous ventricular ectopic beats (VEBs) and ventricular tachycardia (VT) were prominent in TG mice but not present in NTG mice. The frequency of VEB and VT episodes in TG mice increased with age (P < 0.01). Ventricular collagen content was greater in TG mice than in NTG mice (P <0.001) and correlated with age (r = 0.71, P < 0.01). The number of VEBs or VT episodes correlated with age (r = 0.83 and r = 0.73) and the content of total or cross-linked collagen (r = 0.62∼0.66, all P <0.01). While having no effect in younger ß2-TG mice, ß2-AR blockade reduced the frequency of VTA in old ß2-TG mice with more severe fibrosis. In conclusion, ß2-TG mice exhibit interstitial fibrosis and spontaneous onset of VTA, becoming more severe with aging. The extent of cardiac fibrosis is a major determinant for both the frequency of VTA and proarrhythmic action of ß2-AR activation.


Assuntos
Ventrículos do Coração/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Taquicardia/metabolismo , Antagonistas de Receptores Adrenérgicos beta 2 , Animais , Colágeno/metabolismo , Fibrose/metabolismo , Fibrose/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Adrenérgicos beta 2/genética , Taquicardia/fisiopatologia
20.
Gynecol Obstet Invest ; 79(2): 97-100, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25634306

RESUMO

BACKGROUND/AIMS: Acute fatty liver of pregnancy (AFLP) is a severe liver failure condition that has limited therapeutic approaches. We aimed to evaluate the efficacy of combining plasma exchange (PE) and plasma perfusion (PP) with conventional therapy for the treatment of AFLP using a retrospective analysis. METHODS: Among 22 patients with AFLP, 16 cases were treated with conventional treatment (CT group), while the other 6 cases were treated with PE and PP in addition to conventional therapy (CT+PE+PP group). Treatment efficacy was based primarily on survival and secondarily on liver and kidney functions 2 weeks after treatment. Adverse effects were also assessed at the same time point. RESULTS: In the CT+PE+PP group, 5 (83.3%) patients improved, while 1 (16.7%) patient died of multiple organ dysfunction syndrome. In the CT group, 3 (18.75%) patients improved, while 13 (81.2%) patients died of complications. Liver and kidney functions and survival were significantly improved in the CT+PE+PP group (p < 0.05) compared to the CT group. CONCLUSIONS: Timely application of PE and PP in the early phase of AFLP may be a promising treatment to halt or reverse the progression of AFLP.


Assuntos
Fígado Gorduroso/terapia , Hemoperfusão/métodos , Troca Plasmática/métodos , Complicações na Gravidez/terapia , Adulto , Terapia Combinada , Feminino , Humanos , Gravidez , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
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