Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 200
Filtrar
1.
BMC Cancer ; 21(1): 1063, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34583662

RESUMO

BACKGROUND: Transarterial chemoembolization (TACE) is an effective treatment for patients with hepatocellular carcinoma (HCC). However, the impact of hepatitis B viral (HBV) infection and body mass index (BMI) on TACE is controversial. The present study aimed to compare the influence of HBV and high BMI on TACE outcomes in advanced HCC. METHODS: Based on HBV infection history and BMI, patients were assigned to different subgroups. Blood samples were collected and analyzed by an enzyme-linked immunosorbent assay (ELISA) kit. The primary endpoint was progression-free survival (PFS) and the overall survival (OS) in the population. RESULTS: Compared to overweight combined HBV patients who received TACE, people with normal weight or no viral infection had significantly better OS and PFS. Sex, age, portal vein tumor thrombus, BCLC, ECOG, and tumor diameter are the main risk factors affecting PFS and OS. Except for the postoperative fever, no significant difference was detected in adverse reactions. Irrespective of TACE, the average expression of HMGB1 in hepatitis or obesity patients was higher than that in normal individuals and did not show upregulation after TACE. Patients without overweight or HBV infection had a low expression of serum HMGB1 that was substantially upregulated after TACE. CONCLUSIONS: In this study, overweight combined HBV infection patients had shorter PFS and OS than other HCC patients. Thus, HBV and BMI maybe two factors affecting the efficacy of TACE via upregulated HMGB1.


Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Hepatite B/complicações , Neoplasias Hepáticas/terapia , Sobrepeso/complicações , Fatores Etários , Índice de Massa Corporal , Carcinoma Hepatocelular/mortalidade , Quimioembolização Terapêutica/efeitos adversos , Feminino , Proteína HMGB1/sangue , Hepatite B/sangue , Hepatite B/mortalidade , Vírus da Hepatite B , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Sobrepeso/sangue , Sobrepeso/mortalidade , Veia Porta , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Trombose/complicações , Resultado do Tratamento
2.
Angew Chem Int Ed Engl ; 60(42): 22711-22716, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34411386

RESUMO

Self-assembled chiroptical materials have attracted considerable attention due to their great applications in wide fields. During the chiral self-assembly, it remains unknown how achiral molecules can affect the assembly process and their final chiroptical performance. Herein, we report an achiral molecule directed chiral self-assembly via halogen bonds, exhibiting not only an unprecedented chiral fractal architecture but also significantly amplified circularly polarized luminescence (CPL). Two axially chiral emitters with halogen bond sites co-assemble with an achiral 1,4-diiodotetrafluorobenzene (F4 DIB) and well-ordered chiral fractal structures with asymmetry amplification are obtained. The enhancement of the dissymmetry factors of the assemblies was up to 0.051 and 0.011, which was approximately 100 folds than those of the corresponding molecules. It was found that both the design of the chiral emitter and the highly directional halogen bond played an important role in hierarchically chirality transfer from chiral emitters to the micrometer scale chiral fractal morphology and amplified dissymmetry factors. We hope that this strategy can give a further insight into the fabrication of structurally unique featured highly efficient chiroptical materials.

3.
Exp Biol Med (Maywood) ; : 15353702211033247, 2021 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-34308657

RESUMO

Atherosclerotic plaque destabilization is a dominating cause of acute cardiovascular events such as myocardial infarction and stroke. This study aims to identify genetic biomarkers related to atherosclerotic plaque destabilization using bioinformatics. Three transcriptome datasets of human carotid atherosclerotic plaque samples were downloaded from ArrayExpress and Gene Expression Omnibus databases, including E-MATB-2055, E-TABM-190, and GSE120521. With Robust Rank Aggregation analysis, we documented 46 differentially expressed genes between stable and unstable/ruptured plaques. Functional enrichment analysis using DAVID tool demonstrated that these genes were mainly related to biological functions such as extracellular matrix disassembly, collagen catabolic process, response to mechanical stimulus, and PPAR signaling pathway. A protein-protein interaction network for the differentially expressed genes was constructed, and eight pivotal genes (ITGAM, MMP9, PLAUR, CCR1, CD163, CD36, ADAM8, and IL1RN) were obtained from the network with a connective degree > 5. The expression patterns of these hub differentially expressed genes could be verified in atherosclerotic plaque samples with intraplaque hemorrhage. Using gene set variation analysis, the eight genes were integrated to generate an atherosclerotic plaque destabilization score, which showed a high performance in not only discriminating individuals with myocardial infarction from those with stable coronary illness, but also in predicting future acute cardiovascular events in atherosclerotic patients. In conclusion, the findings of this study will enhance our knowledge on the pathological mechanisms involved in atherosclerotic plaque destabilization, and provide potential gene biomarkers for risk stratification of patients with atherosclerotic cardiovascular disease.

4.
Steroids ; 173: 108879, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34181976

RESUMO

Bile acid transporters are highly expressed in intestinal cells and hepatocytes, and they determine the uptake of drugs in cells by modulating cellular entry and exit. In order to improve the oral bioavailability of drugs and investigate the potential application prospects of drugs used to target cancer, numerous studies have adopted these transporters to identify prodrug strategies. Through the connection of covalent bonds between drugs and bile acids, the resulting bile acid-drug conjugates continue to be recognized as similar to natural unmodified bile acid and is translocated by the transporter. The present mini-review provides a brief summary of recent progress of the application of bile acid-drug conjugates based primarily on ASBT, NTCP, and OATP, with the hope of contributing to subsequent research.

5.
Folia Histochem Cytobiol ; 59(2): 134-143, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34151999

RESUMO

INTRODUCTION: Vascular smooth muscle cells (VSMCs)-based foam cell formation is a crucial factor in the atherosclerosis process. We aimed to explore the mechanism of Golgi a-mannosidase II (GMII) effects on the VSMCs-based foam cell formation. MATERIAL AND METHODS: VSMCs were exposed to different concentrations of low-density lipoproteins (LDLs), lipopolysaccharide (LPS), and/or GMII inhibitor (swainsonine). The qRT-PCR and western blot were used for expression analysis. Oil Red O staining was used to verify changes of lipid droplets in VSMCs. The translocation of the SCAP from the endoplasmic reticulum (ER) to Golgi was detected by immunofluorescence (IF). RESULTS: LPS disrupted the LDLs-mediated regulation of LDL receptor (LDLr) and increased intracellular cholesterol ester, which was inversely inhibited by swainsonine. The activity of a-mannosidase II and GMII expression were decreased by LDLs but increased by the addition of LPS. Conversely, LPS-induced enhancement was reversed by swainsonine. Additionally, swainsonine reversed the LPS-induced increase of intracellular lipid droplets in the presence of LDLs. Expression analysis demonstrated that LDLr, SCAP, and SREBP2 were up-regulated by LPS, but reversed by swainsonine in LDLs-treated cells. IF staining revealed that swainsonine inhibited the translocation of SCAP to Golgi under inflammatory stress. CONCLUSIONS: Collectively, swainsonine restrained LDLr expression to suppress the formation of VSMCs-based foam cells by reducing SREBP2 and SCAP under inflammatory stress conditions, suggesting that GMII contributes to the formation of VSMCs-based foam cells under inflammatory stress.


Assuntos
Células Espumosas/metabolismo , Inflamação/metabolismo , Manosidases/metabolismo , Músculo Liso Vascular/metabolismo , Ésteres do Colesterol/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Inibidores Enzimáticos/farmacologia , Complexo de Golgi/efeitos dos fármacos , Complexo de Golgi/metabolismo , Humanos , Inflamação/induzido quimicamente , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipopolissacarídeos , Manosidases/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Músculo Liso Vascular/citologia , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Swainsonina/farmacologia , Regulação para Cima/efeitos dos fármacos
6.
Ann Clin Lab Sci ; 51(2): 258-261, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33941567

RESUMO

OBJECTIVE: Long QT syndrome is a cardiovascular disease with a prolonged QT interval. CASE REPORT: We report a 22-year-old woman presenting with frequent syncopal episodes two months after childbirth. Electrocardiography showed a sinus rhythm, QT interval prolongation, and Torsade de Pointes. Her mother had experienced an episode of syncope, but her father had not. Genetic analyses revealed that a new mutation in the KCNH2 gene, the c.2108dupA mutation (p.H703Qfs*20, exon8, M_000238), was found in the patient and in her mother and sister. CONCLUSION: The c.2108dupA mutation (p.H703Qfs*20, exon8, M_000238) is the first reported case of a KCNH2 mutation at this site.


Assuntos
Canal de Potássio ERG1/genética , Síndrome do QT Longo/genética , Adulto , Canal de Potássio ERG1/metabolismo , Eletrocardiografia , Família , Feminino , Testes Genéticos , Humanos , Síndrome do QT Longo/metabolismo , Mutação , Linhagem , Torsades de Pointes/genética , Torsades de Pointes/metabolismo , Adulto Jovem
7.
J Mech Behav Biomed Mater ; 120: 104563, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33940485

RESUMO

The mechanical performance of the dentin-adhesive interface contributes significantly to the failure of dental composite restorations. Rational material design can lead to enhanced mechanical performance, but this requires accurate characterization of the mechanical behavior at the dentin-adhesive interface. The mechanical performance of the interface is typically characterized using bond strength tests, such as the micro-tensile test. These tests are plagued by multiple limitations including large variations in the test results. The challenges associated with conventional tensile tests limit our ability to unravel the complex relationships that affect mechanical behavior at the dentin-adhesive interface. This study used the diametral compression test to overcome the challenges inherent in conventional bond strength tests. The bovine femur cortical bone tissue was considered as a surrogate material (the mineralized tissue) for human dentin. Two different adhesive formulations, which differed by means of their self-strengthening properties, were studied. The tensile behavior of the mineralized tissue, the adhesive polymer, and the bond strength of the mineralized tissue - adhesive interface was determined using the diametral compression test. The diametral compression test improved the repeatability for both the tensile and bond strength tests. The rate dependent mechanical behavior was observed for both single material and interfacial material systems. The tensile strength and bond strength of the mineralized tissue-adhesive interface was greater for the self-strengthening formulation as compared to the control.


Assuntos
Colagem Dentária , Adesivos Teciduais , Animais , Bovinos , Resinas Compostas , Dentina , Adesivos Dentinários , Humanos , Teste de Materiais , Cimentos de Resina , Propriedades de Superfície , Resistência à Tração
8.
Chem Commun (Camb) ; 57(45): 5562-5565, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-33969855

RESUMO

Palladium-catalyzed asymmetric functionalization of unbiased methylene C(sp3)-H bonds is a long-standing challenge. Here, we report a Pd(ii)-catalyzed highly enantioselective arylation of unbiased methylene C(sp3)-H bonds enabled by a strongly coordinating bidentate 2-pyridinylisopropyl (PIP) directing group and an easily accessible 3,3'-F2-BINOL chiral ligand. The use of aryl iodides with the combination of 3,3'-F2-BINOL was beneficial for high enantiocontrol. A range of aliphatic amides and aryl iodides were tolerated, providing the desired arylated products in high enantioselectivities (up to 96% ee). The PIP directing group could be removed under mild conditions without erosion of enantiopurity.

9.
Eur Radiol ; 31(10): 7913-7924, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33825032

RESUMO

OBJECTIVE: To develop and validate a radiomics signature based on magnetic resonance imaging (MRI) from multicenter datasets for preoperative prediction of pathologic response to neoadjuvant chemotherapy (NAC) in patients with osteosarcoma. METHODS: We retrospectively enrolled 102 patients with histologically confirmed osteosarcoma who received chemotherapy before treatment from 4 hospitals (68 in the primary cohort and 34 in the external validation cohort). Quantitative imaging features were extracted from contrast-enhanced fat-suppressed T1-weighted images (CE FS T1WI). Four classification methods, i.e., the least absolute shrinkage and selection operator logistic regression (LASSO-LR), support vector machine (SVM), Gaussian process (GP), and Naive Bayes (NB) algorithm, were compared for feature selection and radiomics signature construction. The predictive performance of the radiomics signatures was assessed with the area under receiver operating characteristics curve (AUC), calibration curve, and decision curve analysis (DCA). RESULTS: Thirteen radiomics features selected based on the LASSO-LR classifier were adopted to construct the radiomics signature, which was significantly associated with the pathologic response. The prediction model achieved the best performance between good and poor responders with an AUC of 0.882 (95% CI, 0.837-0.918) in the primary cohort. Calibration curves showed good agreement. Similarly, findings were validated in the external validation cohort with good performance (AUC, 0.842 [95% CI, 0.793-0.883]) and good calibration. DCA analysis confirmed the clinical utility of the selected radiomics signature. CONCLUSION: The constructed CE FS T1WI-radiomics signature with excellent performance could provide a potential tool to predict pathologic response to NAC in patients with osteosarcoma. KEY POINTS: • The radiomics signature based on multicenter contrast-enhanced MRI was useful to predict response to NAC. • The prediction model obtained with the LASSO-LR classifier achieved the best performance. • The baseline clinical characteristics were not associated with response to NAC.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Teorema de Bayes , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/tratamento farmacológico , Humanos , Imageamento por Ressonância Magnética , Terapia Neoadjuvante , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/tratamento farmacológico , Estudos Retrospectivos
10.
Org Lett ; 23(6): 2048-2051, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33683896

RESUMO

γ-Lactam containing α,ß-contiguous stereogenic centers stands out as a pivotal motif in various bioactive compounds, while its efficient synthesis still needs to be enhanced. Herein, an asymmetric C-H activation strategy for accessing α,ß-stereospecific γ-lactams in good yields (≤79%) with high enantio- and diastereoselectivities (≤96% ee and >20:1 dr) was described, which serves as an effective supplement to the existing strategies.

11.
Hum Vaccin Immunother ; 17(7): 2197-2204, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-33566720

RESUMO

Meningococcal meningitis caused by Neisseria meningitidis is a reportable infectious disease in China, due to the high incidence of meningitis in the era before the availability of vaccines. The disease incidence was markedly reduced after meningococcal vaccination was introduced in the 1980s. Currently, there are polysaccharide, conjugate, and combined vaccine formulations against meningococcal meningitis in the Chinese market, almost all of which are produced by domestic manufacturers. It is necessary to further enhance national meningococcal surveillance to improve the level of prevention and control of meningococcus. However, the immune efficacy and persistence of immunity of vaccines should be monitored. More importantly, additional investments should be made to develop serogroup B meningococcal vaccines.


Assuntos
Meningite Meningocócica , Infecções Meningocócicas , Vacinas Meningocócicas , Neisseria meningitidis , China/epidemiologia , Humanos , Meningite Meningocócica/epidemiologia , Meningite Meningocócica/prevenção & controle , Infecções Meningocócicas/epidemiologia , Infecções Meningocócicas/prevenção & controle , Vacinas Conjugadas
12.
Biomed Res Int ; 2021: 6674471, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33614787

RESUMO

Objective: To develop and externally validate a CT-based radiomics nomogram for pretreatment prediction of relapse in osteosarcoma patients within one year. Materials and Methods: In this multicenter retrospective study, a total of 80 patients (training cohort: 63 patients from three hospitals; validation cohort: 17 patients from three other hospitals) with osteosarcoma, undergoing pretreatment CT between August 2010 and December 2018, were identified from multicenter databases. Radiomics features were extracted and selected from tumor regions on CT image, and then, the radiomics signature was constructed. The radiomics nomogram that incorporated the radiomics signature and clinical-based risk factors was developed to predict relapse risk with a multivariate Cox regression model using the training cohort and validated using the external validation cohort. The performance of the nomogram was assessed concerning discrimination, calibration, reclassification, and clinical usefulness. Results: Kaplan-Meier curves based on the radiomics signature showed a significant difference between the high-risk and the low-risk groups in both training and validation cohorts (P < 0.001 and P = 0.015, respectively). The radiomics nomogram achieved good discriminant results in the training cohort (C-index: 0.779) and the validation cohort (C-index: 0.710) as well as good calibration. Decision curve analysis revealed that the proposed model significantly improved the clinical benefit compared with the clinical-based nomogram (P < 0.001). Conclusions: This multicenter study demonstrates that a radiomics nomogram incorporated the radiomics signature and clinical-based risk factors can increase the predictive value of the osteosarcoma relapse risk, which supports the clinical application in different institutions.


Assuntos
Neoplasias Ósseas , Recidiva Local de Neoplasia , Osteossarcoma , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Idoso , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/epidemiologia , Neoplasias Ósseas/patologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Nomogramas , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/epidemiologia , Osteossarcoma/patologia , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
13.
Langmuir ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33533619

RESUMO

The past decade has seen increased research interest in studying bicontinuous structures formed via colloidal self-assembly due to their many useful applications. A new type of colloidal gel, solvent segregation-driven gel (SeedGel), has been recently demonstrated as an effective approach to arrest bicontinuous structures with unique and intriguing properties, such as thermoreversibility, structural reproducibility, and sensitive temperature response. Here, using a model system with silica particles in the 2,6-lutidine/water binary solvent, we investigate the factors controlling the domain size of a SeedGel system by varying the particle concentration, solvent ratio, and quenching protocol. A phase diagram is identified to produce SeedGels for this model system. Our results indicate that by adjusting the sample composition, it is possible to realize bicontinuous domains with well-controlled repeating distances (periodicities). In addition, the effect of quenching rate on the domain size is systematically investigated, showing that it is a very sensitive parameter to control domain sizes. By further heating SeedGel up into the spinodal region, the structure evolution under high temperatures is also investigated and discussed. These results provide important insights into how to control bicontinuous structures in SeedGel systems.

14.
World J Surg Oncol ; 19(1): 29, 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33499882

RESUMO

BACKGROUND: Aberrant DNA methylation is significantly associated with breast cancer. METHODS: In this study, we aimed to determine novel methylation biomarkers using a bioinformatics analysis approach that could have clinical value for breast cancer diagnosis and prognosis. Firstly, differentially methylated DNA patterns were detected in breast cancer samples by comparing publicly available datasets (GSE72245 and GSE88883). Methylation levels in 7 selected methylation biomarkers were also estimated using the online tool UALCAN. Next, we evaluated the diagnostic value of these selected biomarkers in two independent cohorts, as well as in two mixed cohorts, through ROC curve analysis. Finally, prognostic value of the selected methylation biomarkers was evaluated breast cancer by the Kaplan-Meier plot analysis. RESULTS: In this study, a total of 23 significant differentially methylated sites, corresponding to 9 different genes, were identified in breast cancer datasets. Among the 9 identified genes, ADCY4, CPXM1, DNM3, GNG4, MAST1, mir129-2, PRDM14, and ZNF177 were hypermethylated. Importantly, individual value of each selected methylation gene was greater than 0.9, whereas predictive value for all genes combined was 0.9998. We also found the AUC for the combined signature of 7 genes (ADCY4, CPXM1, DNM3, GNG4, MAST1, PRDM14, ZNF177) was 0.9998 [95% CI 0.9994-1], and the AUC for the combined signature of 3 genes (MAST1, PRDM14, and ZNF177) was 0.9991 [95% CI 0.9976-1]. Results from additional validation analyses showed that MAST1, PRDM14, and ZNF177 had high sensitivity, specificity, and accuracy for breast cancer diagnosis. Lastly, patient survival analysis revealed that high expression of ADCY4, CPXM1, DNM3, PRDM14, PRKCB, and ZNF177 were significantly associated with better overall survival. CONCLUSIONS: Methylation pattern of MAST1, PRDM14, and ZNF177 may represent new diagnostic biomarkers for breast cancer, while methylation of ADCY4, CPXM1, DNM3, PRDM14, PRKCB, and ZNF177 may hold prognostic potential for breast cancer.


Assuntos
Neoplasias da Mama , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Prognóstico
16.
Drug Chem Toxicol ; 44(3): 294-301, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-30895830

RESUMO

Diterpene alkaloids (DAs) have a broad spectrum of pharmacological activities, but exhibiting extremely serious cardiotoxicity to induce arrhythmia, heart arrest, even death. This study aimed to evaluate the cardiotoxicity of three diester diterpene alkaloids (DDAs) including aconitine (AC), mesaconitine (MAC), hypaconitine (HAC) and three monoester diterpene alkaloids (MDAs) including 14-α-benzoylaconine (BAC), 14-α-benzoylmesaconine (BMAC), 14-α-benzoylhypaconine (BHAC) on zebrafish. Firstly, the zebrafish embryos after a 72-hour post fertilization were treated with different doses of AC, MAC, HAC, and BAC, BMAC and BHAC for 2, 10 and 24 h, respectively. The heart rates of the treated embryos were calculated and the morphological images of body, together with heart fluorescence were obtained. Results demonstrated that AC, MAC, and HAC at low doses (15.6 and 31.3 µM) decreased the heart rates and increased them at high doses (62.5, 125, and 250 µM), while BAC, BMAC, and BHAC decreased the heart rates in the dose range of 31.3-250 µM, but the highest dose (500 µM) of BAC and BMAC increased the heart rates. In addition, AC, MAC, and HAC exhibited serious organic and functional toxicities, while BAC, BMAC, and BHAC did not. It could be induced that DDAs expressed stronger cardiotoxicities than MDAs, which might be due to that they were known as the Na+ channel activators and K+ channel inhibitors, respectively. The ß-acetate at C-8 position, along with the protonated nitrogen on ring A of their chemical structures contributed more for their different cardiotoxicities. This is the first study on cardiotoxicity comparison of DAs, providing references for the rational and safe application of these compounds and some plant species containing them to reduce side effects while retaining therapeutic efficacy.

17.
J Cardiovasc Pharmacol ; 77(4): 508-518, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33136767

RESUMO

ABSTRACT: Foam cells are the main pathological components of atherosclerosis. Therapies reducing foam cell formation can effectively prevent atherosclerotic diseases and cardiovascular events. Beyond lowering plasma cholesterol levels, the pleiotropic functions of statins in atherosclerosis have not been fully elucidated. In the present study, atorvastatin reduced cholesterol content and increased cholesterol efflux from foam cells in a concentration-dependent manner. Atorvastatin (10 µM) inhibited foam cell formation within 48 hours. Furthermore, we found that atorvastatin inhibited foam cell formation by promoting lipophagy, which was manifested by increased autophagy-related gene 5 (Atg5) expression, elevated ratio of microtubule-associated protein1 light chain 3 (LC3) II to LC3I, reduced p62 expression, and increased LC3 and lipid droplets colocalization in foam cells treated with atorvastatin. The autophagy inducer, rapamycin (Rap), did not increase the lipophagy enhancement effect of atorvastatin, but the autophagy inhibitor, 3-methyladenine, suppressed the effect of atorvastatin on Atg5 expression and the LC3II/LC3I ratio, as well as the increased p62 expression, suppressed lipophagy, attenuated cholesterol efflux and increased cholesterol content in foam cells. Further analysis revealed that atorvastatin promoted lipophagy by upregulating adenosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation, and downregulating mammalian target of rapamycin phosphorylation, whereas the AMPK inhibiter, compound C, attenuated these effects. In conclusion, atorvastatin reduced lipid accumulation and promoted cholesterol efflux by enhancing lipophagy in foam cells and thereby inhibited foam cell formation. The enhanced lipophagy of foam cells was exerted through the AMPK/mammalian target of rapamycin signaling pathway.

18.
Neurosci Lett ; 741: 135457, 2021 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-33171211

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Many factors can explain the mechanism. However, the precise mechanism that contributes to the decreased number of dopaminergic neurons is unknown. Our study shows that oxidative stress is increased in models of PD compared with WT mice; Thioredoxin reductase 1(TR1) has emerged as an important antioxidant agent in dopaminergic neurons. In summary, our findings demonstrate that the overexpression of TR1 could be developed into a novel neuroprotective strategy for PD and that the reduction of the expression of GSK-3ß and NF-κB could also be promising therapeutic strategies for PD. This research suggests a new direction in the treatment of PD.


Assuntos
Fármacos Neuroprotetores/administração & dosagem , Estresse Oxidativo , Doença de Parkinson/metabolismo , Tiorredoxina Redutase 1/administração & dosagem , Tiorredoxina Redutase 1/metabolismo , Animais , Apoptose , Linhagem Celular , Mesencéfalo/metabolismo , Camundongos , Neurônios/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
19.
Exp Brain Res ; 239(2): 475-490, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33230666

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Several factors, including neuroinflammation, neuronal excitotoxicity, genetic mutations and incorrect protein folding are involved in PD pathophysiology. However, the precise mechanism that contributes to the decreased number of dopaminergic neurons is unknown. A growing body of research suggests that oxidative stress is a major factor in PD. Therefore, antioxidant therapy is an important approach for treating PD. The thioredoxin system is an important antioxidant system, and thioredoxin reductase 1 (TR1) is a major member of the thioredoxin system. The present study demonstrates that oxidative stress is increased and that the expression of TR1 is decreased in the SNc of A53T mice; TR1 has emerged as an important antioxidant agent in dopaminergic neurons. Therefore, we over-expressed TR1 in the MPP+-induced cellular model and in the A53T transgenic mouse model of PD. We confirmed that the overexpression of TR1 in neuronal cells decreased DNA damage and malondialdehyde (MDA) and ROS generation, increased T-SOD and GSH production, and decreased the ER stress, and autophagy in the PD model. In summary, our findings demonstrate that the overexpression of TR1 could be effective as a novel neuroprotective strategy for PD. This research suggests a novel direction in the treatment of PD.

20.
Biomed Pharmacother ; 134: 111121, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33341668

RESUMO

Exessive drinking is commonly associated with a wide spectrum of liver injuries. The term alcoholic liver disease (ALD) is generally used to refer to this spectrum of hepatic abnormalities, and the term hepatic steatosis denotes early lesions. Puerariae Lobatae Radix (PLR) is a common traditional Chinese medicine and has been widely used as an efficient treatment for alcohol-induced damage. Flavonoids are the principal components of PLR that could potentially be responsible for the activation of alcohol metabolism and lipid-lowering effects. However, little is known about the mechanisms underlying their activity against alcoholic injury. In this study, PLR flavonoids (PLF) were obtained by microwave extraction. A 2% ethanol solution was used to establish a model of alcoholic fatty liver disease by exposure of zebrafish larvae for 32 h, and then the zebrafish were administered PLF and puerarin. The results showed that PLF and puerarin significantly decreased lipid accumulation and the levels of total cholesterol and triglycerides in zebrafish larvae. Moreover, PLF and puerarin downregulated the expression of genes related to alcohol and lipid metabolism (CYP2y3, CYP3a65, ADH8a, ADH8b, HMGCRB, and FASN), endoplasmic reticulum stress, and DNA damage (CHOP, EDEM1, GADD45αa, and ATF6) and reduced levels of inflammatory factors (IL-1ß, TNF-α) in zebrafish larvae. PLF and puerarin increased the phosphorylation of AMP-activated protein kinase-α (AMPKα) and decreased the total protein level of ACC1. The findings suggested that PLF and puerarin alleviated alcohol-induced hepatic steatosis in zebrafish larvae by regulating alcohol and lipid metabolism, which was closely related to the regulation of the AMPKα-ACC signaling pathway. In conclusion, the study provided a possible therapeutic drug for ALD treatment.


Assuntos
Etanol/metabolismo , Fígado Gorduroso Alcoólico/prevenção & controle , Flavonoides/farmacologia , Isoflavonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pueraria , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Flavonoides/isolamento & purificação , Regulação Enzimológica da Expressão Gênica , Mediadores da Inflamação/metabolismo , Isoflavonas/isolamento & purificação , Fígado/metabolismo , Fígado/patologia , Pueraria/química , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...