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1.
Biomark Med ; 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38648095

RESUMO

Objective: To perform a bibliometric analysis in the field of biomarkers for systemic lupus erythematosus. Methods: Publications were from Web of Science. Microsoft Excel, VOSviewer, Science Mapping Analysis software Tool, CiteSpace and Tableau were used for analysis. Results: A total of 1112 publications were identified; 1503 institutions from 69 countries contributed, with the highest outputs from China and Karolinska University Hospital. Petri had a tremendous impact. Academic collaborations were localized. Lupus and Arthritis & Rheumatology were the top two journals in terms of publications and citations. Lymphocyte, autoantibody, type I interferon, genetic polymorphisms and urinary biomarkers have been high-frequency themes. Conclusion: Global collaboration needs to be further strengthened. Immune cell, cytokine and gene-level research as a whole and noninvasive tests are the future trends.

2.
J Cardiovasc Dev Dis ; 10(10)2023 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-37887886

RESUMO

Cellular senescence (CS), classically considered a stable cell cycle withdrawal, is hallmarked by a progressive decrease in cell growth, differentiation, and biological activities. Senescent cells (SNCs) display a complicated senescence-associated secretory phenotype (SASP), encompassing a variety of pro-inflammatory factors that exert influence on the biology of both the cell and surrounding tissue. Among global mortality causes, cardiovascular diseases (CVDs) stand out, significantly impacting the living quality and functional abilities of patients. Recent data suggest the accumulation of SNCs in aged or diseased cardiovascular systems, suggesting their potential role in impairing cardiovascular function. CS operates as a double-edged sword: while it can stimulate the restoration of organs under physiological conditions, it can also participate in organ and tissue dysfunction and pave the way for multiple chronic diseases under pathological states. This review explores the mechanisms that underlie CS and delves into the distinctive features that characterize SNCs. Furthermore, we describe the involvement of SNCs in the progression of CVDs. Finally, the study provides a summary of emerging interventions that either promote or suppress senescence and discusses their therapeutic potential in CVDs.

3.
Environ Sci Pollut Res Int ; 30(39): 91140-91157, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37474858

RESUMO

Cancer is a chronic disease that seriously endangers human health, and studies on its association with greenspace have been published. We aimed to systematically review the epidemiological evidence and obtain the best available evidence. PubMed, Web of Science, Embase, and Cochrane Library were used as search databases, the time limit was September 12, 2022, and the cited articles were manually supplemented. Two researchers independently performed literature screening and data extraction. We performed a meta-analysis of data using a normalized difference vegetation index (NDVI) as the greenspace measure, providing hazard ratio (HR) and corresponding 95% CI. After standardization of the data, we used a random effects model for pooling. We also assessed the risk of bias for each study and the quality of each evidence body. We identified 10,108 items and included 14 studies from 11 institutions in eight countries. All studies had a low risk of bias. Quantitative analysis of 13 studies found a beneficial association of greenspace with the mortality of lung cancer (pooled HR [95% CI]=0.965 [0.947, 0.983]) and prostate cancer (HR [95% CI]=0.939 [0.898, 0.980]) based on 0.1-unit NDVI increment and a potential beneficial association with the incidence of prostate, lung, and breast cancer. Greenspace had opposite associations with cancer mortality for urban and rural populations. Indirect comparisons did not find statistically significant differences in the effects of greenspace on different cancer outcomes. The evidence body assessment was considered to be "very low." This review indicated potential beneficial associations between greenspace for lung, prostate, and breast cancer outcomes. However, there was a lack of mediation analysis to explore the underlying mechanism of a causal association. Meanwhile, the interstudy heterogeneity was large. Therefore, future studies should consider more accurate exposure assessment and more comprehensive covariate coverage, while focusing on mediating analysis. PROSPERO: CRD42022361068.


Assuntos
Neoplasias da Mama , Parques Recreativos , Masculino , Humanos , Estudos de Coortes , Causalidade , Modelos de Riscos Proporcionais
4.
Crit Rev Food Sci Nutr ; : 1-19, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36794398

RESUMO

INTRODUCTION: Micronutrients are clinically important in managing COVID-19, and numerous studies have been conducted, but inconsistent findings exist. OBJECTIVE: To explore the association between micronutrients and COVID-19. METHODS: PubMed, Web of Science, Embase, Cochrane Library and Scopus for study search on July 30, 2022 and October 15, 2022. Literature selection, data extraction and quality assessment were performed in a double-blinded, group discussion format. Meta-analysis with overlapping associations were reconsolidated using random effects models, and narrative evidence was performed in tabular presentations. RESULTS: 57 reviews and 57 latest original studies were included. 21 reviews and 53 original studies were of moderate to high quality. Vitamin D, vitamin B, zinc, selenium, and ferritin levels differed between patients and healthy people. Vitamin D and zinc deficiencies increased COVID-19 infection by 0.97-fold/0.39-fold and 1.53-fold. Vitamin D deficiency increased severity 0.86-fold, while low vitamin B and selenium levels reduced severity. Vitamin D and calcium deficiencies increased ICU admission by 1.09 and 4.09-fold. Vitamin D deficiency increased mechanical ventilation by 0.4-fold. Vitamin D, zinc, and calcium deficiencies increased COVID-19 mortality by 0.53-fold, 0.46-fold, and 5.99-fold, respectively. CONCLUSION: The associations between vitamin D, zinc, and calcium deficiencies and adverse evolution of COVID-19 were positive, while the association between vitamin C and COVID-19 was insignificant.REGISTRATION: PROSPERO CRD42022353953.

5.
Heliyon ; 9(2): e13509, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36825183

RESUMO

Introduction: Heart failure is a rapidly growing public health problem and has become a major cause of hospitalization in middle-aged and older adults. Biomarkers are clinically important in managing heart failure and have attracted more attention from researchers in recent years. This study aimed to evaluate the global research of heart failure biomarkers by bibliometrics and to identify the hot spots and perspectives for further advancement. Methods: Selection of relevant documents was from the Web of Science Core Collection. Microsoft Excel, VOSviewer, SciMA, and CiteSpace software were used for bibliometric analysis. Results: As of October 29, 2021, 5,978 documents for heart failure biomarkers have been identified from 1989 to 2021. European Journal of Heart Failure and Circulation respectively ranked first in terms of the number of publications and the number of co-citations. A total of 5,698 institutions from 90 countries participated in these publications, with the USA leading with 2,045 documents. The most productive institution was Harvard University. Januzzi, J.L. and Maisel, A.S. were the most productive and most cited authors respectively. Natriuretic peptide, copeptin, valsartan, ferric carboxymaltose, empagliflozin, preserved ejection fraction, myocardial fibrosis, and heart transplantation were hot themes. Conclusions: Extensive national and inter-institutional collaboration should be enhanced to bridge the gap between developed and less developed countries in heart failure biomarkers research. The research in this field seems to have reached a relatively mature stage, with a decrease in research fervor in recent years. The study of the natriuretic peptide family still has high centrality, with advances in the study of expression products and inflammatory markers. Cardiac fibrosis, cardiac remodeling, and therapies regarding heart failure have become hot spots.

6.
J Cardiovasc Pharmacol ; 81(1): 4-14, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36607775

RESUMO

ABSTRACT: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used to treat diabetes mellitus. Abundant evidence has shown that SGLT2 inhibitors can reduce hospitalization for heart failure (HF) in patients with or without diabetes. An increasing number of studies are being conducted on the mechanisms of action of SGLT2 inhibitors in HF. Our review summarizes a series of clinical trials on the cardioprotective effects of SGLT2 inhibitors in the treatment of HF. We have summarized several classical SGLT2 inhibitors in cardioprotection research, including empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, and sotagliflozin. In addition, we provided a brief overview of the safety and benefits of SGLT2 inhibitors. Finally, we focused on the mechanisms of SGLT2 inhibitors in the treatment of HF, including ion-exchange regulation, volume regulation, ventricular remodeling, and cardiac energy metabolism. Exploring the mechanisms of SGLT2 inhibitors has provided insight into repurposing these diabetic drugs for the treatment of HF.


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Canagliflozina/efeitos adversos
7.
Int J Hypertens ; 2022: 2432567, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35535214

RESUMO

Hypertension induces both structural and functional changes in blood vessels, thereby increasing endothelial dysfunction, which in turn, contributes to an increase in blood pressure. A popular and widely used noninvasive tool, flow-mediated dilation (FMD), is used to examine peripheral artery endothelium-dependent dilation. This study aimed to compare the efficacies of different classes of antihypertensive agents based on their effects on FMD. PubMed, Embase, and Cochrane Library were queried till November 1, 2020. Comparative studies on the efficacies of two or more antihypertensive agents or placebos for hypertensive patients were included. The outcomes were variations in mean systolic and diastolic blood pressure. Two reviewers independently reviewed and filtered the literature and extracted the data; the Cochrane "risk of bias" method was used to evaluate the methodological quality of the randomized controlled trials. A network meta-analysis was performed using Stata 15.0 software with a total of 49 studies. Subgroup analysis based on age and duration of treatments was performed. As compared to the placebo group, patients receiving the antihypertensive drugs exhibited significantly enhanced FMD (ARB + CCB: 4.01%, 95% CI, 0.92-7.11%, p < 0.001; ACEI + ARB: 2.81%, 95% CI, 1.19-4.43%, p < 0.001; ACEI: 2.55%, 95% CI, 1.34-3.77%, p < 0.001; ARB: 2.22%, 95% CI, 1.05-3.38%, p < 0.001; ß-blocker: 2.23%, 95% CI, 0.93-3.52%, p < 0.001). In the SUCRA curve for network meta-analysis, the combination of CCB and ARB was found to be the most effective in increasing FMD (SUCRA = 89.0%), followed by ACEI monotherapy (SUCRA = 74.2%). ARB combined with CCB was superior in improving the endothelial function measured as the FMD; ACEI monotherapy was the most effective treatment among the antihypertension medications. There were no significant differences between antihypertensive drug-based monotherapies.

9.
Mol Pharm ; 17(1): 229-238, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31765158

RESUMO

Eukaryotic translation initiation factors 3i (eIF3i) is a proto-oncogene that is overexpressed in various tumors, reducing its expression by eIF3i shRNA is a promising strategy to inhibit tumor growth or metastasis. Tumor cell is the target of eIF3i shRNA so that tumor-site accumulation could be important for fulfilling its therapeutic effect. Thus, the iRGD modified liposome (R-LP) was rationally synthesized to enhance the antitumor effect by active targeted delivery of eIF3i shRNA to B16F10 melanoma cells. R-LP encapsulating eIF3i shRNA gene (R-LP/sheIF3i) were prepared by a film dispersion method. The transfection experiment proves that R-LP could effectively transfect B16F10 cells. R-LP/sheIF3i notably restrained the migration, invasion, and adhesion of melanoma cells in vitro. In a mouse model of lung metastasis, R-LP/sheIF3i administered by intravenous injection suppressed pulmonary metastasis of melanoma by dramatically downregulated eIF3i expression and subsequently inhibiting tumor neovascularization and tumor cells proliferation in vivo. Our results provide a basis for tumor cells targeting strategies to reduce the expression of eIF3i by RNAi in the treatment of tumor metastasis.


Assuntos
Fator de Iniciação 3 em Eucariotos/genética , Terapia Genética , Neoplasias Pulmonares/secundário , Melanoma Experimental/secundário , Melanoma Experimental/terapia , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Fator de Iniciação 3 em Eucariotos/metabolismo , Lipossomos/química , Lipossomos/ultraestrutura , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Masculino , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Neovascularização Patológica/genética , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , RNA Interferente Pequeno , Transfecção , Transplante Homólogo
10.
Micromachines (Basel) ; 10(5)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096645

RESUMO

Capacitive sensing is a key technique to measure the test mass movement with a high resolution for space-borne gravitational wave detectors, such as Laser Interferometer Space Antenna (LISA) and TianQin. The capacitance resolution requirement of TianQin is higher than that of LISA, as the arm length of TianQin is about 15 times shorter. In this paper, the transfer function and capacitance measurement noise of the circuit are modeled and analyzed. Figure-of-merits, including the product of the inductance L and the quality factor Q of the transformer, are proposed to optimize the transformer and the capacitance measurement resolution of the circuit. The LQ product improvement and the resonant frequency augmentation are the key factors to enhance the capacitance measurement resolution. We fabricated a transformer with a high LQ product over a wide frequency band. The evaluation showed that the transformer can generate a capacitance resolution of 0.11 aF/Hz1/2 at a resonant frequency of 200 kHz, and the amplitude of the injection wave would be 0.6 V. This result supports the potential application of the proposed transformer in space-borne gravitational wave detection and demonstrates that it could relieve the stringent requirements for other parameters in the TianQin mission.

11.
Org Biomol Chem ; 17(14): 3497-3506, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30888376

RESUMO

A route to synthesize 3-aryl-2-oxazolidinones is developed, which is achieved through a three component reaction between CO2, aryl amines, and epoxides with a binary organocatalytic system composed of organocatalysts and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). The method allows wide scopes of epoxide and aryl amine substrates with various functional groups under mild reaction conditions. The control experiments indicate that a cyclic carbonate is formed via cycloaddition of epoxides with CO2, which further reacts with the ß-amino alcohol originating from epoxides and aryl amines, resulting in the formation of 3-aryl-2-oxazolidinones finally.

12.
Bioorg Med Chem Lett ; 29(3): 383-388, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30579795

RESUMO

As a part of our ongoing research to develop novel URAT1 inhibitors, 19 compounds (1a-1s) based on carboxylic acid bioisosteres were synthesized and tested for in vitro URAT1 inhibitor activity (IC50). The structure-activity relationship (SAR) exploration led to the discovery of a highly potent novel URAT1 inhibitor 1g, which was 225-fold more potent than the parent lesinurad in vitro (IC50 = 0.032 µM for 1g against human URAT1 vs 7.20 µM for lesinurad). Besides, 3D-QSAR pharmacophore models were established based on the activity of the compounds (1a-1s) by Accelrys Discovery Studio 2.5/HypoGen. The best hypothesis, Hypo 1, was validated by three methods (cost analysis, Fisher's randomization and leave-one-out). Although compound 1g is among the most potent URAT1 inhibitors currently under development in clinical trials, the Hypo1 appears to be favorable for future lead optimization.


Assuntos
Ácidos Carboxílicos/farmacologia , Ésteres/farmacologia , Gota/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Triazóis/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/química , Gota/metabolismo , Humanos , Hiperuricemia/metabolismo , Estrutura Molecular , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Triazóis/química
13.
Sensors (Basel) ; 18(4)2018 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-29670021

RESUMO

A method for automatic compensation of misalignment angles during matching the scale factors of two pairs of the accelerometers in developing the rotating accelerometer gravity gradient instrument (GGI) is proposed and demonstrated in this paper. The purpose of automatic scale factor matching of the four accelerometers in GGI is to suppress the common mode acceleration of the moving-based platforms. However, taking the full model equation of the accelerometer into consideration, the other two orthogonal axes which is the pendulous axis and the output axis, will also sense the common mode acceleration and reduce the suppression performance. The coefficients from the two axes to the output are δO and δP respectively, called the misalignment angles. The angle δO, coupling with the acceleration along the pendulous axis perpendicular to the rotational plane, will not be modulated by the rotation and gives little contribution to the scale factors matching. On the other hand, because of coupling with the acceleration along the centripetal direction in the rotating plane, the angle δP would produce a component with 90 degrees phase delay relative to the scale factor component. Hence, the δP component coincides exactly with the sensitive direction of the orthogonal accelerometers. To improve the common mode acceleration rejection, the misalignment angle δP is compensated by injecting a trimming current, which is proportional to the output of an orthogonal accelerometer, into the torque coil of the accelerometer during the scale factor matching. The experimental results show that the common linear acceleration suppression achieved three orders after the scale factors balance and five orders after the misalignment angles compensation, which is almost down to the noise level of the used accelerometers of 1~2 × 10−7 g/√Hz (1 g ≈ 9.8 m/s²).

14.
Molecules ; 23(2)2018 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-29382075

RESUMO

In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a-1x and 1ha-1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0.035 µM against human URAT1 for 1h vs. 7.18 µM and 0.28 µM for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors.


Assuntos
Metano/análogos & derivados , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Ácido Úrico/metabolismo , Uricosúricos/síntese química , Benzobromarona/farmacologia , Transporte Biológico Ativo/efeitos dos fármacos , Radioisótopos de Carbono , Desenho de Fármacos , Expressão Gênica , Células HEK293 , Humanos , Metano/síntese química , Metano/farmacologia , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Relação Estrutura-Atividade , Tioglicolatos/farmacologia , Triazóis/farmacologia , Uricosúricos/farmacologia
15.
Sensors (Basel) ; 17(11)2017 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-29156587

RESUMO

A subnano-g electrostatic force-rebalanced flexure accelerometer is designed for the rotating accelerometer gravity gradient instrument. This accelerometer has a large proof mass, which is supported inversely by two pairs of parallel leaf springs and is centered between two fixed capacitor plates. This novel design enables the proof mass to move exactly along the sensitive direction and exhibits a high rejection ratio at its cross-axis directions. Benefiting from large proof mass, high vacuum packaging, and air-tight sealing, the thermal Brownian noise of the accelerometer is lowered down to less than 0.2 ng / Hz with a quality factor of 15 and a natural resonant frequency of about 7.4 Hz . The accelerometer's designed measurement range is about ±1 mg. Based on the correlation analysis between a commercial triaxial seismometer and our accelerometer, the demonstrated self-noise of our accelerometers is reduced to lower than 0.3 ng / Hz over the frequency ranging from 0.2 to 2 Hz, which meets the requirement of the rotating accelerometer gravity gradiometer.

16.
Sensors (Basel) ; 17(11)2017 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-29077015

RESUMO

A new and simple method to adjust the scale factor of a magnetic force feedback accelerometer is presented, which could be used in developing a rotating accelerometer gravity gradient instrument (GGI). Adjusting and matching the acceleration-to-current transfer function of the four accelerometers automatically is one of the basic and necessary technologies for rejecting the common mode accelerations in the development of GGI. In order to adjust the scale factor of the magnetic force rebalance accelerometer, an external current is injected and combined with the normal feedback current; they are then applied together to the torque coil of the magnetic actuator. The injected current could be varied proportionally according to the external adjustment needs, and the change in the acceleration-to-current transfer function then realized dynamically. The new adjustment method has the advantages of no extra assembly and ease of operation. Changes in the scale factors range from 33% smaller to 100% larger are verified experimentally by adjusting the different external coefficients. The static noise of the used accelerometer is compared under conditions with and without the injecting current, and the experimental results find no change at the current noise level, which further confirms the validity of the presented method.

17.
Med Chem ; 13(3): 260-281, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27633583

RESUMO

BACKGROUND: Gout is the most common inflammatory arthritis, which, if left untreated or inadequately treated, will lead to joint destruction, bone erosion and disability due to the crystal deposition. Uric acid transporter 1 (URAT1) was the promising therapeutic target for urate-lowering therapy. OBJECTIVE: The goal of this work is to understand the structure-activity relationship (SAR) of a potent lesinurad-based hit, sodium 2-((5-bromo-4-((4-cyclopropyl-naphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1c), and based on that discover a more potent URAT1 inhibitor. METHODS: The SAR of 1c was systematically explored and the in vitro URAT1 inhibitory activity of synthesized compounds 1a-1t was determined by the inhibition of URAT1-mediated [8-14C]uric acid uptake by human embryonic kidney 293 (HEK293) cells stably expressing human URAT1. RESULTS: Twenty compounds 1a-1t were synthesized. SAR analysis was performed. Two highly active URAT1 inhibitors, sodium 2-((5-bromo-4-((4-n-propylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1j) and sodium 2-((5-bromo-4-((4-bromonaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1m), were identified, which were 78- and 76-fold more active than parent lesinurad in in vitro URAT1 inhibitory assay, respectively (IC50 values for 1j and 1m were 0.092 µM and 0.094 µM, respectively, against human URAT1 vs 7.18 µM for lesinurad). CONCLUSION: Two highly active URAT1 inhibitors were discovered. The SAR exploration also identified more flexible naphthyltriazolylmethane as a novel molecular skeleton that will be valuable for the design of URAT1 inhibitors, as indicated by the observation that many of the synthesized naphthyltriazolylmethane- bearing derivatives (1b-1d, 1g, 1j and 1m) showed significantly improved UART1 inhibitory activity (sub-micromolar IC50 values) as compared with lesinurad which has the rigid naphthyltriazole skeleton.


Assuntos
Descoberta de Drogas , Gota/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Compostos de Sulfidrila/farmacologia , Triazóis/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Triazóis/química
18.
Molecules ; 21(11)2016 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-27854343

RESUMO

In order to systematically explore and understand the structure-activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH2, 18 compounds (1a-1r) were designed, synthesized and subjected to in vitro URAT1 inhibitory assay. The SAR exploration led to the discovery of a highly potent flexible URAT1 inhibitor, 1q, which was 31-fold more potent than parent lesinurad (IC50 = 0.23 µM against human URAT1 for 1q vs 7.18 µM for lesinurad). The present study discovered a flexible molecular scaffold, as represented by 1q, which might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors, and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity.


Assuntos
Ácido Butírico/química , Ácido Butírico/farmacologia , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Ácido Butírico/síntese química , Linhagem Celular , Técnicas de Química Combinatória , Humanos , Concentração Inibidora 50 , Estrutura Molecular
19.
Sci Rep ; 6: 32427, 2016 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-27576898

RESUMO

Cervical cancer presents extremely low PEDF expression which is associated with tumor progression and poor prognosis. In this study, folate receptor α (FRα)-targeted nano-liposomes (FLP) were designed to enhance the anti-tumor effect by targeting delivery of exogenous PEDF gene to cervical cancer cells. The targeting molecule F-PEG-Chol was firstly synthesized by a novel simpler method. FLP encapsulating PEDF gene (FLP/PEDF) with a typical lipid-membrane structure were prepared by a film dispersion method. The transfection experiment found FLP could effectively transfect human cervical cancer cells (HeLa cells). FLP/PEDF significantly inhibited the growth of HeLa cells and human umbilical vein endothelial cells (HUVEC cells) and suppressed adhension, invasion and migration of HeLa cells in vitro. In the abdominal metastatic tumor model of cervical cancer, FLP/PEDF administered by intraperitoneal injection exhibited a superior anti-tumor effect probably due to the up-regulated PEDF. FLP/PEDF could not only sharply reduce the microvessel density but also dramatically inhibit proliferation and markedly induce apoptosis of tumor cells in vivo. Moreover, the preliminary safety investigation revealed that FLP/PEDF had no obvious toxicity. These results clearly showed that FLP were desired carriers for PEDF gene and FLP/PEDF might represent a potential novel strategy for gene therapy of cervical cancer.


Assuntos
Proteínas do Olho/genética , Receptor 1 de Folato/genética , Neovascularização Patológica/tratamento farmacológico , Fatores de Crescimento Neural/genética , Serpinas/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Portadores de Fármacos/administração & dosagem , Proteínas do Olho/uso terapêutico , Feminino , Receptor 1 de Folato/metabolismo , Terapia Genética , Vetores Genéticos , Células HeLa , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Microvasos/efeitos dos fármacos , Microvasos/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Fatores de Crescimento Neural/uso terapêutico , Serpinas/uso terapêutico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Eur J Pharmacol ; 762: 364-71, 2015 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-26057693

RESUMO

Angiotensin II-receptor blockers (ARBs), similar to HMG-CoA reductase inhibitors (statins), could improve lipid metabolism abnormalities. There might be some cross-talking pathways between statins and ARBs to produce additive beneficial effects on lipid metabolism in dyslipidemia. However, few studies investigate the effects of ARBs on the therapeutic efficacy of statins in dyslipidemia. The present study was designed to systematically evaluate the effects of telmisartan on the therapeutic efficacy of pitavastatin on lowering lipid level and reducing fat deposition by employing a dyslipidemia model, guinea pigs. 48 Male guinea pigs fed with high-fat diet were randomly grouped and treated with vehicle, telmisartan, pitavastatin or telmisartan/pitavastatin combinations. After treatment for eight weeks, telmisartan could significantly enhance the therapeutic efficacy of pitavastatin by extremely reducing body weight gain, weight of adipose tissue and adipocyte size. However, telmisartan/pitavastatin combinations could not further improve lipid levels on the basis of pitavastain, though single telmisartan markedly decreased triglyceride (TG) and slightly increased high density lipoprotein cholesterol (HDL-C). Moreover, telmisartan/pitavastatin combinations significantly upregulated the gene expression level of peroxisome proliferator-activated receptor (PPAR)-δ, but no effects on the expression of PPAR-α/γ, leptin and adiponectin compared to monotherapy. Taken together, our studies provided new evidences that telmisartan has an additive beneficial influence on decreasing fat deposition and weight gain through PPAR-δ pathway but cannot enhance the therapeutic efficacy of pitavastatin on lowering lipid levels. The combinational administration of telmisartan and pitavastatin could be a potential therapeutic strategy for dyslipidemia related obesity and worthy of further investigation in obese animal models.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Dislipidemias/induzido quimicamente , Dislipidemias/tratamento farmacológico , Quinolinas/farmacologia , Adipócitos/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Benzimidazóis/uso terapêutico , Benzoatos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Interações Medicamentosas , Dislipidemias/metabolismo , Dislipidemias/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Cobaias , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Quinolinas/uso terapêutico , Telmisartan
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