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1.
Br J Cancer ; 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34815524

RESUMO

BACKGROUND: Castration-resistant prostate cancer (CRPC) patients frequently develop neuroendocrine differentiation, with high mortality and no effective treatment. However, the regulatory mechanism that connects neuroendocrine differentiation and metabolic adaptation in response to therapeutic resistance of prostate cancer remain to be unravelled. METHODS: By unbiased cross-correlation between RNA-sequencing, database signatures, and ChIP analysis, combining in vitro cell lines and in vivo animal models, we identified that PCK1 is a pivotal regulator in therapy-induced neuroendocrine differentiation of prostate cancer through a LIF/ZBTB46-driven glucose metabolism pathway. RESULTS: Upregulation of PCK1 supports cell proliferation and reciprocally increases ZBTB46 levels to promote the expression of neuroendocrine markers that are conducive to the development of neuroendocrine characteristic CRPC. PCK1 and neuroendocrine marker expressions are regulated by the ZBTB46 transcription factor upon activation of LIF signalling. Targeting PCK1 can reduce the neuroendocrine phenotype and decrease the growth of prostate cancer cells in vitro and in vivo. CONCLUSION: Our study uncovers LIF/ZBTB46 signalling activation as a key mechanism for upregulating PCK1-driven glucose metabolism and neuroendocrine differentiation of CRPC, which may yield significant improvements in prostate cancer treatment after ADT using PCK1 inhibitors.

2.
Oncogenesis ; 10(11): 81, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34799554

RESUMO

Neuroendocrine differentiation (NED) is associated with WNT signaling activation and can be significantly observed after failure of androgen-deprivation therapy (ADT) for prostatic adenocarcinomas. Cytokine signaling is stimulated in NED prostate cancer; however, how ADT-upregulated WNT signaling promotes activation of cytokine signaling and contributes to NED of prostate cancer is poorly understood. In this study, we identified ADT-mediated upregulation of transcription factor 7 like 1 (TCF7L1), which increases the cytokine response and enhances NED of prostate cancer through interleukin (IL)-8/C-X-C motif chemokine receptor type 2 (CXCR2) signaling activation. ADT induced the secretion of WNT4 which upon engagement of TCF7L1 in prostate cancer cells, enhanced IL-8 and CXCR2 expressions. TCF7L1 directly binds to the regulatory sequence region of IL-8 and CXCR2 through WNT4 activation, thus upregulating IL-8/CXCR2 signaling-driven NED and cell motility. Analysis of prostate tissue samples collected from small-cell neuroendocrine prostate cancer (SCPC) and castration-resistant prostate cancer (CRPC) tumors showed an increased intensity of nuclear TCF7L1 associated with CXCR2. Our results suggest that induction of WNT4/TCF7L1 results in increased NED and malignancy in prostate cancer that is linked to dysregulation of androgen receptor signaling and activation of the IL-8/CXCR2 pathway.

3.
Nat Prod Res ; : 1-9, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34498972

RESUMO

A new indole diketopiperazine alkaloid, named penilline D (1), together with five known indole alkaloid analogues (2-5, 11), two meroterpenoids (6 and 12), and four butenolide derivatives (7-10), were isolated from the Antarctic fungus Penicillium sp. SCSIO 05705. Extensive spectroscopic analysis and electronic circular dichroism (ECD) calculation were used to elucidate the structure of penilline D (1), including its absolute configuration. All isolated compounds (1-12) were evaluated for their cytotoxic, antibacterial and enzyme inhibitory activities against acetylcholinesterase (AChE) and pancreatic lipase (PL). Among them, compound 5 exhibited moderate in vitro cytotoxic activity against the 143B cell line with IC50 value of 12.64 ± 0.78 µM. Compound 6 showed strong inhibitory activity against AChE with IC50 value of 0.36 nM (IC50 18.7 nM for Tacrine), while compounds 6 and 11 showed weak PL enzyme inhibitory activity. Furthermore, an in silico molecular docking study was also performed between 6 and AChE.

4.
Nat Prod Res ; : 1-8, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34542359

RESUMO

A new glyoxylate-containing benzene derivative, methyl 2-(4-hydroxy-3-(3'-methyl-2'-butenyl)phenyl)-2-oxoacetate (1), together with ten known compounds (2-11), were isolated from the marine algicolous fungus, Aspergillus sp. SCSIO 41304. Their planar structures and absolute configurations were elucidated by detailed NMR, MS spectroscopic analysis and comparing with literature data. Compound 1 was isolated as a new fungal secondary metabolite, possessing a methyl glyoxylate moiety R-CO-CO-OCH3, which is rare in natural sources. All the isolated compounds (1-11) were tested for their antibacterial and enzyme inhibitory activities against acetylcholinesterase (AChE) and pancreatic lipase (PL). Among these compounds, aspulvinone H (4) showed moderate inhibition against AChE and PL with IC50 values of 25.95 and 47.06 µM, respectively. Further molecular docking simulation exhibited that compound 4 could well bind to the catalytic pockets of the AChE and PL.

5.
Front Oncol ; 11: 672052, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33996600

RESUMO

Posttransplant lymphoproliferative disorder (PTLD) is a rare complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with poor prognosis. We report a patient with PTLD involved central nervous system (CNS) who treated with zanubrutinib, a second-generation Bruton tyrosine kinase (BTK) inhibitor. Our report supports the efficacy of bruton tyrosine kinase inhibitor zanubrutinib in the treatment of CNS-PTLD, which provides a new therapeutic option.

6.
Phytochemistry ; 186: 112730, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33740577

RESUMO

Six undescribed 4-quinolone alkaloids, including four racemic mixtures, (±)-oxypenicinolines A-D, and two related ones, penicinolines F and G, together with seven known analogues, were isolated from the mangrove-derived fungus Penicillium steckii SCSIO 41025 (Trichocomaceae). The racemates were separated by HPLC using chiral columns. Their structures including absolute configurations were elucidated by extensive spectroscopic analysis, electronic circular dichroism (ECD) experiments, and single-crystal X-ray diffraction analysis. Structurally, (±)-oxypenicinolines A-D shared with an unusual 6/6/5/5 tetracyclic system incorporating a rare tetrahydro-pyrrolyl moiety. A plausible biosynthetic pathway for pyrrolyl 4-quinolone alkaloids is proposed. (±)-oxypenicinoline A and quinolactacide displayed α-glucosidase inhibitory activity with the IC50 values of 317.8 and 365.9 µΜ, respectively, which were more potent than that of acarbose (461.0 µM). Additionally, penicinoline and penicinoline E showed weak inhibitions toward acetylcholinesterase (AChE).


Assuntos
Alcaloides , Penicillium , 4-Quinolonas , Fungos , Estrutura Molecular
7.
Commun Biol ; 4(1): 22, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33398073

RESUMO

Nerve growth factor (NGF) contributes to the progression of malignancy. However, the functional role and regulatory mechanisms of NGF in the development of neuroendocrine prostate cancer (NEPC) are unclear. Here, we show that an androgen-deprivation therapy (ADT)-stimulated transcription factor, ZBTB46, upregulated NGF via ZBTB46 mediated-transcriptional activation of NGF. NGF regulates NEPC differentiation by physically interacting with a G-protein-coupled receptor, cholinergic receptor muscarinic 4 (CHRM4), after ADT. Pharmacologic NGF blockade and NGF knockdown markedly inhibited CHRM4-mediated NEPC differentiation and AKT-MYCN signaling activation. CHRM4 stimulation was associated with ADT resistance and was significantly correlated with increased NGF in high-grade and small-cell neuroendocrine prostate cancer (SCNC) patient samples. Our results reveal a role of the NGF in the development of NEPC that is linked to ZBTB46 upregulation and CHRM4 accumulation. Our study provides evidence that the NGF-CHRM4 axis has potential to be considered as a therapeutic target to impair NEPC progression.


Assuntos
Adenocarcinoma/metabolismo , Carcinoma Neuroendócrino/etiologia , Fator de Crescimento Neural/metabolismo , Neoplasias da Próstata/metabolismo , Fatores de Transcrição/metabolismo , Adenocarcinoma/tratamento farmacológico , Antagonistas de Androgênios/efeitos adversos , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Estudos de Casos e Controles , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Células PC-3 , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Receptor Muscarínico M4/metabolismo
8.
Nat Prod Res ; 35(23): 5266-5270, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32264697

RESUMO

Twelve indole alkaloids, including α-cyclopiazonic acid (CPA) (1), nine 2-oxo indole CPA derivatives (2-10), and two open-ring indole CPA derivatives (11 and 12), were isolated from the fermentation broth of a deep-sea derived fungus Aspergillus sp. SCSIO 41024. Their structures and absolute configurations were elucidated mainly by using extensive NMR spectroscopic, mass spectrometric and single crystal X-ray diffraction analysis. To the best of our knowledge, the crystallographic data of 3 and 7 were firstly reported, and the absolute configuration of 3 was confirmed for the first time by the single crystal X-ray diffraction analysis. Most isolated compounds were tested for their antimicrobial, antitumor and radical scavenging activities. In addition, compounds 1, 2 and 11 showed moderate antioxidative activity against DPPH with IC50 values of 190.1, 31.9, 228.4 µg/mL, respectively.

9.
Nat Prod Res ; : 1-8, 2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33356598

RESUMO

A new diketopiperazine, cyclo-(d-8-acetoxyl-Pro-l-Leu) (1), together with eight known compounds (2-9) including three enterotoxins (2-4), four diketopiperazines (5-8) and maltol (9), were isolated from the mangrove derived-soil Streptomyces sp. SCSIO 41400. The planar structures of all compounds were determined from analysis of NMR spectra, MS, optical rotation and comparing with literature data. The absolute configuration of compound 1 was assigned by electronic circular dichroism (ECD). The isolated compounds (1-9) were tested for their acetyl cholinesterase (AChE) and pancreatic lipase (PL) enzyme inhibitory activities. Among them, the new diketopiperazine (1) displayed preferable PL enzyme inhibitory activity with IC50 value of 27.3 µg/mL, while compounds 2, 5 and 6 showed weak PL enzyme inhibitory activity. Further molecular docking simulation exhibited that compound 1 could be well bind with the catalytic pocket of the PL. Besides, compound 9 showed moderate antibacterial activity against Methicillin-resistant Staphylococcus aureus with MIC value of 12.5 µg/mL, which was comparable to that of the positive control ampicillin with MIC value of 3.125 µg/mL.

10.
Oncogene ; 39(44): 6757-6775, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32963351

RESUMO

Neuroendocrine (NE) differentiation is a well-recognized phenotypic change of prostate cancer after androgen deprivation therapy (ADT), and it ultimately develops into an aggressive subset of this disease. However, the contribution of signaling pathways that lead to metabolic disorders and NE differentiation of prostate cancer remains unclear. In this study, we identified that ADT induced upregulation of the succinate-CoA ligase GDP-forming beta subunit (SUCLG2), which regulates succinate metabolism and NE differentiation of prostate cancer. We demonstrated a connection that upregulation of epidermal growth factor receptor (EGFR)-leukemia inhibitory factor receptor (LIFR) signaling induced SUCLG2 expression in prostate cancer cells. The LIFR is upregulated by nuclear EGFR, which acts as a transcriptional regulator, directly binds to the LIFR promoter, and drives NE differentiation and glycolysis of prostate cancer. LIFR upregulation is associated with SUCLG2, which increased succinate synthesis and enzymatic activities of mitochondrial nucleoside diphosphate kinase (NDPK) in prostate cancer cells. Knockdown of SUCLG2 suppressed NE differentiation in cultured cells and reduced prostate tumor growth in a xenograft model. Analysis of prostate tissue samples showed increased intensity of nuclear EGFR associated with the LIFR and SUCLG2 in castration-resistant prostate cancer tumors. Our study provides a mechanism whereby ADT upregulates EGFR-LIFR signaling that activates SUCLG2, which subsequently stimulates the metabolic changes associated with NE differentiation and aggressive prostate cancer phenotype.


Assuntos
Antagonistas de Androgênios/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/genética , Tumores Neuroendócrinos/genética , Neoplasias de Próstata Resistentes à Castração/genética , Succinato-CoA Ligases/metabolismo , Antagonistas de Androgênios/uso terapêutico , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular Tumoral , Núcleo Celular/patologia , Transdiferenciação Celular/efeitos dos fármacos , Transdiferenciação Celular/genética , Receptores ErbB/metabolismo , Técnicas de Silenciamento de Genes , Glicólise/efeitos dos fármacos , Glicólise/genética , Humanos , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/metabolismo , Masculino , Camundongos , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Regiões Promotoras Genéticas , Próstata/efeitos dos fármacos , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Succinato-CoA Ligases/genética , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
ACS Omega ; 5(25): 15620-15630, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32637838

RESUMO

The electronic and vibrational structures of trinickel metal string complexes [Ni3(dpa)4X2]1-,0,1+ (X = Cl, NCS) were investigated using both theoretical calculations and spectroscopic methods. We used the density functional theory (DFT) method B3LYP*-D3, including less exact exchange energy and the van der Waals interaction of metal ions, to obtain the geometries and vibrational structures, which were found to be in excellent agreement with the experimental data. The ground state of Ni3(dpa)4X2 is an antiferromagnetic (AF) singlet state, and the next state is a quintet state, which was detected using temperature-dependent Raman spectroscopy under a magnetic field. The vibrational structure of the quintet state is nearly identical to that of the AF state, according to the measured Raman spectra, except that the stretching of Ni-Cl is blue-shifted from 282.5 cm-1 in the AF state to 283.8 cm-1 in the quintet state. Two oxidized Ni3 complexes were found to have [Ni3]7+ cores, the doublet [Ni3(dpa)4]3+ without axial ligands and the quartet [Ni3(dpa)4X2]+. Complex [Ni3(dpa)4X2]-, which was produced from a reduction reaction by gold nanoparticles at room temperature, consists of a quartet state as the ground state and a doublet state lying nearby.

12.
Med Sci Monit ; 26: e920682, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32187175

RESUMO

BACKGROUND TaohongSiwu decoction (THSWT), a traditional herbal formula, has been used to treat cardiovascular and cerebrovascular diseases such as essential hypertension (EH) in China. However, the pharmacological mechanism is not clear. To investigate the mechanisms of THSWT in the treatment of EH, we performed compounds, targets prediction and network analysis using a network pharmacology method. MATERIAL AND METHODS We selected chemical constituents and targets of THSWT according to TCMSP and UniProtKB databases and collected therapeutic targets on EH from Online Mendelian Inheritance in Man (OMIM), Drugbank and DisGeNET databases. The protein-protein interaction (PPI) was analyzed by using String database. Then network was constructed by using Cytoscape_v3.7.1, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was performed by using Database for Annotation, Visualization and Integrated Discovery (DAVID) software. RESULTS The results of our network pharmacology research showed that the THSWT, composed of 6 Chinese herbs, contained 15 compounds, and 23 genes regulated the main signaling pathways related to EH. Moreover, the PPI network based on targets of THSWT on EH revealed the interaction relationship between targets. These core compounds were 6 of the 15 disease-related compounds in the network, kaempferol, quercetin, luteolin, Myricanone, beta-sitosterol, baicalein, and the core genes contained ADRB2, CALM1, HMOX1, JUN, PPARG, and VEGFA, which were regulated by more than 3 compounds and significantly associated with Calcium signaling pathway, cGMP-PKG signaling pathway, cAMP signaling pathway, PI3K-Akt signaling pathway, Rap1 signaling pathway, and Ras signaling pathway. CONCLUSIONS This network pharmacological study can reveal potential mechanisms of multi-target and multi-component THSWT in the treatment of EH, provide a scientific basis for studying the mechanism.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Hipertensão Essencial/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , China , Bases de Dados Genéticas , Humanos , Mapas de Interação de Proteínas , Resultado do Tratamento
13.
Artigo em Inglês | MEDLINE | ID: mdl-31781277

RESUMO

Objectives: To evaluate the efficacy and safety of compound Kushen injection (CKI) combined with chemo treatment (chemo) for non-small-cell lung cancer (NSCLC). Methods: We systematically searched the literature published in seven databases, including Embase, PubMed, central, MEDLINE, CNKI, Wanfang, and VIP, from their inception to April 2019 for all randomized controlled trials (RCTs) comparing CKI plus chemo with chemo alone in patients with NSCLC. Our main end point was clinical efficiency and the secondary outcomes were Karnofsky performance score (KPS), immune function, and adverse events. The Cochrane risk of bias tool was applied for quality assessment. Results: 10 studies involving 1019 participants were included. The clinical response rate (relative risk (RR) = 1.21, 95% confidence interval (CI): 1.06 to 1.37; P=0.003), KPS (RR = 2.18, 95% CI: 1.49 to 3.17; P < 0.0001), immune function (mean differences (MD) = 0.82, 95% CI: 0.12 to 1.52; P=0.02) and adverse effects (RR = 0.67, 95% CI: 0.60 to 0.74; P < 0.00001) in the CKI plus chemo group showed significant differences when compared with chemo alone. Conclusions: CKI combined with chemo can improve clinical efficiency, KPS, and immune function and reduce adverse reactions in patients with NSCLC when compared with chemo alone. However, more rigorously designed RCTs are needed to validate this benefit, as some of the included RCTs are of low methodological quality.

14.
Environ Pollut ; 254(Pt A): 112848, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31421578

RESUMO

This study demonstrates the use of positive matrix factorization (PMF) in a region with a major Petrochemical Complex, a prominent source of volatile organic compounds (VOCs), as a showcase of PMF applications. The PMF analysis fully exploited the quality and quantity of the observation data, sufficed by a cluster of 9 monitoring sites within a 20 km radius of the petro-complex. Each site provided continuous data of 54 speciated VOCs and meteorological variables. Wind characteristics were highly seasonal and played a decisive role in the source-receptor relationship, hence the dataset was divided into three sub-sets in accordance with the prevailing wind flows. A full year of real-time data were analyzed by PMF to resolve into various distinct source types including petrochemical, urban, evaporative, long-range air parcels, etc., with some sites receiving more petro-influence than others. To minimize subjectivity in the assignment of the PMF source factors, as commonly seen in some PMF works, this study attempted to solidify PMF results by supporting with two tools of spatially/temporally resolved air-quality model simulations and observation data. By exploiting the two supporting tools, the dynamic process of individual sources to a receptor were rationalized. Percent contributions from these sources to the receptor sites were calculated by summing over the occurrence of different source types. Interestingly, although the Petro-complex is the single largest local VOC source in the 20 km radius study domain, all monitoring sites in the region received far less influence from the Petro-complex than from other emission types within or outside the region, which together add up to more than 70% of the total VOC abundance.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar/estatística & dados numéricos , Monitoramento Ambiental/métodos , Compostos Orgânicos Voláteis/análise , Poluição do Ar/análise , Modelos Químicos , Vento
15.
Plant Direct ; 3(8): e00157, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31406958

RESUMO

The competition between L (lip) and SP (sepal/petal) complexes in P-code model determines the identity of complex perianth patterns in orchids. Orchid tetraspanin gene Auxin Activation Factor (AAF) orthologs, whose expression strongly correlated with the expansion and size of the perianth after P code established, were identified. Virus-induced gene silencing (VIGS) of OAGL6-2 in L complex resulted in smaller lips and the down-regulation of Oncidium OnAAF. VIGS of PeMADS9 in L complex resulted in the enlarged lips and up-regulation of Phalaenopsis PaAAF. Furthermore, the larger size of Phalaenopsis variety flowers was associated with higher PaAAF expression, larger and more cells in the perianth. Thus, a rule is established that whenever bigger perianth organs are made in orchids, higher OnAAF/PaAAF expression is observed after their identities are determined by P-code complexes. Ectopic expression Arabidopsis AtAAF significantly increased the size of flower organs by promoting cell expansion in transgenic Arabidopsis due to the enhancement of the efficiency of the auxin response and the subsequent suppression of the jasmonic acid (JA) biosynthesis genes (DAD1/OPR3) and BIGPETAL gene during late flower development. In addition, auxin-controlled phenotypes, such as indehiscent anthers, enhanced drought tolerance, and increased lateral root formation, were also observed in 35S::AtAAF plants. Furthermore, 35S::AtAAF root tips maintained gravitropism during auxin treatment. In contrast, the opposite phenotype was observed in palmitoylation-deficient AtAAF mutants. Our data demonstrate an interaction between the tetraspanin AAF and auxin/JA that regulates the size of flower organs and impacts various developmental processes.

16.
Clin Cancer Res ; 25(13): 4128-4140, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30962287

RESUMO

PURPOSE: The molecular targets for castration-resistant prostate cancer (CRPC) are unknown because the disease inevitably recurs, and therapeutic approaches for patients with CRPC remain less well understood. We sought to investigate regulatory mechanisms that result in increased therapeutic resistance, which is associated with neuroendocrine differentiation of prostate cancer and linked to dysregulation of the androgen-responsive pathway. EXPERIMENTAL DESIGN: The underlying intracellular mechanism that sustains the oncogenic network involved in neuroendocrine differentiation and therapeutic resistance of prostate cancer was evaluated to investigate and identify effectors. Multiple sets of samples with prostate adenocarcinomas and CRPC were assessed via IHC and other assays. RESULTS: We demonstrated that leukemia inhibitory factor (LIF) was induced by androgen deprivation therapy (ADT) and was upregulated by ZBTB46 in prostate cancer to promote CRPC and neuroendocrine differentiation. LIF was found to be induced in patients with prostate cancer after ADT and was associated with enriched nuclear ZBTB46 staining in high-grade prostate tumors. In prostate cancer cells, high ZBTB46 output was responsible for the activation of LIF-STAT3 signaling and neuroendocrine-like features. The abundance of LIF was mediated by ADT-induced ZBTB46 through a physical interaction with the regulatory sequence of LIF. Analysis of serum from patients showed that cases of higher tumor grade and metastatic prostate cancer exhibited higher LIF titers. CONCLUSIONS: Our findings suggest that LIF is a potent serum biomarker for diagnosing advanced prostate cancer and that targeting the ZBTB46-LIF axis may therefore inhibit CRPC development and neuroendocrine differentiation after ADT.


Assuntos
Fator Inibidor de Leucemia/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Fatores de Transcrição/metabolismo , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Modelos Biológicos , Gradação de Tumores , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Ligação Proteica , Receptores Androgênicos/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Zhen Ci Yan Jiu ; 44(1): 19-24, 2019 Jan 25.
Artigo em Chinês | MEDLINE | ID: mdl-30773857

RESUMO

OBJECTIVE: To observe the effect of acupuncture on activities of microglia in traumatic brain injury (TBI) rats. METHODS: Fifty-four male SD rats were randomly and equally divided into normal control, model and acupuncture groups according to the random number table (n=18 rats in each group). The TBI model was established by using a free fall brain injury striking device after exposing the local cranial bone (to induce the left parietal cerebral contusion). Acupoints "Baihui" (GV20), "Shuigou" (GV26), "Fengfu" (GV16), "Yamen" (GV15) and bilateral "Hegu" (LII4) were stimulated intensively by twirling the filiform needles with force at a range of >360° and a frequency of 160-180 cycles/min for 10 sec in every acupoint, once every 5 min during the 15 minutes' needle retaining. The treatment was given once every day for successive 14 days. The rats of the normal and model groups were grabbed and fixed with the same procedure. The behavioral changes were tested using modified neurological severity score (mNSS). The histopathological changes of the injured cerebral cortex tissues were observed by using hematoxylin-eosin (H.E.) staining, and the fluorescence intensity of Iba-1 (marker of microglia) positive products in the surrounding tissue of the cerebral focus was displayed by immunofluorescence staining, and the contents of neuron specific enolate (NSE) and neurite outgrowth inhibitor-A (Nogo-A) in serum (indicating a secondary nerve damage) were assayed by ELISA. RESULTS: The mNSS scores were significantly increased on day 1, 3, 7 and 14 in the model group in comparison with the normal group (P<0.01) and considerably decreased at the 4 time-points after acupuncture intervention relevant to the model group (P<0.05, P<0.01). H.E. staining showed that modeling induced pathological changes such as the excursion of cell nucleus, cellular swel-ling, vacuole-like change, neuron death, karyopyknosis dissolution, and proliferation of fibrous tissue were relatively milder in the acupuncture group. The average fluorescence intensity values of Iba-1-positive products, serum NSE and Nogo-A contents on day 3, 7 and 14 were significantly higher in the model group than in the normal group (P<0.05, P<0.01), and notably down-regulated in the acupuncture group than in the model group (P<0.05, P<0.01, except Nogo-A on day 3). CONCLUSION: Acupuncture intervention may accelerate neurological function recovery in TBI rats, which is closely related to its effects in inhibiting the activation of microglia and secondary nerve damage.


Assuntos
Terapia por Acupuntura , Lesões Encefálicas Traumáticas , Animais , Masculino , Microglia , Proteínas Nogo , Ratos , Ratos Sprague-Dawley
18.
Cancer Lett ; 440-441: 35-46, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30312731

RESUMO

Androgen receptor (AR) targeting is an important therapeutic strategy for treating prostate cancer. Most tumors progress to castration-resistant prostate cancer (CRPC) and develop the neuroendocrine (NE) phenotype under androgen deprivation therapy (ADT). The molecular basis for NE transdifferentiation after ADT remains incompletely understood. Herein, we show that an immunocyte expression protein, ZBTB46, induces inflammatory response gene expression and contributes to NE differentiation of prostate cancer cells. We demonstrated a molecular mechanism whereby ZBTB46 can be regulated by the androgen-responsive gene, SPDEF, and is associated with NE prostate cancer (NEPC) differentiation. In addition, ZBTB46 acts as a transcriptional coactivator that binds to the promoter of prostaglandin-endoperoxide synthase 1 (PTGS1) and transcriptionally regulated PTGS1 levels. Overexpression of ZBTB46 decreases the sensitivity of the combination of enzalutamide and a PTGS1 inhibitor; however, knockdown of ZBTB46 sensitizes the PTGS1 inhibitor and reduces tumor malignancy. ZBTB46 is inversely correlated with SPDEF and is increased in higher tumor grades and small-cell NE prostate cancer (SCNC) patients, which are positively associated with PTGS1. Our findings suggest that the induction of ZBTB46 results in increased PTGS1 expression, which is associated with NEPC progression and linked to the dysregulation of the AR-SPDEF pathway.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Ciclo-Oxigenase 1/metabolismo , Tumores Neuroendócrinos/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Nus , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-ets/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Nanoscale ; 10(35): 16613-16620, 2018 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-30155532

RESUMO

Novel electroactive triphenylamine-based polyamide (PA) films with a purposeful porous structure have been designed and prepared by a simple route. Polymer thin films containing well dispersed electrolyte salts were prepared first, then channels of pores could be generated within the polymer film by washing the salts out. With the help of the porous channels, the diffusion rate between electroactive species and the electrolyte during the electrochemical process could be effectively increased. Consequently, the driving potential and electrochromic response time can be efficiently improved through this approach. Novel porous PA films with optimal results both in optical transparency and electrochemical properties could be readily obtained by choosing a commonly used supporting electrolyte TBABF4 as a salt in this study. When the PA films containing un-washed TBABF4 salt were further assembled into electrochromic devices (ECDs), the salt could then be leached out during the electrochemical redox switching process to form a porous film structure and also serves as a supporting electrolyte in ECDs simultaneously. Therefore, EC performance such as the driving potential and response time could be enhanced obviously by this simplified fabrication procedure of ECDs.

20.
Neuroimage Clin ; 20: 476-484, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30128286

RESUMO

Objective: Neural disruption and cognitive impairment have been reported in patients with carotid stenosis (CS), but carotid artery stenting (CAS) may not contribute to the cognitive recovery. Although functional hyper-connectivity is one of the physiological over-compensation phenomena in neurological diseases, the literature on the cognitive influence of functional hyper-connectivity in CS patients is limited. We aimed to investigate the longitudinal changes of hyper-connectivity after CAS and its association with cognition in CS patients. Methods: Thirteen patients with unilateral CS and 17 controls without CS were included. Cognitive function was evaluated at baseline, and resting-state functional MRI was performed 1 week before and 1 month and 1 year after CAS. Comparisons of functional connectivity (FC) between CS patients and controls in multiple brain networks were performed. Results: In patients before CAS, FC in the cerebral hemispheres ipsilateral and contralateral to CS was mainly decreased and increased, respectively, compared with normal controls. Part of the FC alterations gradually recovered to the normal condition after CAS. The stronger FC abnormality (both hypo- and hyper-connectivity compared with normal controls) was associated with poorer cognitive performances, especially in memory and executive functions. Conclusion: The study demonstrated the lateralization of hyper-connectivity and hypo-connectivity in patients with unilateral CS in contrast to the FC in normal controls. These FC alterations were associated with poor cognitive performances and tended to recover after CAS, implying that hyper-connectivity is served as a compensation for neural challenge.


Assuntos
Encéfalo/diagnóstico por imagem , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/cirurgia , Cognição/fisiologia , Lateralidade Funcional/fisiologia , Reperfusão/métodos , Idoso , Idoso de 80 Anos ou mais , Angioplastia/instrumentação , Angioplastia/métodos , Encéfalo/fisiopatologia , Estenose das Carótidas/fisiopatologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Reperfusão/instrumentação , Stents
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