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1.
Metallomics ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31650140

RESUMO

Cadmium (Cd) is a persistent environmental contaminant and induces neurotoxicity in animals. Trehalose (Tre) exhibits powerful neuroprotective effects in certain brain injury models. Herein, we revealed the specific molecular mechanism underlying the protective effects of Tre against Cd-induced brain damage in rats. Firstly, the results showed that Tre significantly ameliorated brain pathological injury induced by Cd. Secondly, Cd-induced down-regulation of total anti-oxidation capacity (T-AOC) and up-regulation of methane dicarboxylic aldehyde (MDA) in brain tissues were significantly reversed by Tre treatment. Importantly, the augmentation of nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) caused by Cd was significantly inhibited by Tre treatment. Thirdly, the levels of autophagy marker proteins were measured and the results showed that Tre significantly reversed the up-regulation of light chain 3II (LC-3II) and sequestosome 1 (SQSTM-1/p62) caused by Cd exposure. Finally, the apoptosis rate and the levels of apoptosis marker proteins including B cell leukemia/lymphoma 2 (Bcl2) and Bcl2-associated X protein (Bax) were also measured and the results showed that Cd-induced apoptosis was markedly inhibited by Tre treatment. Collectively, our data suggested that Tre exerted its neuroprotective effects by ameliorating oxidative stress, autophagy inhibition, and apoptosis induced by Cd in rat brains. In addition, the Nrf2 signaling pathway, which is continuously activated by Cd, may contribute to brain injury.

2.
Protein Pept Lett ; 26(9): 648-663, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31218945

RESUMO

After decades of efforts, tuberculosis has been well controlled in most places. The existing drugs are no longer sufficient for the treatment of drug-resistant Mycobacterium tuberculosis due to significant toxicity and selective pressure, especially for XDR-TB. In order to accelerate the development of high-efficiency, low-toxic antituberculosis drugs, it is particularly important to use Computer Aided Drug Design (CADD) for rational drug design. Here, we systematically reviewed the specific role of molecular simulation in the discovery of new antituberculosis drugs. The purpose of this review is to overview current applications of molecular simulation methods in the discovery of antituberculosis drugs. Furthermore, the unique advantages of molecular simulation was discussed in revealing the mechanism of drug resistance. The comprehensive use of different molecular simulation methods will help reveal the mechanism of drug resistance and improve the efficiency of rational drug design. With the help of molecular simulation methods such as QM/MM method, the mechanisms of biochemical reactions catalyzed by enzymes at atomic level in Mycobacterium tuberculosis has been deeply analyzed. QSAR and virtual screening both accelerate the development of highefficiency, low-toxic potential antituberculosis drugs. Improving the accuracy of existing algorithms and developing more efficient new methods for CADD will always be a hot topic in the future. It is of great value to utilize molecular dynamics simulation to investigate complex systems that cannot be studied in experiments, especially for drug resistance of Mycobacterium tuberculosis.


Assuntos
Antituberculosos/química , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Algoritmos , Antituberculosos/farmacologia , Projeto Auxiliado por Computador , Teoria da Densidade Funcional , Desenho de Drogas , Farmacorresistência Bacteriana , Humanos , Relação Quantitativa Estrutura-Atividade
3.
Cardiology ; 142(3): 149-157, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31163415

RESUMO

OBJECTIVES: To explore the association between single-nucleotide polymorphisms (SNPs) in MTHFR and APOE and the risk of CAD and, more importantly, the severity of CAD and the profile of serum lipids, we performed a case-control study in a Chinese Han population. METHODS: A total of 1,207 cases of consecutive CAD-suspected inpatients were recruited, and 406 CAD cases and 231 non-CAD controls were enrolled for the final analysis after screening for exclusion criteria. All subjects had undergone coronary angiography, and the severity of CAD was evaluated by 2 cardiologists according to the Gensini scores. The genotypes of MTHFR and APOEwere detected using real-time PCR, and then verified by Sanger sequencing. Environmental risk factors, such as age, sex, smoking, alcohol consumption, hypertension, diabetes, dyslipidemia, and BMI were collected. Statistical analyses (the χ2 test, binary logistic regression analysis, and ordinal polytomous logistic regression analysis) were performed with SPSS v16.0. RESULTS: The genotypes ofall the subjects included in the CAD and non-CAD groups in this study were successfully detected, with an agreement of 100% with Sanger sequencing. The distributions of genotypes CT and TT at MTHFR C667T were higher in CAD cases than in non-CAD controls (OR 1.99, 95% CI 1.34-2.95; OR 1.77, 95% CI 1.18-2.67; p < 0.05), whereas genotype AC at MTHFR A1298Cwas lower in CAD cases (OR 0.71, 95% CI 0.50-1.02; p < 0.05). A significant association was observed in genotypes CT and TT at MTHFR C667T and the risk of CAD (OR 1.44, 95% CI 1.27-3.67; OR 1.56, 95% CI 0.88-2.78; p < 0.05). Both genotypes and alleles of APOE were comparable in the CAD cases and non-CAD controls (p > 0.05). The genotype TT at MTHFR C667T and ε4+ at APOE were more likely to be found in the CAD subgroup with a Gensini score ≥72 (p = 0.040 and p = 0.028, respectively). Meanwhile, in the patients with genotype TT,a higher level of serum Hcy was detected, while genotype ε4+ patients possessed higher levels of serum apolipoprotein E (ApoE) and low-density lipoprotein cholesterol (LDL-C) than other genotypes. CONCLUSION: This study revealed that the SNP site of MTHFR C667Tis associatedwith the risk of CAD in this Chinese Han population. In addition, the genotypes of TT in MTHFR C667T and ε4+in APOE may increase the severity of CAD, and higher Hcy, LDL-C, and ApoE levels may be involved in this pathogenic process.

4.
Int J Biol Macromol ; 126: 653-661, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30594625

RESUMO

Flavonoids are widely distributed phytochemicals in vegetables, fruits and medicinal plants. Recent studies demonstrate that some natural flavonoids are potent inhibitors of the human UDP-glucuronosyltransferase 1A1 (UGT1A1), a key enzyme in detoxification of endogenous harmful compounds such as bilirubin. In this study, the inhibitory effects of 56 natural and synthetic flavonoids on UGT1A1 were assayed, while the structure-inhibition relationships of flavonoids as UGT1A1 inhibitors were investigated. The results demonstrated that the C-3 and C-7 hydroxyl groups on the flavone skeleton would enhance UGT1A1 inhibition, while flavonoid glycosides displayed weaker inhibitory effects than their corresponding aglycones. Further investigation on inhibition kinetics of two strong flavonoid-type UGT1A1 inhibitors, acacetin and kaempferol, yielded interesting results. Both flavonoids were competitive inhibitors against UGT1A1-mediated NHPN-O-glucuronidation, but were mixed and competitive inhibitors toward UGT1A1-mediated NCHN-O-glucuronidation, respectively. Furthermore, docking simulations showed that the binding areas of NHPN, kaempferol and acacetin on UGT1A1 were highly overlapping, and convergence with the binding area of bilirubin within UGT1A1. In summary, detailed structure-inhibition relationships of flavonoids as UGT1A1 inhibitors were investigated carefully and the findings shed new light on the interactions between flavonoids and UGT1A1, and will contribute considerably to the development of flavonoid-type drugs without strong UGT1A1 inhibition.


Assuntos
Flavonoides/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Domínio Catalítico , Flavonas/química , Flavonas/farmacologia , Flavonoides/química , Corantes Fluorescentes/metabolismo , Glucuronosiltransferase/química , Glucuronosiltransferase/metabolismo , Humanos , Concentração Inibidora 50 , Quempferóis/química , Quempferóis/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Especificidade por Substrato/efeitos dos fármacos
5.
Materials (Basel) ; 11(10)2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-30274154

RESUMO

NiAl-based composites reinforced by CrMnFeCoNi high-entropy alloy (HEA) particles were fabricated by mechanical alloying (MA) and spark plasma sintering (SPS). The microstructure, mechanical, and tribological properties of the NiAl-HEA composites were investigated. Microstructural analyses show that after SPS, the HEA phase homogenously distributed in the NiAl matrix. Non-uniform diffusion of various elements occurred during the high temperature sintering process. Transmission electron microscope (TEM) observation of the composites revealed that many nano particle of Al2O3 generated at the grain boundary. The yield strength significantly increased after adding HEA particles. The compressive strength of the composites increased with the contents of HEA increasing, which should be attributed to the second phase hardening effect of HEA particles and fine grain strengthening effect. The composite of 10 wt.% HEA exhibited significant room temperature compressive properties, with the ultimate compressive strength of 2692 MPa and the compressive strain of 34.2%, respectively. The results of the wear tests show that the addition of HEA will reduce the wear resistance of composites to some extent and slightly increase the coefficients of friction (COFs) of the composites.

6.
Drug Des Devel Ther ; 12: 2213-2221, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30038487

RESUMO

Introduction: Nonalcoholic steatohepatitis (NASH) is largely driven by the dysregulation of liver metabolism and inflammation. Bile acids and their receptor Farnesoid X receptor (FXR) play a critical role in the disease development. Here, we investigated whether INT-767, the newly-identified dual FXR/TGR5 agonist, can protect rat from liver injury during NASH. Materials and methods: NASH model was established by feeding the male SD rats with high-fat diet for 16 weeks. INT-767 was given by gavage to NASH rats from week 13 to week 16. At the end of 16 weeks, liver and serum were harvested, and bile acids, glucose and lipid metabolism, liver injury and histological features were evaluated. Results: INT-767 treatment significantly alleviates high-fat caused liver damage characterized with lipid accumulation and hepatic infiltration of immune cells. INT-767 robustly restores the lipid, glucose metabolism to normal level, attenuates insulin resistance through upregulating FXR level and reverting the dysregulation of its target genes in liver metabolism. Molecularly INT-767 also attenuates the pro-inflammatory response by suppression of TNF-α and NF-κB signaling pathway. Conclusion: INT-767 may be an attractive candidate for a potential novel strategy on the treatment of NASH.

7.
Cancer Manag Res ; 10: 1647-1655, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29970964

RESUMO

Purpose: The aim of this study was to investigate whether the expression of the ligand-gated Ca2+ channel transient receptor potential vanilloid type-1 (TRPV1) in primary human renal cell carcinoma (RCC) is associated with clinicopathological features. Patients and methods: Fresh and frozen primary tumor and normal peritumoral kidney tissues from 127 patients diagnosed with RCC were analyzed for TRPV1 expression by quantitative reverse transcription polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry. Results: Quantitative RT-PCR revealed that TRPV1 was decreased 3.20-fold in RCC tissue vs normal peritumoral kidney tissue (p=0.012). Significantly different TRPV1 mRNA expression was detected in RCC tissues of different Fuhrman grades and histopathological subtypes (F=4.282, p=0.015 and F=5.205, p=0.014, respectively). Decreased TRPV1 expression was correlated with RCC histopathological subtype (R=-0.554, p=0.003) and Fuhrman grade (R=-0.525, p=0.006). Western blot analysis of TRPV1 protein expression showed similar results. Immunohistochemical analysis showed strong expression of TRPV1 in kidney tubules but demonstrated weak or no immunostaining in RCC tissues. Conclusion: TRPV1 expression was decreased in RCC, which was significantly associated with tumor Fuhrman grades and histopathological subtypes. It seems to suggest that TRPV1 expression may be a valuable tool to predict the extent of RCC progression.

8.
J Pathol ; 246(1): 89-102, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29926931

RESUMO

Characterising the activated oncogenic signalling that leads to advanced breast cancer is of clinical importance. Here, we showed that SET domain, bifurcated 1 (SETDB1), a histone H3 lysine 9 methyltransferase, is aberrantly expressed and behaves as an oncogenic driver in breast cancer. SETDB1 enhances c-MYC and cyclin D1 expression by promoting the internal ribosome entry site (IRES)-mediated translation of MYC/CCND1 mRNA, resulting in prominent signalling of c-MYC to promote cell cycle progression, and provides a growth/self-renewal advantage to breast cancer cells. The activated c-MYC-BMI1 axis is essential for SETDB1-mediated breast tumourigenesis, because silencing of either c-MYC or BMI1 profoundly impairs the enhanced growth/colony formation conferred by SETDB1. Furthermore, c-MYC directly binds to the SETDB1 promoter region and enhances its transcription, suggesting a positive regulatory interplay between SETDB1 and c-MYC. In this study, we identified SETDB1 as a prominent oncogene and characterised the underlying mechanism whereby SETDB1 drives breast cancer, providing a therapeutic rationale for targeting SETDB1-BMI1 signalling in breast cancer. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

9.
Ann Hepatol ; 17(3): 355-363, 2018 May-June.
Artigo em Inglês | MEDLINE | ID: mdl-29735795

RESUMO

INTRODUCTION AND AIM: Autophagy and its regulated pathways participate in many important cellular physiology and pathological processes involving protein aggregates, damaged mitochondria, excessive peroxisomes, ribosomes, and invading pathogens. This study aimed to review recently published studies and further describe the long noncoding RNA (lncRNA)-regulated autophagy during drug-induced liver injury (DILI). MATERIAL AND METHODS: DILI, autophagy, autophagy-related genes (ATGs), and lncRNA were used as key words to search published studies from PubMed, Google Scholar, and Web of Science. All related studies were reviewed and analyzed. RESULTS: Many studies explicitly indicated that DILI and its progression to acute liver failure were causatively linked to endoplasmic reticulum stress and subsequently induced autophagy, which protect hepatocytes during DILI. LncRNA, as a noncoding RNA, influences the regulation of the expression of ATGs to manipulate autophagy. CONCLUSIONS: This review described the recent findings on autophagy and its possible lncRNA-miRNA-associated pathways, thereby providing new insights for further studies on the pathogenesis of DILI.

10.
PLoS One ; 13(4): e0195844, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29659618

RESUMO

We previously demonstrated that transient receptor potential vanilloid subfamily 5 (TRPV5) expression was decreased in renal cell carcinoma (RCC) compared with that in normal kidney tissues, a finding that was correlated with vitamin D receptor (VDR) expression, but further investigations is warranted. The aim of this study was to elucidate whether VDR could regulate the expression of TRPV5 and affect proliferation and metastasis in RCC. In this study, we used lentivirus to conduct the model of VDR overexpression and knockdown caki-1 and 786-O RCC cell lines in vitro. The results demonstrated that VDR overexpression significantly inhibited RCC cells proliferation, migration and invasion, and promoted apoptosis by the MTT, transwell cell migration/invasion and flow cytometry assays, respectively. However, VDR knockdown in RCC cells had the opposite effect. The RNA-sequence assay, which was assessed in caki-1 cells after VDR overexpression and knockdown, also indicated that significantly differentially expressed genes were associated with cell apoptotic, differentiation, proliferation and migration. RT-PCR and western blot analysis showed that VDR knockdown increased TRPV5 expression and VDR overexpression decreased TRPV5 expression in caki-1 cells. Furthermore, knockdown of TRPV5 expression suppressed the VDR knockdown-induced change in the proliferation, migration and invasion in caki-1 cells. Taken together, these findings confirmed that VDR functions as a tumour suppressor in RCC cells and suppresses the proliferation, migration and invasion of RCC through regulating the expression of TRPV5.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Receptores de Calcitriol/metabolismo , Canais de Cátion TRPV/genética , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Técnicas de Inativação de Genes , Vetores Genéticos/genética , Humanos , Lentivirus/genética
11.
Sci Adv ; 4(3): eaar6018, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29536049

RESUMO

As one of the most fascinating cathode candidates for Na-ion batteries (NIBs), P2-type Na layered oxides usually exhibit various single-phase domains accompanied by different Na+/vacancy-ordered superstructures, depending on the Na concentration when explored in a limited electrochemical window. Therefore, their Na+ kinetics and cycling stability at high rates are subjected to these superstructures, incurring obvious voltage plateaus in the electrochemical profiles and insufficient battery performance as cathode materials for NIBs. We show that this problem can be effectively diminished by reasonable structure modulation to construct a completely disordered arrangement of Na-vacancy within Na layers. The combined analysis of scanning transmission electron microscopy, ex situ x-ray absorption spectroscopy, and operando x-ray diffraction experiments, coupled with density functional theory calculations, reveals that Na+/vacancy disordering between the transition metal oxide slabs ensures both fast Na mobility (10-10 to 10-9 cm2 s-1) and a low Na diffusion barrier (170 meV) in P2-type compounds. As a consequence, the designed P2-Na2/3Ni1/3Mn1/3Ti1/3O2 displays extra-long cycle life (83.9% capacity retention after 500 cycles at 1 C) and unprecedented rate capability (77.5% of the initial capacity at a high rate of 20 C). These findings open up a new route to precisely design high-rate cathode materials for rechargeable NIBs.

12.
Exp Cell Res ; 360(2): 81-93, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28870599

RESUMO

Immortalized human hepatocytes (IHH) could provide an unlimited supply of hepatocytes, but insufficient differentiation and phenotypic instability restrict their clinical application. This study aimed to determine the role of hepatocyte nuclear factor 4A (HNF4A) in hepatic differentiation of IHH, and whether encapsulation of IHH overexpressing HNF4A could improve liver function and survival in rats with acute liver failure (ALF). Primary human hepatocytes were transduced with lentivirus-mediated catalytic subunit of human telomerase reverse transcriptase (hTERT) to establish IHH. Cells were analyzed for telomerase activity, proliferative capacity, hepatocyte markers, and tumorigenicity (c-myc) expression. Hepatocyte markers, hepatocellular functions, and morphology were studied in the HNF4A-overexpressing IHH. Hepatocyte markers and karyotype analysis were completed in the primary hepatocytes using shRNA knockdown of HNF4A. Nuclear translocation of ß-catenin was assessed. Rat models of ALF were treated with encapsulated IHH or HNF4A-overexpressing IHH. A HNF4A-positive IHH line was established, which was non-tumorigenic and conserved properties of primary hepatocytes. HNF4A overexpression significantly enhanced mRNA levels of genes related to hepatic differentiation in IHH. Urea levels were increased by the overexpression of HNF4A, as measured 24h after ammonium chloride addition, similar to that of primary hepatocytes. Chromosomal abnormalities were observed in primary hepatocytes transfected with HNF4A shRNA. HNF4α overexpression could significantly promote ß-catenin activation. Transplantation of HNF4A overexpressing IHH resulted in better liver function and survival of rats with ALF compared with IHH. HNF4A improved hepatic differentiation of IHH. Transplantation of HNF4A-overexpressing IHH could improve the liver function and survival in a rat model of ALF.


Assuntos
Diferenciação Celular/genética , Fator 4 Nuclear de Hepatócito/fisiologia , Hepatócitos/fisiologia , Hepatócitos/transplante , Falência Hepática Aguda/terapia , Fígado/fisiologia , Adulto , Animais , Linhagem Celular Transformada , Sobrevivência Celular/genética , Células Cultivadas , Hepatócitos/patologia , Humanos , Falência Hepática Aguda/genética , Falência Hepática Aguda/patologia , Transplante de Fígado/métodos , Masculino , Ratos , Ratos Sprague-Dawley
13.
Artigo em Inglês | MEDLINE | ID: mdl-28480383

RESUMO

BACKGROUND: Traditional Chinese medicine Taraxacum officinale has been widely used to treat various inflammatory diseases. Taraxasterol is one of the main active components isolated from Taraxacum officinale. Recently, we have demonstrated that taraxasterol has the in vitro anti-inflammatory effects. This study aims to determine the in vivo anti-inflammatory effects of taraxasterol against animal models. MATERIALS AND METHODS: Anti-inflammatory effects were assessed in four animal models by using dimethylbenzene-induced mouse ear edema, carrageenan-induced rat paw edema, acetic acid-induced mouse vascular permeability and cotton pellet-induced rat granuloma tests. RESULTS: Our results demonstrated that taraxasterol dose-dependently attenuated dimethylbenzene-induced mouse ear edema and carrageenan-induced rat paw edema, decreased acetic acid-induced mouse vascular permeability and inhibited cotton pellet-induced rat granuloma formation. CONCLUSION: Our finding indicates that taraxasterol has obvious in vivo anti-inflammatory effects against animal models. It will provide experimental evidences for the traditional use of Taraxacum officinale and taraxasterol in inflammatory diseases.


Assuntos
Anti-Inflamatórios/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Edema/tratamento farmacológico , Granuloma/tratamento farmacológico , Esteróis/administração & dosagem , Taraxacum/química , Triterpenos/administração & dosagem , Animais , Permeabilidade Capilar/efeitos dos fármacos , Modelos Animais de Doenças , Edema/fisiopatologia , Granuloma/fisiopatologia , Humanos , Masculino , Camundongos , Ratos , Ratos Wistar
14.
Adv Mater ; 29(19)2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28295700

RESUMO

Sodium-ion batteries (SIBs) have been considered as potential candidates for stationary energy storage because of the low cost and wide availability of Na sources. O3-type layered oxides have been considered as one of the most promising cathodes for SIBs. However, they commonly show inevitable complicated phase transitions and sluggish kinetics, incurring rapid capacity decline and poor rate capability. Here, a series of sodium-sufficient O3-type NaNi0.5 Mn0.5-x Ti x O2 (0 ≤ x ≤ 0.5) cathodes for SIBs is reported and the mechanisms behind their excellent electrochemical performance are studied in comparison to those of their respective end-members. The combined analysis of in situ X-ray diffraction, ex situ X-ray absorption spectroscopy, and scanning transmission electron microscopy for NaNi0.5 Mn0.2 Ti0.3 O2 reveals that the O3-type phase transforms reversibly into a P3-type phase upon Na+ deintercalation/intercalation. The substitution of Ti for Mn enlarges interslab distance and could restrain the unfavorable and irreversible multiphase transformation in the high voltage regions that is usually observed in O3-type NaNi0.5 Mn0.5 O2 , resulting in improved Na cell performance. This integration of macroscale and atomicscale engineering strategy might open up the modulation of the chemical and physical properties in layered oxides and grasp new insight into the optimal design of high-performance cathode materials for SIBs.

15.
Clin Spine Surg ; 30(3): E189-E191, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28323698

RESUMO

STUDY DESIGN: Histologic, immunohistochemical (IHC), and enzyme-linked immunosorbent assay analysis of the human ligamentum flavum (LF). OBJECTIVE: The purpose of this study was to determine the level of expression of lysophosphatidic acid (LPA) in the LF from lumbar spinal stenosis (LSS) patients and to analyze the relationship among LPA, LPA receptors (LPARs), and LF hypertrophy. SUMMARY OF BACKGROUND DATA: LF hypertrophy and fibrosis are important causes of LSS. LPA is involved in the fibrotic process in multiple organ systems. Therefore, we hypothesized that LPA and its receptors might also play a role in degeneration of the LF in LSS patients. METHODS: Forty-one LF samples were enrolled in this study. The thickness of the LF was measured by magnetic resonance imaging. Histologic analysis using hematoxylin and eosin and Masson trichrome stain was performed for each LF to evaluate the architecture of the extracellular matrix. The content of LPA and connective tissue growth factor (CTGF) in LF samples was analyzed using enzyme-linked immunosorbent assay. The expression of LPAR1 was determined by IHC. RESULTS: Degeneration of the LF was characterized by an increase in disorganized elastic fibers and fibrotic transformation by extracellular collagen deposition. The thickness of the LF and the concentration of LPA and CTGF in the hypertrophic LF group were significantly higher than the control group. Furthermore, the LPA and CTGF concentrations had a positive correlation with the LF thickness (r=0.91, P<0.001 and r=0.943, P<0.001, respectively). On the basis of IHC analysis, the expression of LPAR1 was increased in the hypertrophy group. CONCLUSIONS: The increased expression of LPA and LPAR1 is associated with the fibrosis and hypertrophy of the LF in patients with LSS. Further study on the mechanism underlying LF fibrosis may lead to new therapies for LF hypertrophy and fibrosis.


Assuntos
Ligamento Amarelo/metabolismo , Ligamento Amarelo/patologia , Lisofosfolipídeos/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Estenose Espinal/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Feminino , Fibrose/etiologia , Humanos , Hipertrofia/etiologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estatística como Assunto , Adulto Jovem
16.
Biosci Rep ; 37(2)2017 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-28250135

RESUMO

The present study was designed to investigate the role of circulating miRNA-21 (miR-21) in vascular restenosis of lower extremity arterial occlusive disease (LEAOD) patients after interventional therapy. A total of 412 LEAOD patients were enrolled randomly in the present study. According to computed tomography angiography (CTA) and ankle-brachial index (ABI), patients were assigned into the restenosis group and the non-restenosis group. miR-21 expression was detected with quantitative real-time PCR (qRT-PCR) before and after patients underwent interventional therapy. A follow-up period of 6 months was achieved. A receiver operating characteristic (ROC) curve was drawn and the area under the curve (AUC) was calculated to assess the predictive value of miR-21 in vascular restenosis. Patients were older in the restenosis group than in the non-restenosis group. The percentages of patients with diabetes and hypertension were higher in the restenosis group than in the non-restenosis group, and the Fontaine stage exhibited a significant difference between the two groups. miR-21 expression was higher in the restenosis group than in the non-restenosis group. miR-21 expression level was related to age, diabetes and hypertension in the restenosis group. Using miR-21 to predict vascular restenosis yielded an AUC of 0.938 (95% confidence interval (CI): 0.898-0.977), with Youden index of 0.817, sensitivity of 83.5% and specificity of 98.2%. Logistic regression analysis revealed that diabetes and miR-21 expression were the major risk factors for vascular restenosis of LEAOD. miR-21 can be used as a predictive indicator for vascular restenosis of LEAOD after interventional therapy.


Assuntos
Arteriopatias Oclusivas/sangue , Arteriopatias Oclusivas/patologia , Oclusão de Enxerto Vascular/sangue , Oclusão de Enxerto Vascular/patologia , Extremidade Inferior/patologia , MicroRNAs/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Arteriopatias Oclusivas/terapia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Fatores de Risco
17.
Int Immunopharmacol ; 44: 105-114, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28092862

RESUMO

BACKGROUND: Astragalus membranaceus Bunge is one of the oldest and most frequently used crude herbs in traditional Chinese medicine. The total flavonoids of Astragalus (TFA) are the main active components isolated from Astragalus membranaceus Bunge. Our recent study has shown its potential immunomodulatory and anti-inflammatory effects in vivo and in vitro. However, its anti-arthritic effects and mechanisms of action involved have not been elucidated. The aim of this study was to evaluate the protective effects and possible mechanisms of TFA on Freund's complete adjuvant (FCA)-induced arthritis in rats. METHODS: Wistar rats were intradermally injected FCA into the right hind metatarsal footpads to establish adjuvant-arthritic model. The rats were intragastrically administered daily with TFA at 25, 50 and 100mg/kg for 28days after FCA induction. Body weight, primary paw swelling, arthritis index, thymus and spleen indices were measured. The levels of serum tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, prostaglandin (PG)E2, osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) were determined using ELISA. Histopathological changes and scores in joint tissues were examined using hematoxylin and eosin (H&E). The expression of nuclear factor (NF)-κB p65 in synovial tissues was assayed using immunohistochemical method. RESULTS: TFA significantly increased body weight, attenuated primary paw swelling and arthritis index, decreased thymus and spleen indices of rats induced by FCA. Furthermore, TFA significantly inhibited serum TNF-α, IL-1ß, PGE2 and RANKL production, and promoted serum OPG production and OPG/RANKL ratio of rats induced by FCA. Histopathological examination indicated that TFA significantly attenuated inflammatory cell infiltration, synovial hyperplasia, pannus formation, and bone and cartilage damage. Immunohistochemical assay indicated that TFA inhibited NF-κB p65 expression in synovial tissues of rats induced by FCA. CONCLUSIONS: These results suggest that TFA exerts potential protective effects against FCA-induced arthritis in rats by regulating OPG/RANKL/NF-κB pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Astrágalo (Planta)/imunologia , Flavonoides/uso terapêutico , Osteoprotegerina/sangue , Ligante RANK/sangue , Animais , Dinoprostona/sangue , Humanos , Interleucina-1beta/sangue , Masculino , Medicina Tradicional Chinesa , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Membrana Sinovial/metabolismo , Fator de Necrose Tumoral alfa/sangue
18.
Acta Pharmacol Sin ; 38(2): 252-263, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27840412

RESUMO

Oblongifolin C (OC) and guttiferone K (GUTK) are two anticancer compounds extracted from Garcinia yunnanensis Hu, but they act by different mechanisms. In this study we investigated whether a combination of OC and GUTK (1:1 molar ratio) could produce synergistic anticancer effects against human colorectal cancer cells in vitro. For comparison, we also examined the anticancer efficacy of ethanol extracts from G yunnanensis fruit, which contain OC and GUTK up to 5%. Compared to OC and GUTK alone, the combination of OC and GUTK as well as the ethanol extracts more potently inhibited the cancer cell growth with IC50 values of 3.4 µmol/L and 3.85 µg/mL, respectively. Furthermore, OC and GUTK displayed synergistic inhibition on HCT116 cells: co-treatment with OC and GUTK induced more prominent apoptosis than treatment with either drug alone. Moreover, the combination of OC and GUTK markedly increased cleavage of casapse-3 and PARP, and enhanced cellular ROS production and increased JNK protein phosphorylation. In addition, the combination of OC and GUTK exerted stronger effects under nutrient-deprived conditions than in complete medium, suggesting that autophagy played an essential role in regulating OC- and GUTK-mediated cell death. OC and GUTK are the main components that contribute to the anticancer activity of G yunnanensis and the compounds have apoptosis-inducing effects in HCT116 cells in vitro.


Assuntos
Apoptose/efeitos dos fármacos , Benzofenonas/farmacologia , Garcinia/química , Terpenos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Benzofenonas/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Frutas/química , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Terpenos/isolamento & purificação
19.
Nan Fang Yi Ke Da Xue Xue Bao ; 36(9): 1221-1225, 2016 08 20.
Artigo em Chinês | MEDLINE | ID: mdl-27687654

RESUMO

OBJECTIVE: To explore the relationship between waist-to-hip ratio (WHR) and chronic kidney disease (CKD) in non-diabetic subjects and compare the difference between male and female subjects. METHODS: We performed a cross-sectional survey among 2142 community-based southern Chinese participants without diabetes from June to October 2012. We divided all the participants into 4 groups according to the gender-specific quartiles of WHR. Logistic regression models were used to explore the associations of WHR with CKD in these subjects. RESULTS: In the unadjusted model, WHR was significantly associated with CKD in women (OR=7.29, 95% CI: 3.56-16.32, P<0.001), and the association was still significant (OR=6.13, 95% CI: 2.56-15.20, P=0.003 ) after adjustment for the potential confounders (including age, history of hypertension, coronary heart disease, current smoker, physical inactivity, education level, systolic blood pressure, diastolic blood pressure, serum triglyceride, serum high density lipoprotein, blood glucose, and BMI). The odds ratio (OR) for having CKD in the highest versus lowest quartile of WHR levels was 2.44 (95% CI: 0.98-4.97, P=0.103) in men in the unadjusted model. CONCLUSION: WHR levels are associated with CKD in non-diabetic women but not in non-diabetic male subjects.


Assuntos
Insuficiência Renal Crônica/epidemiologia , Relação Cintura-Quadril , Índice de Massa Corporal , Estudos Transversais , Diabetes Mellitus , Feminino , Humanos , Masculino , Obesidade , Razão de Chances , Fatores de Risco
20.
Dis Model Mech ; 9(11): 1357-1366, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27736740

RESUMO

Brandt's voles have an annual cycle of body weight and adiposity. These changes can be induced in the laboratory by manipulation of photoperiod. In the present study, male captive-bred Brandt's voles aged 35 days were acclimated to a short day (SD) photoperiod (8L:16D) for 70 days. A subgroup of individuals (n=16) were implanted with transmitters to monitor physical activity and body temperature. They were then randomly allocated into long day (LD=16L:8D) (n=19, 8 with transmitters) and SD (n=18, 8 with transmitters) groups for an additional 70 days. We monitored aspects of energy balance, glucose and insulin tolerance (GTT and ITT), body composition and organ fat content after exposure to the different photoperiods. LD voles increased in weight for 35 days and then re-established stability at a higher level. At the end of the experiment LD-exposed voles had greater white adipose tissue mass than SD voles (P=0.003). During weight gain they did not differ in their food intake or digestive efficiency; however, daily energy expenditure was significantly reduced in the LD compared with SD animals (ANCOVA, P<0.05) and there was a trend to reduced resting metabolic rate RMR (P=0.075). Physical activity levels were unchanged. Despite different levels of fat storage, the GTT and ITT responses of SD and LD voles were not significantly different, and these traits were not correlated to body fatness. Hence, the photoperiod-induced obesity was independent on disruptions to glucose homeostasis, indicating a potential adaptive decoupling of these states in evolutionary time. Fat content in both the liver and muscle showed no significant difference between LD and SD animals. How voles overcome the common negative aspects of fat storage might make them a useful model for understanding the phenomenon of 'healthy obesity'.


Assuntos
Arvicolinae/fisiologia , Obesidade/patologia , Fotoperíodo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/patologia , Adiposidade , Animais , Arvicolinae/genética , Composição Corporal , Peso Corporal , Tamanho Celular , Modelos Animais de Doenças , Metabolismo Energético , Regulação da Expressão Gênica , Teste de Tolerância a Glucose , Homeostase , Inflamação/patologia , Insulina/metabolismo , Masculino , Obesidade/genética
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