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1.
Mol Pharm ; 17(10): 3966-3978, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-32902299

RESUMO

The organic anion transporting polypeptide 2B1 (OATP2B1), which is encoded by the SLCO2B1 gene, plays important roles in the absorption and disposition of its substrate drugs. Nonsynonymous variations of SLCO2B1 change its amino acid sequence and may alter its function. However, so far, very few genetic variants of SLCO2B1 have been functionally characterized. In the present study, first of all, 14 nonsynonymous single nucleotide variants (SNVs) of SLCO2B1 have been identified from the dbSNP database. Then, human embryonic kidney (HEK293) cells were employed as the expression system and functional studies were carried out for these 14 SNVs using substrates 4',5'-dibromofluorescein (DBF), estrone-3-sulfate (E3S), atorvastatin, and rosuvastatin. Our results showed that four nonsynonymous rare variants, namely, SLCO2B1 c.332G > A (p.R111Q), c.1184C > A (p.P395H), c.1624G > A (p.V542M), and c.1998C > A (p.F666L), have great effect on the function of OATP2B1. Surface biotinylation and immunoblot analysis indicated that the variant c.1184C > A (p.P395H) almost completely disrupted OATP2B1's expression on the plasma membrane. According to the three-dimensional structural model of OATP2B1 we developed, these four mutated residues are not located at the substrate binding region of OATP2B1. Their significant effect on the function of OATP2B1 could probably be attributed to jeopardizing OATP2B1's surface expression as exemplified by c.1184C > A (p.P395H), altering the transporter's overall structure and affecting its interactions with other proteins or the lipid bilayer. Taken together, our results demonstrated that rare coding variants could have a great impact on the function and expression of OATP2B1.

2.
J Med Internet Res ; 22(9): e16053, 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32940613

RESUMO

BACKGROUND: Apps for real-time continuous glucose monitoring (CGM) on smartphones and other devices linked to CGM systems have recently been developed, and such CGM apps are also coming into use in Japan. In comparison with conventional retrospective CGM, the use of CGM apps improves patients' own blood glucose control, which is expected to help slow the progression of type 2 diabetes mellitus (DM) and prevent complications, but the effect of their introduction on medical costs remains unknown. OBJECTIVE: Our objective in this study was to perform an economic appraisal of CGM apps from the viewpoint of assessing public medical costs associated with type 2 DM, using the probability of developing type 2 DM-associated complications, and data on medical costs and utility value to carry out a medical cost simulation using a Markov model in order to ascertain the cost-effectiveness of the apps. METHODS: We developed a Markov model with the transition states of insulin therapy, nephrosis, dialysis, and cardiovascular disease, all of which have a major effect on medical costs, to identify changes in medical costs and utility values resulting from the introduction of a CGM app and calculated the incremental cost-effectiveness ratio (ICER). RESULTS: The ICER for CGM app use was US $33,039/quality-adjusted life year (QALY). CONCLUSIONS: Sensitivity analyses showed that, with the exception of conditions where the transition probability of insulin therapy, utility value, or increased medical costs increases, the ICER for the introduction of CGM apps was below the threshold of US $43,478/QALY used by the Central Social Insurance Medical Council. Our results provide basic data on the cost-effectiveness of introducing CGM apps, which are currently starting to come into use.

3.
Nat Prod Res ; : 1-8, 2020 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-32571087

RESUMO

Two new nor-lignans, pulvin A (1) and moellenoside C (2), along with two known compounds (3-4) were isolated from the whole plant of Selaginella pulvinate (Hook. & Grev.) Maxim. The structures of the new compounds were established on the basis of spectroscopic data and acid hydrolysis. All the isolates were investigated for their antihyperglycemic activities in 3T3-L1 adipocytes. The results showed that compounds 1 and 2 promoted the glucose consumption prominently in 3T3-L1 adipocytes in a dose-response manner. Compound 1 and 2 induced 1.14-1.73 folds and 1.03-1.55 folds changes relative to the basal level, respectively, in the concentration range of 12.5 µM to 50 µM.

4.
Clin Neuroradiol ; 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32239261

RESUMO

PURPOSE: The prognosis after endovascular treatment (EVT) of acute arterial occlusions due to intracranial atherosclerotic disease (ICAD) may differ from those due to embolism. The aim was to evaluate whether safety and efficacy of EVT differ among patients with middle cerebral artery (MCA) M1 occlusion from ICAD or embolism. METHODS: A database review was conducted to identify EVT patients with acute MCA M1 occlusion from November 2013 to December 2018.The patients were divided into the ICAD group and embolic group according to the etiology of occlusion. Using propensity score analysis, patients with ICAD-related occlusion and embolism underwent 1:1 matching. Angiographic results, complications, and clinical outcomes were compared. RESULTS: A total of 217 patients (ICAD: 51; embolism: 166) were identified. After propensity score matching, 45 patients with ICAD-related occlusion and 45 with embolism were matched. All baseline covariates except atrial fibrillation were statistically indistinguishable. The rate of successful reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] 2b-3) was similar between the two groups, while the rate of mTICI 3 in the ICAD group was higher. No statistical difference was observed in the rate of postprocedural intracranial hemorrhage. The rate of favorable outcome (modified Rankin Scale [mRS] ≤2) and mortality at 90 days was comparable. CONCLUSION: This propensity score analysis demonstrated that the EVT patients with acute ICAD-related MCA M1 occlusion had similar angiographic and clinical outcomes compared to those with M1 embolism on a similar baseline condition.

5.
Nano Lett ; 20(5): 3449-3458, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32255345

RESUMO

Flexible strain sensors have been widely investigated with their rapid development in human-machine interfaces, soft robots, and medical care monitoring. Here, we report a new in situ catalytic strategy toward the fabrication of metallic aerogel hybrids, which are composed of vanadium nitride (VN) nanosheets decorated with well-defined vertically aligned carbon nanotube arrays (VN/CNTs) for the first time. In this architecture, the two-dimensional VN nanosheets as the main bone structure are favorable for the flexible devices due to their excellent structural compatibility during the repetitive deforming process. In addition, the sandwiched aerogel hybrids form highly conductive 3D network, affording outstanding sensitivity for the strain-responsive behaviors. Further, the VN/CNTs-based flexible strain sensors are successfully fabricated, showing a high gauge factor of 386 within a small strain of 10%, fast response, and extraordinary durability. The monitoring of physical signals and an actual real-time human-machine controlling system based on the sensors are also presented.

6.
Fitoterapia ; 143: 104562, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32199960

RESUMO

A new cyclopeptide, pulvpeptin A (1), two pairs of norlignan lignanosides, tamariscinosides G and H (2, 3), together with five known compounds (4-8) were isolated from Selaginella pulvinata. The structures were elucidated by spectroscopic data and chemical degradation. The activity of tamariscinoside G (2) was evaluated by stimulating glucose uptake in 3T3-L1 adipocytes. The results showed 1.49-fold increase in glucose uptake in 3T3-L1 cells relative to basal.

7.
J Agric Food Chem ; 68(7): 2063-2070, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32009392

RESUMO

Luteolin is a typical flavonoid and broadly distributed in the plants. Oral bioavailability of luteolin is low owing to extensive metabolism. Regioselective glucuronidation by UDP-glucuronosyltransferases (UGTs) and liver uptake by organic anion transporting polypeptides (OATPs) of luteolin and consequent glucuronidation metabolites were studied. Luteolin-3'-O-glucuronide (L-3'-G) and luteolin-7-O-glucuronide (L-7-G) were the major metabolites in human liver microsomes. Further study demonstrated that UGT1A9 played a predominant role in the glucuronidation of luteolin. Transporter study showed that OATP1B1- and 1B3-transfected cells selectively uptake L-3'-G into cells but not luteolin or L-7-G. After intravenous administration of luteolin to mice, the area under the curve of L-3'-G in the plasma was the highest among luteolin, L-3'-G, and L-7-G. In the liver, the concentration of L-3'-G was significantly greater than L-7-G. In conclusion, OATP1B1 and OATP1B3 play an important role in the liver disposition of luteolin and its glucuronidation metabolites.


Assuntos
Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Fígado/metabolismo , Luteolina/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Transporte Biológico , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Luteolina/química , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética
8.
Biochim Biophys Acta Biomembr ; 1862(5): 183210, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32006472

RESUMO

Organic anion transporting polypeptide 1B1 (OATP1B1) is a key hepatic uptake transporter whose inhibition could lead to adverse drug-drug and drug-food interactions. Flavonoids are widely distributed in food and beverages and thus our bodies are frequently exposed to them. Therefore, investigation of the interactions between OATP1B1 and flavonoids could be of great significance. In the present study, 25 common flavonoids were investigated for their interactions with OATP1B1 using the fluorescent substrate 2',7'-dichlorofluorescein (DCF) and three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis. Kinetic study showed that OATP1B1-mediated DCF uptake exhibited a monophasic saturation kinetics with a Km value of 9.7 ± 2.4 µM. Inhibition assay for flavonoids on OATP1B1-mediated DCF uptake was performed and their IC50 values were determined upon which reliable and predictive CoMFA (q2 = 0.604, r2 = 0.841) and CoMSIA (q2 = 0.534, r2 = 0.807) models were developed. Our experimental and computational results showed that flavonoid aglycones interacted with OATP1B1 much stronger than their glycosides such as 3-O- and 7-O-glycosides as bulky hydrophilic and hydrogen-bond forming substituents at C-3 and C-7 positions on rings A and C were unfavorable for their binding. On the other hand, the presence of hydrogen-bond forming groups on ring B was beneficial as long as the number of hydroxyl groups was not >2. Our results also indicated that flavones usually interacted with OATP1B1 much stronger than their 3-hydroxyflavone counterparts (flavonols). The obtained information and 3D-QSAR models could be useful for elucidating and predicting the interactions between flavonoids and human OATP1B1.


Assuntos
Flavonoides/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/química , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Transporte Biológico , Interações Medicamentosas , Fluoresceínas , Células HEK293 , Humanos , Cinética , Fígado/metabolismo , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/metabolismo , Relação Quantitativa Estrutura-Atividade
9.
J Agric Food Chem ; 68(6): 1579-1587, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31760750

RESUMO

Organic anion transporter 3 (OAT3) plays a critical role in the renal excretion of many xenobiotics. Because steviol acyl glucuronide (SVAG), an OAT3 substrate, is the major circulating metabolite after oral ingestion of steviol glycosides and is excreted into the urine, inhibition of OAT3 activity may alter pharmacokinetic profiles of SVAG. The present study showed that drugs such as probenecid and glimepiride displayed potent inhibition toward the OAT3-mediated SVAG transport, with IC50 values of 4.9 and 0.8 µM, respectively. No species differences were observed. Probenecid and glimepiride could significantly elevate plasma concentrations of SVAG after oral administration of rebaudioside A, with significant increases in plasma maximum (Cmax) and area under the plasma time-concentration curve values. The inhibitory effect on the OAT3-mediated SVAG transport exemplified a unique case between drugs and the metabolite of a food additive. Our data suggest that caution should be exercised when giving steviol glycoside products to human subjects with compromised renal function.


Assuntos
Diterpenos de Caurano/metabolismo , Glucosídeos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Probenecid/metabolismo , Compostos de Sulfonilureia/metabolismo , Animais , Transporte Biológico , Diterpenos de Caurano/química , Glucosídeos/química , Células HEK293 , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Probenecid/administração & dosagem , Probenecid/química , Ratos , Ratos Sprague-Dawley , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/química
11.
Life Sci ; 239: 116951, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31626787

RESUMO

Glia is an important component of the nervous system that is involved in neurotransmitter uptake, signal transduction, myelin synthesis, neurodevelopment, and immune response. Exosomes are extracellular vesicles that are secreted from certain types of cells, and are known to mediate glia function. Glia-derived exosomes (GDEs) can transport proteins, nucleotides and cellular waste, and exert both protective and toxic effects on the nervous system. GDEs promote glia-neuron communication, anti-stress responses, anti-inflammation and neurite outgrowth, and may also be involved in neurological disease such as glioma, glioblastoma, Alzheimer's disease, Parkinson disease and neuronal HIV infections. This review summarizes the current research on GDEs and their functions, with emphasis on their therapeutic potential.


Assuntos
Exossomos/metabolismo , Neuroglia/metabolismo , Animais , Comunicação Celular/fisiologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiologia , Exossomos/fisiologia , Humanos , Neuroglia/fisiologia , Neurônios , Neurotransmissores , Transdução de Sinais
12.
J AOAC Int ; 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31561752

RESUMO

Background: Peucedani Radix is a popular traditional Chinese medicine herb with a long history in China. Praeruptorin A (PA), praeruptorin B (PB), and praeruptorin E (PE) are usually taken as important quality indexes of Peucedani Radix. Objective: To establish a rapid method for simultaneous determination of PA, PB, PE, and moisture contents in Peucedani Radix using near-infrared (NIR) spectroscopy and chemometrics. Methods: One hundred twenty Peucedani Radix samples were analyzed with HPLC as a reference method. The NIR spectral scanning range was from 12000 cm-1 to 4000 cm-1. Partial least squares (PLS) regression algorithm was used to establish calibration models. Three variable selection methods were investigated, including variable importance in projection (VIP), competitive adaptive reweighted sampling (CARS), and Monte Carlo uninformative variable elimination (MCUVE). The performances of the established models were evaluated by root-mean-square error (RMSEC) and determination coefficient (Rc²) of calibration set, root-mean-square error (RMSEP) and determination coefficient (Rp²) of prediction set, and residual predictive deviation (RPD). Results: A clear ranking of the performance of the calibration models could be as follows: CARS-PLS > MCUVE-PLS > VIP-PLS > Full-PLS. For CARS-PLS, Rp², RMSEP, and RPD of the prediction set are as follows: 0.9204, 0.0860%, and 3.5850 for PA; 0.8011, 0.0431%, and 2.0868 for PB; 0.8043, 0.0367%, and 2.1569 for PE; and 0.9249, 0.3350%, and 3.6551 for moisture, respectively. Conclusions: The NIR spectroscopy combined with CARS-PLS calibration models could be used for rapid and accurate determination of PA, PB, PE, and moisture contents in Peucedani Radix samples.

13.
Acta Biochim Biophys Sin (Shanghai) ; 51(9): 925-933, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31435637

RESUMO

In study, we aimed to determine the mechanisms underlying the gastroprotective effects of sodium copper chlorophyllin (SCC) against ethanol-induced gastric ulcer injury in mice. First, the gastroprotective effects of SCC against gastric ulcer induced by ethanol were assessed. Then, biochemical, histopathological, immunohistochemistry assays, and western blot analysis were conducted to determine the possible mechanisms of action underlying the effects of SCC. Compared to the effects of omeprazole (OME) in a confirmed mouse model of ethanol-induced gastric ulcer injury, treatment with various doses of SCC resulted in up-regulation of Bcl-2 and down-regulation of the pro-apoptotic protein Bax. Significant decreases in the levels of the malondialdehyde (MDA), myeloperoxidase (MPO), and NO in the gastric tissues were observed. Furthermore, inflammatory cytokine analysis revealed that SCC treatment inhibited the expressions of TNF-α and IL-6, greatly reduced the phosphorylation level of IκB, and repressed the nuclear translocation of NF-κB p65, which demonstrated that SCC inhibited the activation of the NF-κB pathway. The present findings suggest that the protective effects of SCC may be beneficial as a potential preventive and therapeutic agent for gastric ulcer through the NF-κB pathway. Taken together, SCC administration significantly decreased the levels of MPO, NO, and MDA in gastric tissue and exerted a powerful anti-inflammatory activity as demonstrated by reduction in the secretions of proinflammatory mediators such as IL-6 and TNF-α in the serum of mice exposed to ethanol.


Assuntos
Clorofilídios/uso terapêutico , Etanol/efeitos adversos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/prevenção & controle , Animais , Feminino , Interleucina-6/metabolismo , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Peroxidase/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo
14.
J Agric Food Chem ; 67(32): 9079-9087, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31353905

RESUMO

Organic anion transporting polypeptides (OATPs) 1B1 and 1B3 are two highly homologous transporters expressed in the human liver. However, epigallocatechin gallate (EGCG), which is the most predominant catechin in green tea, has opposite effects on the function of OATP1B1 and OATP1B3. In the present study, the critical structural domains and amino acid residues for the activation of OATP1B3 by EGCG have been determined by characterizing the function of a series of OATP1B3-derived chimeric transporters, site-directed mutagenesis, and kinetic studies. Our results showed that G45 and F555 in transmembrane domains 1 and 10 are the most important amino acid residues for OATP1B3 activation. Kinetic studies showed that the activation of OATP1B3 by EGCG at a low substrate concentration was due to its increased substrate binding affinity. However, EGCG caused increased Km and decreased Vmax for 1B3-G45A and 1B3-F555H. The flexibility at position 45 and aromaticity at position 555 might be important for OATP1B3 activation. While 1B3-G45A and 1B3-F555H could not be activated by EGCG, their transport activity for EGCG was comparable to that of wild-type OATP1B3. In conclusion, the present study elucidated the molecular mechanism for OATP1B3 activation by EGCG.


Assuntos
Catequina/análogos & derivados , Extratos Vegetais/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/química , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Motivos de Aminoácidos , Camellia sinensis/química , Catequina/química , Catequina/metabolismo , Células HEK293 , Humanos , Cinética , Fígado/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/química , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Modelos Moleculares , Extratos Vegetais/química , Domínios Proteicos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética
15.
Chem Biol Interact ; 310: 108745, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31299240

RESUMO

Ursodeoxycholic acid (UDCA) is a major effective constituent of bear bile powder, which is widely used as function food in China and is documented in the Chinese pharmacopoeia as a traditional Chinese medicine. UDCA has been developed as the only accepted therapy by the US FDA for primary biliary cholangitis. Recently, the US FDA granted accelerated approval to obeticholic acid (OCA), a semisynthetic bile acid derivative from chenodeoxycholic acid, for primary biliary cholangitis. However, some perplexing toxicities of UDCA have been reported in the clinic. The present work aimed to investigate the difference between UDCA and OCA in regard to potential metabolic activation through acyl glucuronidation and hepatic accumulation of consequent acyl glucuronides. Our results demonstrated that the metabolic fates of UDCA and OCA were similar. Both UDCA and OCA were predominantly metabolically activated by conjugation to the acyl glucuronide in human liver microsomes. UGT1A3 played a predominant role in the carboxyl glucuronidation of both UDCA and OCA, while UGT2B7 played a major role in their hydroxyl glucuronidation. Further uptake studies revealed that OATP1B1- and 1B3-transfected cells could selectively uptake UDCA acyl glucuronide, but not UDCA, OCA, and OCA acyl glucuronide. In summary, the liver disposition of OCA is different from that of UDCA due to hepatic uptake, and liver accumulation of UDCA acyl glucuronide might be related to the perplexing toxicities of UDCA.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Glucuronídeos/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Microssomos Hepáticos/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Ácido Ursodesoxicólico/metabolismo , Animais , Transporte Biológico , Ácido Quenodesoxicólico/metabolismo , Humanos , Medicina Tradicional Chinesa , Ursidae , Ácido Ursodesoxicólico/análogos & derivados , Ácido Ursodesoxicólico/toxicidade
16.
World Neurosurg ; 130: e444-e448, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31252077

RESUMO

INTRODUCTION: Analysis of safety and effectiveness of stent angioplasty for failure of thrombectomy in patients with acute intracranial atherosclerotic occlusion. METHODS: Retrospective continuous analysis of the clinical data of 458 patients with acute stroke undergoing endovascular artery thrombectomy in Changhai Hospital of Second Military Medical University from May 2013 to February 2018. Patients with acute intracranial atherosclerotic occlusion treating with stent implantation were included and the safety and effectiveness of stent angioplasty was evaluated. RESULTS: There was successful stent release in 55 patients. There were 36 cases (65.5%) with occlusion located in the anterior circulation and 19 cases (34.5%) in the posterior circulation. Twenty patients underwent intravenous thrombolysis before surgery, and the time of admission to intravenous thrombolysis was (39.9 ± 13.2) minutes. Fifty-four patients (98.2%) achieved modified thrombolysis in cerebral infarction 2b-3 recanalization. The National Institutes of Health Stroke Scale score 2.0 (0.0,6.0) 7 days after surgery was significantly improved compared with the preoperative National Institutes of Health Stroke Scale score 12.5 (6.0-20.0) (Z = -4.073, P < 0.05). Intracranial hemorrhage occurred in 7 patients (12.7%) after surgery, among them, symptomatic intracranial hemorrhage occurred in 2 cases (3.6%). CTP examination of the skull 3-5 days after operation showed: Among 39 cases (70.9%): 33 cases (84.6%) were patency, 4 cases (10.3%) were occlusion, 2 cases (5.1%) were moderate stenosis, and 16 cases (29.1%) were not examined by computed tomography perfusion. Ninety-day follow-up showed that a total of 43 cases were followed up, and 12 cases were lost to follow-up. Thirty-four patients (79.1%) had a good prognosis 90 days after surgery (modified Rankin scale score 0-2) and 9 patients died (20.9%). CONCLUSION: When thrombectomy in patients with acute intracranial atherosclerotic occlusion fails, stent angioplasty is safe and effective; however, short-term stent reocclusion after surgery cannot be ignored. Because of the small sample size, larger multicenter clinical studies are needed to confirm this result.


Assuntos
Angioplastia/métodos , Arteriosclerose Intracraniana/cirurgia , Reoperação , Trombectomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Angioplastia/efeitos adversos , Angioplastia/instrumentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Stents , Resultado do Tratamento
17.
Cell Death Dis ; 10(7): 493, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235688

RESUMO

Necroptosis is a form of regulated necrosis controlled by receptor-interacting kinase 1 (RIPK1 or RIP1), RIPK3 (RIP3), and pseudokinase mixed lineage kinase domain-like protein (MLKL). Increasing evidence suggests that necroptosis is closely associated with pathologies including inflammatory diseases, neurodegenerative diseases, and cancer metastasis. Herein, we discovered the small-molecule PK6 and its derivatives as a novel class of necroptosis inhibitors that directly block the kinase activity of RIPK1. Optimization of PK6 led to PK68, which has improved efficacy for the inhibition of RIPK1-dependent necroptosis, with an EC50 of around 14-22 nM in human and mouse cells. PK68 efficiently blocks cellular activation of RIPK1, RIPK3, and MLKL upon necroptosis stimuli. PK68 displays reasonable selectivity for inhibition of RIPK1 kinase activity and favorable pharmacokinetic properties. Importantly, PK68 provides strong protection against TNF-α-induced systemic inflammatory response syndrome in vivo. Moreover, pre-treatment of PK68 significantly represses metastasis of both melanoma cells and lung carcinoma cells in mice. Together, our study demonstrates that PK68 is a potent and selective inhibitor of RIPK1 and also highlights its great potential for use in the treatment of inflammatory disorders and cancer metastasis.

18.
Fitoterapia ; 137: 104190, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31163199

RESUMO

The genus Tripterygium belongs to the family Celastraceae, and contains three species, i.e. Tripterygium wilfordii Hook. F, Tripterygium hypoglaucum (Levl.) Hutch. and Tripterygium regelii Sprague et Takeda. All three species are reported to have excellent medicinal properties that help to cure rheumatoid arthritis, nephrotic syndrome, systemic lupus erythematosus and widely used as a folk medicine in China. Phytochemical studies have led to discovering more than 500 secondary metabolites in this genus, including five main types: sesquiterpenoids, diterpenes, triterpenoids, flavonoids, lignans. This work provides structurally grouping statistic of 198 secondary metabolites of Tripterygium species published from 2008 to the present, as well as pharmacological knowledges in the past five years. The information will be helpful for developing the new discoveries of medicinal value related to the genus Tripterygium.


Assuntos
Tripterygium/química , Tripterygium/classificação , Animais , Anti-Inflamatórios/química , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Antivirais/química , Diterpenos/química , Flavonoides/química , Humanos , Imunossupressores/química , Lignanas/química , Estrutura Molecular , Fármacos Neuroprotetores/química , Compostos Fitoquímicos/química , Metabolismo Secundário , Sesquiterpenos/química , Triterpenos/química
19.
ACS Appl Mater Interfaces ; 11(7): 7522-7528, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30693756

RESUMO

An important factor for the high performance of light-harvesting devices is the presence of surface trappings. Therefore, understanding and controlling the carrier recombination of the organic-inorganic hybrid perovskite surface is critical for the device design and optimization. Here, we report the use of aluminum zinc oxide (AZO) as the anode to construct a p-n junction structure MAPbBr3 nuclear radiation detector. The AZO/MAPbBr3/Au detector can tolerate an electrical field of 500 V·cm-1 and exhibit a very low leakage current of ∼9 nA, which is 1 order of magnitude lower than that of the standard ohmic contact device. The interface state density of AZO/MAPbBr3 contact was reduced from 2.17 × 1010 to 8.7 × 108 cm-2 by annealing at 100 °C under an Ar atmosphere. Consequently, a photocurrent to dark current ratio of 190 was realized when exposed to a green light-emitting diode with a wavelength of 520 nm (∼200 mW·cm-2). Simultaneously, a high X-ray sensitivity of ∼529 µC·Gyair-1 cm-2 was achieved under 80 kVp X-ray at an electric field of 50 V·cm-1. These results demonstrate the use of surface engineering to further optimize the performance of MAPbBr3 detectors, which have many potential applications in medical and security detection with low radiation dose brought to the human body.

20.
Biopharm Drug Dispos ; 40(2): 70-80, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30698830

RESUMO

Multidrug resistance (MDR) is common in patients and has been linked to transforming growth factor-ß1 (TGF-ß1) and overexpression of drug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), although the molecular mechanisms remain largely unknown. This study aimed to investigate the mechanisms underlying TGF-ß1-induced MDR in hepatocellular carcinoma (HCC) cells. It was found that TGF-ß1 upregulated HOX transcript antisense RNA (HOTAIR) expression in HCC cells. When drosophila mothers against decapentaplegic 4 (SMAD4) was silenced, HOTAIR expression was accordingly reduced. Meanwhile, miR-145 expression was increased in the case HOTAIR was silenced. If the enhancer of zeste homolog 2 (EZH2) was knocked down using small interfering RNA (siRNA), miR-145 expression was decreased. Then, the regulatory role of miR-145 in P-gp and BCRP expression was explored. The results showed that the expression of P-gp and BCRP protein was suppressed by miR-145 through binding to the 3'-untranslated regions (3'-UTRs) of P-gp and BCRP. In conclusion, our study revealed a novel mechanism explaining TGF-ß1-induced MDR in HCC through upregulating P-gp and BCRP via the SMAD4/HOTAIR/miR-145 axis.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , RNA Longo não Codificante/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Sequência de Bases , Transporte Biológico , Células CHO , Carcinoma Hepatocelular/metabolismo , Cricetulus , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HCT116 , Células Hep G2 , Humanos , Mesilato de Imatinib/farmacocinética , Mesilato de Imatinib/farmacologia , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Longo não Codificante/genética
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