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1.
Life Sci ; 239: 116951, 2019 Oct 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.

2.
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.

3.
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.

4.
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
5.
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
6.
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.

7.
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
8.
Cell Death Dis ; 10(7): 493, 2019 Jun 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.

9.
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.

10.
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
11.
Chin Med ; 13: 53, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386416

RESUMO

Background: Major depressive disorder (MDD) is a highly heterogeneous disease. Further classification may characterize its heterogeneity. The purpose of this study was to examine whether metabolomic variables could differentiate traditional Chinese medicine (TCM) diagnostic subtypes of MDD. Methods: Fifty medication-free patients who were experiencing a recurrent depressive episode were classified into Liver Qi Stagnation (LQS, n = 30) and Heart and Spleen Deficiency (HSD, n = 20) subtypes according to TCM diagnosis. Healthy volunteers (n = 28) were included as controls. Gas chromatography-mass spectrometry (GC-MS) was used to examine serum and urinary metabolomic profiles. Results: Twenty-eight metabolites were identified for good separations between TCM subtypes and healthy controls in serum samples. Both TCM subtypes had similar profiles in proteinogenic branched-chain amino acids (BCAAs) (valine, leucine, and isoleucine) and energy metabolism-related metabolites that were differentiated from healthy controls. The LQS subtype additionally differed from healthy controls in multiple amino acid metabolites that are involved in biosynthesis of monoamine and amino acid neurotransmitters, including phenylalanine, 3-hydroxybutric acid, o-tyrosine, glycine, l-tryptophan, and N-acetyl-l-aspartic acid. Threonic acid, methionine, stearic acid, and isobutyric acid are differentially associated with the two subtypes. Conclusions: While both TCM subtypes are associated with aberrant BCAA and energy metabolism, the LQS subtype may represent an MDD subpopulation characterized by abnormalities in the biosynthesis of monoamine and amino acid neurotransmitters and closer associations with stress-related pathophysiology. The metabolites differentially associated with the two subtypes are promising biomarkers for predicting TCM subtype-specific antidepressant response [registered at http://www.clinicaltrials.gov (NCT02346682) on January 27, 2015].

12.
J Enzyme Inhib Med Chem ; 33(1): 1554-1564, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30244610

RESUMO

To identify anticancer agents with high potency and low toxicity, a series of (Z)-styrylbenzene derivatives were synthesised and evaluated for anticancer activities using a panel of nine cancer cell lines and two noncancerous cell lines. Most derivatives exhibited significant anti-proliferative activities against five cancer cell lines, including MGC-803 and BEL-7402. (Z)-3-(p-Tolyl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile (6h) showed a strong inhibitory effect on MGC-803 cells (IC50 < 0.01 µM) and exhibited stronger anti-proliferative activity than taxol (IC50 < 0.06 ± 0.01 µM). The IC50 value of 6h in L-02 cells was 10,000-fold higher than in MGC-803 cells. Compound 6h inhibited proliferation of BEL-7402 cells by arresting at the G2/M phase through up-regulation of cyclin B1 expression, down-regulation of cyclin A and D1 expression, and induction of apoptosis. In addition, 6h inhibited the migration of BEL-7402 cells and the formation of cell colonies.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Estilbenos/síntese química , Estilbenos/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Estereoisomerismo , Estilbenos/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
13.
Molecules ; 23(9)2018 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-30177642

RESUMO

The aim of the present study was to determine the cytotoxic effects of a series of novel dehydroepiandrosterone derivatives containing triazole at the C16 position on human cancer cells. The cancer cells used in the present study were A549, Hela, HepG-2, BEL7402, MCF-7, and HCT116. Several of the synthesised compounds exhibited potent antiproliferative effects. The most promising compound was (E)-3-hydroxy-16-((1-(4-iodophenyl)-1H-1,2,3-triazole-4-yl)methylene)-10,13-dimet-hyl-1,3,4,7,8,9,10,11,12,13,15,16-dodecahydro-2H-cyclopenta[a]phenanthren-17(14)-one (compound 2n), which showed considerably high antiproliferative activity in the HepG-2 cell line, with an IC50 value of 9.10 µM, and considerably high activity against the MCF-7 cell line, with an IC50 value of 9.18 µM. Flow cytometry assays demonstrated that compound 2n exerted antiproliferative effects by arresting cells in the G2 phase of the cell cycle and inducing apoptosis.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desidroepiandrosterona/análogos & derivados , Triazóis/síntese química , Triazóis/farmacologia , Células A549 , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Estrutura Molecular , Triazóis/química
14.
Anticancer Drugs ; 29(10): 995-1003, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30106753

RESUMO

The hedgehog-smoothened (HH/SMO) pathway has been proposed as a potential therapeutic target for hematological malignancies. Our previous studies designed a series of HH inhibitors with novel scaffolds distinctive from vismodegib, the first Food and Drug Administration-approved HH inhibitor for the treatment of basal-cell carcinoma and medulloblastoma. In the present study, we evaluated these HH inhibitors against blood cancers and found that HH78 displayed potent activity in suppressing the HH signaling pathway. HH78 competitively bound to SMO and suppressed the transcriptional activity of GLI by the luciferase reporter gene assay and the measurement of HH/SMO-downregulated genes, including cyclin D2, cyclin E, PTCH1, PTCH2, and GLI. HH78 at low micromolar concentrations induced significant cancer cell apoptosis showed by increased caspase-3 activation, annexin V-staining and downregulated prosurvival proteins, including c-Myc, Bcl-2, Mcl-1, and Bcl-xL. In contrast, vismodegib did not show any effects on these apoptotic events. HH78 also suppressed the activation of the AKT/mTOR pathway, which cross-talks with the HH/SMO pathway. Finally, HH78 inhibited the growth of human leukemia K562 in nude mice xenografts with no overt toxicity. Collectively, the present study identified a novel HH inhibitor with great potential for the treatment of hematological malignancies.

15.
Oncol Lett ; 16(3): 3690-3698, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30127979

RESUMO

The objective of the present study was to investigate the tumor-associated vascular changes in hepatocellular carcinoma (HCC) following treatment with transarterial chemoembolization (TACE) combined with sorafenib. The data of 20 patients were retrospectively analyzed. Patients underwent treatment depending on their chosen regimens (orally administered sorafenib was recommended, however the cost prevented some study articipants from selecting this course). Based on this, the patients were divided into TACE combined with sorafenib (TS) (n=10) and TACE-only treatment groups (n=10). Digital subtraction angiography images of all patients were analyzed by 2 radiologists who were blind to the type of treatment administered. The diameters of the hepatic and proper hepatic arteries, and hepatic artery branches (tumor-associated arteries), the splenic, left gastric and gastroduodenal arteries or portal veins (non-tumor-associated arteries) and the number of microvascular vessels were compared prior to and following sorafenib treatment in the TS group, between the first and second sessions of TACE in the TACE-only group and between the TS and TACE-only groups. In the TS group, the diameters of the hepatic and proper hepatic arteries, their branches and the number of microvascular vessels were significantly decreased following sorafenib treatment (P<0.05), while the diameters of the splenic, gastroduodenal and left gastric arteries were not significantly altered (P>0.05). In the TACE-only group, the diameters of the hepatic, proper hepatic, splenic, left gastric and gastroduodenal arteries were not significantly different between the first and second TACE sessions (P>0.05), while the diameters of the hepatic artery branches and the number of microvascular vessels were significantly altered (P<0.05). TACE combined with sorafenib significantly decreased the diameters of the tumor-associated arteries and the number of tumor microvascular vessels when compared with TACE treatment alone (P<0.05). No significant difference in the diameters of the portal vein and its branches between the two groups was observed (P>0.05). Treatment with TACE combined with sorafenib may significantly affect the tumor-associated vasculature compared with treatment with TACE alone in HCC.

16.
Onco Targets Ther ; 11: 4283-4300, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30100735

RESUMO

Background: The aim of this study was to determine the inhibition effects of Radix tetrastigma hemsleyani (RTH) flavonoids on human lung adenocarcinoma A549 cells and the underlying molecular mechanism. RTH is an important Chinese traditional herb that has been widely used in cancer therapy. As an important type of active substance, RTH flavones (RTHF) have been shown to have good antiproliferative effects on various cancer cells. MicroRNAs (miRNAs) are small, noncoding RNA molecules that play important roles in cancer progression and prevention. However, the miRNA profile of RTHF-treated A549 cells has not yet been studied. Materials and methods: The miRNA expression profile changes of A549 cell treated with RTHF were determined using the miRNA-seq analysis. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of differentially expressed miRNAs' (DE-miRNAs) target genes were carried out. Results: In this study, we identified 162 miRNAs that displayed expression changes >1.2-fold in RTHF-treated A549 cells. GO analysis results showed that target genes of DE-miRNAs were significantly enriched in protein binding, binding, cell, cell part, intracellular, cellular process, single-organism process, and single-organism cellular process. Pathway analysis illustrated that target genes of DE-miRNAs are mainly involved in endocytosis, axon guidance, lysosome, melanogenesis, and acute myeloid leukemia pathway. Conclusion: These results may assist in the better understanding of the anticancer effects of RTHF in A549 cells.

17.
Molecules ; 23(5)2018 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-29772747

RESUMO

Compound-3 is an oral monophosphate prodrug of gemcitabine. Previous data showed that Compound-3 was more potent than gemcitabine and it was orally active in a tumor xenograft model. In the present study, the metabolism of Compound-3 was investigated in several well-known in vitro matrices. While relatively stable in human and rat plasma, Compound-3 demonstrated noticeable metabolism in liver and intestinal microsomes in the presence of NADPH and human hepatocytes. Compound-3 could also be hydrolyzed by alkaline phosphatase, leading to gemcitabine formation. Metabolite identification using accurate mass- and information-based scan techniques revealed that Compound-3 was subjected to sequential metabolism, forming alcohol, aldehyde and carboxylic acid metabolites, respectively. Results from reaction phenotyping studies indicated that cytochrome P450 4F2 (CYP4F2) was a key CYP isozyme involved in Compound-3 metabolism. Interaction assays suggested that CYP4F2 activity could be inhibited by Compound-3 or an antiparasitic prodrug pafuramidine. Because CYP4F2 is a key CYP isozyme involved in the metabolism of eicosanoids and therapeutic drugs, clinical relevance of drug-drug interactions mediated via CYP4F2 inhibition warrants further investigation.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacocinética , Família 4 do Citocromo P450/metabolismo , Desoxicitidina/análogos & derivados , Ésteres/farmacocinética , Pró-Fármacos/farmacocinética , Animais , Benzamidinas/farmacocinética , Células Cultivadas , Inibidores das Enzimas do Citocromo P-450/química , Desoxicitidina/química , Desoxicitidina/farmacocinética , Interações de Medicamentos , Ésteres/química , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , NADP/metabolismo , Pró-Fármacos/química , Ratos
18.
Sensors (Basel) ; 18(4)2018 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-29565295

RESUMO

In water-quality, early warning systems and qualitative detection of contaminants are always challenging. There are a number of parameters that need to be measured which are not entirely linearly related to pollutant concentrations. Besides the complex correlations between variable water parameters that need to be analyzed also impairs the accuracy of quantitative detection. In aspects of these problems, the application of least-squares support vector machines (LS-SVM) is used to evaluate the water contamination and various conventional water quality sensors quantitatively. The various contaminations may cause different correlative responses of sensors, and also the degree of response is related to the concentration of the injected contaminant. Therefore to enhance the reliability and accuracy of water contamination detection a new method is proposed. In this method, a new relative response parameter is introduced to calculate the differences between water quality parameters and their baselines. A variety of regression models has been examined, as result of its high performance, the regression model based on genetic algorithm (GA) is combined with LS-SVM. In this paper, the practical application of the proposed method is considered, controlled experiments are designed, and data is collected from the experimental setup. The measured data is applied to analyze the water contamination concentration. The evaluation of results validated that the LS-SVM model can adapt to the local nonlinear variations between water quality parameters and contamination concentration with the excellent generalization ability and accuracy. The validity of the proposed approach in concentration evaluation for potassium ferricyanide is proven to be more than 0.5 mg/L in water distribution systems.

19.
Eur J Med Chem ; 149: 110-121, 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29499483

RESUMO

Embryonic stem cell pathways such as hedgehog and Wnt pathways are central to the tumorigenic properties of cancer stem cells (CSC). Since CSCs are characterized by their ability to self-renew, form differentiated progeny, and develop resistance to anticancer therapies, targeting the Wnt and hedgehog signaling pathways has been an important strategy for cancer treatment. Although molecules targeting either Wnt or hedgehog are common, to the best of our knowledge, those targeting both pathways have not been documented. Here we report a small molecule (compound 1) that inhibits both Wnt (IC50 = 0.5 nM) and hedgehog (IC50 = 71 nM) pathways based on reporter gene assays. We further identified that the molecular target of 1 for Wnt pathway inhibition was porcupine (a member of the membrane-bound O-acyltransferase family of proteins), a post-translational modification node in Wnt signaling; while the target of 1 mitigating hedgehog pathway was Smoothened, a key G protein coupled receptor (GPCR) mediating hedgehog signal transduction. Preliminary analysis of structure-activity-relationship identified key functional elements for hedgehog/Wnt inhibition. In in vivo studies, compound 1 demonstrated good oral exposure and bioavailability while eliciting no overt toxicity in mice. An important consideration in cancer treatment is the potential therapeutic escape through compensatory activation of an interconnected pathway when only one signaling pathway is inhibited. Toward this end, compound 1 may not only lead to the development of new therapeutics for Wnt and hedgehog related cancers, but may also help to develop potential cancer treatment which needs to target Wnt and hedgehog signaling simultaneously.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Proteínas Hedgehog/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Aciltransferases/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Proteínas Hedgehog/metabolismo , Humanos , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Receptor Smoothened/antagonistas & inibidores , Relação Estrutura-Atividade
20.
Phytomedicine ; 41: 54-61, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29519319

RESUMO

BACKGROUND: Gnaphalium affine D. Don is a folk medicine of China believed to be efficacious in the treatment of many ailments, including hyperuricemia and gout. PURPOSE: Based on a previous study, we isolated two flavones, luteolin and luteolin-4'-O-glucoside, from G. affine. Our aim was to assess the potential beneficial effects of treatment and mechanisms of these two flavones on hyperuricemia and acute gouty arthritis. METHODS: The model of potassium oxonate (PO)-induced hyperuricemia and monosodium urate (MSU) crystal-induced inflammation in mice has been established. We evaluated serum uric acid (Sur), xanthine oxidase (XO) activity, protein expression of urate transporter 1 (mURAT1) and glucose transporter 9 (mGLUT9) in renal and kidney protection in a hyperuricemia model. In addition, paw swelling and levels of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in serum were assessed in MSU crystal-induced mice. RESULTS: Luteolin and luteolin-4'-O-glucoside showed a potent clinical effect in treating hyperuricemia and gout. We observed that the two flavones possess potent effect in hyperuricemia mice by decreasing the level of mURAT1 and inhibiting XO activity, which contribute to enhancing uric acid (UA) excretion and improving hyperuricemia-induced renal dysfunction. In addition, luteolin and luteolin-4'-O-glucoside also alleviated paw swelling and inflammation induced by MSU crystals. Further investigation implied that luteolin and luteolin-4'-O-glucoside improved the symptoms of inflammation by decreasing the levels of IL-1ß and TNF-α. CONCLUSION: The present study suggests that luteolin and luteolin-4'-O-glucoside could be developed as therapeutics for treating hyperuricemia and gouty arthritis.


Assuntos
Artrite Gotosa/tratamento farmacológico , Glucosídeos/farmacologia , Gnaphalium/química , Hiperuricemia/tratamento farmacológico , Luteolina/farmacologia , Animais , Artrite Gotosa/induzido quimicamente , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Edema/tratamento farmacológico , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hiperuricemia/metabolismo , Interleucina-1beta/metabolismo , Rim/metabolismo , Masculino , Camundongos Endogâmicos ICR , Transportadores de Ânions Orgânicos/metabolismo , Ácido Úrico/sangue , Ácido Úrico/toxicidade , Xantina Oxidase/metabolismo
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