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1.
Nucl Med Commun ; 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32404643

RESUMO

INTRODUCTION: The key point for botulinum toxin type A injection in treating cervical dystonia is to accurately identify dystonic muscles. This study aimed to evaluate the efficacy of technetium-sestamibi single-photon emission computed tomography in identifying target muscles in cervical dystonia. METHODS: In the study group (n = 18), target muscles were selected according to clinical evaluation combined with technetium-sestamibi single-photon emission computed tomography, while in the control group (n = 18), target muscles were selected by clinical evaluation alone. All patients were followed-up at 2 weeks, 1, 3, and 6 months after botulinum toxin type A injection. The primary outcomes were the reduction rates in Toronto Western Spasmodic Torticollis Rating Scale and Tsui score at 1 month. RESULTS: Although the reduction rates in Toronto Western Spasmodic Torticollis Rating Scale and Tsui scores were not different between the two groups at 2 weeks and 1 month, the reduction rates in both scores were significantly higher in the study group at 3 and 6 months. The number of patients receiving re-injection within 6 months was significantly lower in the study group. Also, the re-injection interval was significantly longer in the study group. In the study group, more deep cervical muscles were injected, which concerns especially semispinalis capitis, longissimus capitis, and obliques capitis inferior muscles. CONCLUSION: technetium-sestamibi single-photon emission computed tomography is a useful method for screening target muscles in cervical dystonia. It helps clinicians draw a 'blueprint' for the distribution of dystonic muscles before botulinum toxin type A injection.

2.
Exp Neurol ; 330: 113325, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32325158

RESUMO

Exosomes (EXs) are emerging as novel players in the beneficial effects induced by exercise on vascular diseases. We have recently revealed that moderate exercise enhances the function of circulating endothelial progenitor cell-derived EXs (cEPC-EXs) on protecting endothelial cells against hypoxia injury. However, the relationship between the changes of cEPC-EXs and the effects of exercise on ischemic stroke (IS) is unknown. Here, we investigated whether exercise-regulated EPC-EXs contribute to the beneficial effects of exercise on IS. C57BL/6 mice received moderate treadmill exercise (10 m/min) for 4-wks and then were subjected to middle cerebral artery occlusion (MCAO) stroke. The neurologic deficit score (NDS), infarct volume, microvessel density, cell apoptosis, angiogenesis/neurogenesis, sensorimotor functions were determined on day 2 (acute stage) and/or day 28 (chronic stage) post-stroke. The miR-126 and EPC-EX levels were analyzed by RT-PCR or nanoparticle tracking analysis combined with microbeads and used for correlation analyses. The function of EPC-EXs from exercised mice was detected in a hypoxia neuron model. Cell apoptosis, axon growth ability and gene expressions (cas-3 and Akt) were measured. Our data showed that: i) On day 2, exercised mice had decreased NDS and infarct volume, reduced cell apoptosis rate and cleaved cas-3 level, and a higher microvessel density than those in control (no-exercise) mice. The levels of EPC-EXs in plasma and brain tissue were raised and positively correlated in exercised mice. Meanwhile, the miR-126 level in cEPC-EXs and in ischemic tissue were upregulated in exercised mice. The EPC-EXs and their carried miR-126 levels negatively correlated with the infarct volume and cell apoptosis, whereas positively correlated with microvessel density. In addition, cEPC-EXs from exercised mice elicited protective effects on neurons against hypoxia-induced apoptosis and compromised axon growth ability which were blocked by miR-126 and PI3k inhibitors in vitro. ii) On day 28, exercised mice had less infarct volume, higher microvessel density, angiogenesis/neurogenesis and better sensorimotor functions. The levels of BDNF, p-TrkB/TrkB and p-Akt/Akt were upregulated in the brain of exercised mice. These recovery indexes correlated with the levels of cEPC-EXs and their miR-126. In conclusion, our data suggest that moderate exercise intervention has protective effects on the brain against MCAO-induced ischemic injury in both acute and chronic stages which might via the release of miR-126 enriched EPC-EXs.

3.
J Phys Chem Lett ; : 3422-3429, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32283032

RESUMO

Multiphase reactions of halide ions in aqueous solutions exposed to the atmosphere initiate the formation of molecular halogen compounds in the gas phase. Their photolysis leads to halogen atoms, which are catalytic sinks for ozone, making these processes relevant for the regional and global tropospheric ozone budget. The affinity of halide ions in aqueous solution for the liquid-gas interface, which may influence their reactivity with gaseous species, has been debated. Our study focuses on the surface properties of the bromide ion and its oxidation products. In situ X-ray photoelectron spectroscopy carried out on a liquid jet combined with classical and first-principles molecular dynamics calculations was used to investigate the interfacial depth profile of bromide, hypobromite, hypobromous acid, and bromate. The simulated core electron binding energies support the experimentally observed values, which follow a correlation with bromine oxidation state for the anion series. Bromide ions are homogeneously distributed in the solution. Hypobromous acid, a key species in the multiphase cycling of bromine, is the only species showing surface propensity, which suggests a more important role of the interface in multiphase bromine chemistry than thought so far.

4.
G3 (Bethesda) ; 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32276960

RESUMO

FUS is a nucleic acid binding protein that, when mutated, cause a subset of familial amyotrophic lateral sclerosis (ALS). Expression of FUS in yeast recapitulates several pathological features of the disease-causing mutant proteins, including nuclear to cytoplasmic translocation, formation of cytoplasmic inclusions, and cytotoxicity. Genetic screens using the yeast model of FUS have identified yeast genes and their corresponding human homologs suppressing FUS induced toxicity in yeast, neurons and animal models. To expand the search for human suppressor genes of FUS induced toxicity, we carried out a genome-scale genetic screen using a newly constructed library containing 13570 human genes cloned in an inducible yeast-expression vector. Through multiple rounds of verification, we found 37 human genes that, when overexpressed, suppress FUS induced toxicity in yeast. Human genes with DNA or RNA binding functions are overrepresented among the identified suppressor genes, supporting that perturbations of RNA metabolism is a key underlying mechanism of FUS toxicity.

5.
J Appl Toxicol ; 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32207180

RESUMO

Superparamagnetic iron oxide nanoparticles (SPIONs) are extensively applied in biomedical fields, such as magnetic resonance imaging and as nanocarriers. However, the biosafety of SPIONs is not completely established, especially their effect on the immune system and inflammatory responses. Toll-like receptor (TLR) signaling is essential for many acute and chronic human inflammatory diseases. Regulation of TLR responses with drugs is helpful for these inflammatory conditions. In this study, we investigated the effects of 10 and 30 nm SPIONs on macrophages in the presence or absence of the TLR4 agonist lipopolysaccharide (LPS). We found that SPIONs inhibited the release of inflammatory cytokines induced by LPS both in murine and human macrophages in a concentration-dependent manner. Meanwhile, SPIONs suppressed inducible nitric oxide synthase expression activated by SPIONs in RAW264.7 macrophages. Additionally, TLR4 mRNA transcription and expression were attenuated with SPIONs treatment, which positively correlated with the release of inflammatory cytokines. In summary, our study demonstrates that SPIONs can suppress inflammatory responses, and the underlying mechanism may be regulated by TLR4 expression. Our present work contributes to clarifying the biosafety of SPIONs and provides a potential approach to alleviate human inflammatory diseases.

6.
Oxid Med Cell Longev ; 2020: 4213541, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32051731

RESUMO

Angiotensin-converting enzyme 2 (ACE2) is an emerging cardiovascular protective target that mediates the metabolism of angiotensin (Ang) II into Ang (1-7). Our group has demonstrated that ACE2 overexpression enhances the function of endothelial progenitor cells (EPCs). Here, we investigated whether ACE2-primed EPCs (ACE2-EPCs) can protect cerebral microvascular endothelial cells (ECs) against injury and dysfunction in an in vitro model, with focusing on their exosomal and cytokine paracrine effects on endothelial mitochondria. Human EPCs were transfected with lentivirus containing null or human ACE2 cDNA (denoted as Null-EPCs and ACE2-EPCs, respectively). Their conditioned culture media, w/wo depletion of exosomes (ACE2-EPC-CMEX-, Null-EPC-CMEX-, ACE2-EPC-CM, and Null-EPC-CM), were used for coculture experiments. EC injury and dysfunction model was induced by Ang II before coculture. Apoptosis, angiogenic ability, mitochondrion functions (ROS production, membrane potential, fragmentation), and gene expressions (ACE2, Nox2, and Nox4) of ECs were analyzed. The supernatant was collected for measuring the levels of ACE2, Ang II/Ang-(1-7), and growth factors (VEGF and IGF). Our results showed that (1) ACE2-EPC-CM had higher levels of ACE2, Ang (1-7), VEGF, and IGF than that of Null-EPC-CM. (2) Ang II-injured ECs displayed an increase of apoptotic rate and reduction in tube formation and migration abilities, which were associated with ACE2 downregulation, Ang II/Ang (1-7) imbalance, Nox2/Nox4 upregulation, ROS overproduction, an increase of mitochondrion fragmentation, and a decrease of membrane potential. (3) ACE2-EPC-CM had better protective effects than Null-EPC-CM on Ang II-injured ECs, which were associated with the improvements on ACE2 expression, Ang II/Ang (1-7) balance, and mitochondrial functions. (4) ACE2-EPC-CMEX- and Null-EPC-CMEX- showed reduced effects as compared to ACE2-EPCs-CM and Null-EPCs-CM. In conclusion, our data demonstrate that ACE2 overexpression can enhance the protective effects of EPCs on ECs injury, majorly through the exosomal effects on mitochondrial function.

8.
Int J Nanomedicine ; 14: 9577-9586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824152

RESUMO

Purpose: Quantum dots (QDs) are widely used semiconductor nanomaterials. Indium phosphide/zinc sulfide (InP/ZnS) QDs are becoming potential alternatives to toxic heavy metal-containing QDs. However, the potential toxicity and, in particular, the immunotoxicity of InP/ZnS QDs are unknown. This study aimed to investigate the impacts of InP/ZnS QDs on inflammatory responses both in vivo and in vitro. Methods: Mice and mouse bone marrow-derived macrophages (BMMs) were exposed to polyethylene glycol (PEG) coated InP/ZnS QDs. The infiltration of neutrophils and the release of interleukin-6 (IL-6) were measured using a hematology analyzer and an enzyme-linked immunosorbent assay (ELISA) for the in vivo test. Cytotoxicity, IL-6 secretion, oxidative stress and endoplasmic reticulum (ER) stress were studied in the BMMs, and then, inhibitors of oxidative stress and ER stress were used to explore the mechanism of the InP/ZnS QDs. Results: We found that 20 mg/kg PEG-InP/ZnS QDs increased the number of neutrophils and the levels of IL-6 in both peritoneal lavage fluids and blood, which indicated acute phase inflammation in the mice. PEG-InP/ZnS QDs also activated the BMMs and increased the production of IL-6. In addition, PEG-InP/ZnS QDs triggered oxidative stress and the ER stress-related PERK-ATF4 pathway in the BMMs. Moreover, the inflammatory response caused by the PEG-InP/ZnS QDs could be attenuated in the macrophages by blocking the oxidative stress or the ER stress with inhibitors. Conclusion: InP/ZnS QDs can activate macrophages and induce acute phase inflammation both in vivo and in vitro, which may be regulated by oxidative stress and ER stress. Our present work is expected to help clarify the biosafety of InP/ZnS QDs and promote their safe application in biomedical and engineering fields.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Índio/farmacologia , Macrófagos/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosfinas/farmacologia , Pontos Quânticos/química , Sulfetos/farmacologia , Compostos de Zinco/farmacologia , Animais , Feminino , Depuradores de Radicais Livres/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/genética , Inflamação/patologia , Interleucina-6/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Pontos Quânticos/ultraestrutura , Espécies Reativas de Oxigênio/metabolismo
9.
J Phys Chem Lett ; 10(23): 7433-7438, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31725306

RESUMO

The interaction of water with TiO2 is of substantial scientific and technological interest as it determines the activity of TiO2 in photocatalytic and environmental applications in nanoparticle suspensions in water, in complex appliances, or in pure form interacting with water vapor. The influence of TiO2 nanoparticles on the hydrogen bonding structure of water molecules is an important factor that controls hydration of other species, reactions, or nucleation processes. We use a combination of ambient-pressure X-ray photoelectron spectroscopy and electron yield near-edge X-ray absorption fine structure (NEXAFS) spectroscopy at the oxygen K-edge to investigate the hydrogen bonding structure of adsorbed water on titania nanoparticles in equilibrium with nearly saturated water vapor at 235 K. The results clearly show that the net NEXAFS spectrum of adsorbed water resembles that of liquid, disordered water at 235 K, a temperature at which both homogeneous and heterogeneous freezing of bulk water is anticipated.

10.
Mol Imaging Biol ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31721006

RESUMO

PURPOSE: This study aimed to evaluate the usefulness of [99mTc]sestamibi ([99mTc]MIBI) single photon emission computed tomography (SPECT)/X-ray computed tomography (CT) imaging for the identification of dystonic muscles in primary cervical dystonia (PCD) patients who underwent botulinum neurotoxin type A (BoNT-A) therapy. PROCEDURES: Thirty-six patients with PCD and 10 healthy subjects (control group) who underwent [99mTc]MIBI SPECT/CT were enrolled. The image characteristics of dystonic muscles and normal muscles were evaluated. Muscle/background ratio (MBR) of six representative muscles was calculated for dystonic muscles in PCD group and normal muscles in control group. In PCD patients, target muscles injected with BoNT-A were selected by clinical evaluations and the results of needle electromyography (EMG) were considered as the gold standard. The sensitivity, specificity, and diagnostic efficacy of SPECT/CT were obtained from the receiver operator characteristic (ROC) curve. RESULTS: Twenty-four PCD patients were included in our study eventually, because three PCD patients whose follow-up were lost and 9 PCD patients whose maximum reduction of Tsui scale scores was < 80 % were ruled out. Normal muscles of healthy subjects showed mild symmetrical radioactivity distribution, while in PCD patients, [99mTc]MIBI uptake in dystonic muscles abnormally increased. The mean MBRs of dystonic muscles were significantly higher than those of normal muscles. The sensitivity, specificity, and area under the curve (AUC) of SPECT/CT were 93.2 %, 88.5 %, and 0.908, respectively. CONCLUSIONS: Our study indicated that [99mTc]MIBI SPECT/CT may be a useful method for identifying dystonic muscles and a guide to BoNT-A therapy in PCD patients.

11.
Cancer Lett ; 460: 1-9, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31207320

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, which ranks as the sixth of cancer-related death. Despite the emergence of targeted therapy, advanced-stage HCC remains largely incurable due to low response rate and therapeutic resistance. In this review, we mainly focused on the current progression of multi-kinase inhibitors and immunotherapies in the treatment of HCC. We highlight the mechanism underlying the ineffectiveness of these targeted therapies, including oncogenic alterations in driver genes and downstream pathways, high heterogeneity of HCC, and the mutual interaction of tumor microenvironment that promotes therapeutic resistance. We also discussed how these previous studies suggested for future therapeutic strategies. Besides, the complexity of HCC heterogeneity and cancer revolution need to be recognized in personalized therapy. Establishment of a drug screening system and identification of biomarkers of response is also in urgent need to overcome drug resistance. Meanwhile, a combination of targeted therapies could also be explored as a promising strategy in the future.

12.
Acta Pharmacol Sin ; 40(9): 1219-1227, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31235819

RESUMO

Honokiol (HNK), an active compound isolated from traditional Chinese medicine Magnolia officinalis, has shown potent anticancer activities. In the present study, we investigated the effects of HNK on breast cancer metastasis in vitro and in vivo, as well as the underlying molecular mechanisms. We showed that HNK (10-70 µmol/L) dose-dependently inhibited the viability of human mammary epithelial tumor cell lines MCF7, MDA-MB-231, and mouse mammary tumor cell line 4T1. In the transwell and scratch migration assays, HNK (10, 20, 30 µmol/L) dose-dependently suppressed the invasion and migration of the breast cancer cells. We demonstrated that HNK (10-50 µmol/L) dose-dependently upregulated the epithelial marker E-cadherin and downregulated the mesenchymal markers such as Snail, Slug, and vimentin at the protein level in breast cancer cells. Using a puromycin incorporation assay, we showed that HNK decreased the Snail translation efficiency in the breast cancer cells. In a mouse model of tumor metastasis, administration of HNK (50 mg/kg every day, intraperitoneal (i.p.), 6 times per week for 30 days) significantly decreased the number of metastatic 4T1 cell-derived nodules and ameliorated the histological alterations in the lungs. In addition, HNK-treated mice showed decreased Snail expression and increased E-cadherin expression in metastatic nodules. In conclusion, HNK inhibits EMT in the breast cancer cells by downregulating Snail and Slug protein expression at the mRNA translation level. HNK has potential as an integrative medicine for combating breast cancer by targeting EMT.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Lignanas/uso terapêutico , Fatores de Transcrição da Família Snail/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Compostos de Bifenilo/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Humanos , Lignanas/farmacologia , Neoplasias Pulmonares/secundário , Camundongos Endogâmicos BALB C
13.
J Nat Prod ; 82(5): 1391-1395, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31013089

RESUMO

Raistrickindole A (1), a new indole diketopiperazine alkaloid containing an unusual pyrazino[1',2':2,3][1,2]oxazino[6,5- b]indole tetraheterocyclic ring system, a new benzodiazepine derivative, raistrickin (2), and the known haenamindole (3) and sclerotigenin (4) were isolated from the marine-derived fungus Penicillium raistrickii IMB17-034. Their structures were elucidated by extensive spectroscopic analyses and TDDFT calculations of the NMR and ECD data. Compounds 1 and 2 showed inhibitory activities against the hepatitis C virus.

14.
Cancer Lett ; 454: 14-25, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-30910587

RESUMO

Patients receiving sorafenib treatment for hepatocellular carcinoma (HCC) experience different treatment efficacy. Personalized sorafenib treatment should be achieved through the identification of predictors of therapeutic response. In the current study, we found that high UGT1A9 expression indicated better prognosis for HCC patients treated with sorafenib after surgery. In silico analysis predicted microRNA-200a/-183 as potential regulators of the UGT1A gene family via binding to the shared UGT1A9 3'-UTR. A significant inverse correlation between microRNA-200a/-183 and UGT1A9 mRNA level was observed in a panel of HCC specimens. Direct binding was further demonstrated by luciferase reporter gene vector carrying wild-type or binding site truncated UGT1A9 3'-UTR. MicroRNA-200a/-183 downregulated UGT1A9 expression in a dose-dependent manner and significantly reduced sorafenib ß-D-glucuronide formation in HCC cells. These data indicated that UGT1A9, under epigenetic regulation of microRNA-200a/-183, could predict patients who might benefit from adjuvant sorafenib treatment after surgery.

15.
Oncol Lett ; 17(3): 3203-3210, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30867750

RESUMO

Activation of brown adipose tissue (BAT) is an effective strategy for treating obesity. Hepatocellular carcinoma (HCC) is a life-threatening hepatic malignancy with a high mortality rate. Considering that obesity is a risk factor for HCC, the aim of the present study was to investigate the association between HCC and BAT. Using a mouse model, H22 transplantation led to an increase in liver weight, a decrease in the weight of BAT and white adipose tissue, and an increase in the serum level of triacylglycerol (TG). In the in vivo BAT excision model, the removal of BAT led to increased growth of H22 tumors, which was accompanied by a more marked increase in liver weight and in the serum level of TG. The in vitro and in vivo intervention models with primary brown adipose cells (BACs) indicated that primary BACs can directly decrease the viability of H22 cells and the growth of tumors. In conclusion, BAT is a protective organ or tissue against HCC, and BACs may be a potential therapeutic tool for the treatment of HCC.

16.
Skelet Muscle ; 9(1): 8, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30922397

RESUMO

BACKGROUND: Cancer cachexia as a metabolic syndrome can lead to at least 25% of cancer deaths. The inhibition of muscle atrophy is a main strategy to treat cancer cachexia. In this process, myostatin (MSTN) can exert a dual effect on protein metabolism, including inhibition of protein biosynthesis and enhancement of protein degradation. In this study, we will test the effect on muscle atrophy induced by cancer cachexia of IMB0901, a MSTN inhibitor. METHODS: Two high-throughput screening models against MSTN were developed. By screening, IMB0901, 2-((1-(3,4-dichlorophenyl)-1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) butan-1-ol, was picked out from the compound library. The in vitro cell model and the C26 animal model of muscle atrophy induced by cancer cachexia were used to determine the pharmacological activity of IMB0901. Whether IMB0901 could inhibit the aggravating effect of doxorubicin on muscle wasting was examined in vitro and in vivo. RESULTS: IMB0901 inhibited the MSTN promoter activity, the MSTN signaling pathway, and the MSTN positive feedback regulation. In atrophied C2C12 myotubes, IMB0901 had a potent efficiency of decreasing MSTN expression and modulating MSTN signaling pathway which was activated by C26-conditioned medium (CM). In C2C12 myotubes, the expressions of three common myotube markers, myosin heavy chain (MyHC), myogenic differentiation 1 (MyoD), and myogenin (MyoG), were downregulated by CM, which could be efficiently reversed by IMB0901 via reduction of ubiquitin-mediated proteolysis and enhancement of AKT/mTOR-mediated protein synthesis. In the C26 animal model, IMB0901 mitigated the weight loss of body, quadricep and liver, and protected the quadriceps cell morphology. Furthermore, IMB0901 decreased the expression of two E3 ligases Atrogin-1 and MuRF-1 in the quadriceps in vivo. At the cellular level, IMB0901 had no influence on anti-tumor effect of three chemotherapeutic agents (cisplatin, doxorubicin, and gemcitabine) and lowered doxorubicin-induced upregulation of MSTN in C2C12 myotubes. IMB0901 did not affect the inhibitory effect of doxorubicin on C26 tumor and delayed the weight loss of muscle and adipose tissue caused by C26 tumor and doxorubicin. CONCLUSIONS: IMB0901 inhibits muscle atrophy induced by cancer cachexia by suppressing ubiquitin-mediated proteolysis and promoting protein synthesis. These findings collectively suggest that IMB0901 is a promising leading compound for the management of muscle atrophy induced by cancer cachexia.


Assuntos
Caquexia/complicações , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Miostatina/antagonistas & inibidores , Miostatina/metabolismo , Neoplasias/complicações , Animais , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação para Baixo , Doxorrubicina/farmacologia , Células HEK293 , Humanos , Proteínas Musculares/metabolismo , Atrofia Muscular/etiologia , Regiões Promotoras Genéticas , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima
17.
Mar Drugs ; 17(1)2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30669360

RESUMO

Tetracenomycin X (Tcm X) has been reported to have antitumour activity in various cancers, but there have not been any studies on its activity with respect to lung cancer to date. Therefore, this study aims to investigate the anti-lung cancer activity of Tcm X. In this study, we found that tetracenomycin X showed antitumour activity in vivo and selectively inhibited the proliferation of lung cancer cells without influencing lung fibroblasts. In addition, apoptosis and autophagy did not contribute to the antitumour activity. Tetracenomycin X exerts antitumour activity through cell cycle arrest induced by the downregulation of cyclin D1. To explore the specific mechanism, we found that tetracenomycin X directly induced cyclin D1 proteasomal degradation and indirectly downregulated cyclin D1 via the activation of p38 and c-JUN proteins. All these findings were explored for the first time, which indicated that tetracenomycin X may be a powerful antimitotic class of anticancer drug candidates for the treatment of lung cancer in the future.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Organismos Aquáticos/química , Ciclina D1/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Células A549 , Actinobacteria/química , Antibióticos Antineoplásicos/isolamento & purificação , Antibióticos Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos , Humanos , Pulmão/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Naftacenos/isolamento & purificação , Naftacenos/farmacologia , Naftacenos/uso terapêutico , Proteólise/efeitos dos fármacos
18.
Med Sci Sports Exerc ; 50(10): 2024-2032, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30222687

RESUMO

PURPOSE: Exercise has cardiovascular benefits which might be related to endothelial progenitor cells (EPC). Meanwhile, there is evidence suggesting that EPC-derived exosomes (EPC-EX) promote vascular repair and angiogenesis through their carried microRNA (miR)-126. In this study, we investigated whether exercise could increase the levels of circulating EPC-EX and their miR-126 cargo, and by which promote the protective function of EPC-EX on endothelial cells (EC). METHODS: Plasma EPC-EX from sedentary, low, or moderate exercise mice, respectively, denoted as EPC-EX, EPC-EX, and EPC-EX, were isolated using microbead-based sorting techniques and characterized by nanoparticle tracking analysis, Western blot, and quantitative real-time polymerase chain reaction assessments of biomarkers and miR-126. High glucose (25 mM) with hypoxia (1% O2) was used for inducing an EC injury model. The injured EC were treated by coculturing with vehicle, EPC-EX, EPC-EX, EPC-EX, or EPC-EX + anti-miR-126. After that, EC were used for flow cytometry analysis of apoptosis, assessments of tube formation and migration, and measurements of miR-126 level and its downstream sprouty-related protein-1 (SPRED1) and vascular endothelial growth factor (VEGF). RESULTS: 1) Isolated EPC-EX positively expressed exosomal markers (CD63 and Tsg101) and EPC markers (CD34 and VEGFR2). 2) Exercise intensity dependently elevated plasma level of EPC, EPC-EX/EPC ratio, and miR-126 expression in EPC and EPC-EX. 3) Injured EC displayed apoptosis increment, angiogenic dysfunction and miR-126 reduction. 4) EPC-EX had better effects than EPC-EX and EPC-EX on alleviating those changes of injured EC, accompanied with SPRED1 downregulation and VEGF upregulation. 5) The effects of EPC-EX were abolished by miR-126 knockdown. CONCLUSIONS: Our data demonstrate that exercise can increase EPC-EX release and miR-126 level and enhance the effects of EPC-EX on protecting EC against injury through the SPRED1/VEGF pathway.


Assuntos
Células Progenitoras Endoteliais/metabolismo , Exossomos/metabolismo , MicroRNAs/metabolismo , Condicionamento Físico Animal , Animais , Apoptose , Hipóxia Celular , Movimento Celular , Células Cultivadas , Meios de Cultura , Glucose , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Proteínas Repressoras/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
Biomed Pharmacother ; 106: 1396-1403, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30119212

RESUMO

Osteosarcoma is the most common primary bone malignancy, mainly occurring in children and adolescents. Cytoskeleton-associated protein 2 (CKAP2), which plays important roles in cell proliferation, has been reported to be overexpressed in diverse human cancers. In the present study, we aimed at exploring the expression and functions of CKAP2 in osteosarcoma. The mRNA and protein expression of CKAP2 was analyzed on collected osteosarcoma and control bone cyst tissues. The results indicated that CKAP2 expression was remarkably elevated in osteosarcoma tissues compared with bone cysts tissues. The expression level of CKAP2 in osteosarcoma was associated with overall survival, tumor size and tumor stage. In addition, down-regulation of CKAP2 by RNA interference in osteosarcoma cell lines, MG63 and SW1353, caused a remarkable inhibition in cell proliferation in vitro and xenograft growth in nude mice. Silencing of CKAP2 also significantly induced G0/G1 arrest and cell apoptosis of osteosarcoma cells. Furthermore, phosphorylation levels of Janus kinase 2 (JAK2) and Signal transducers and activators of transcription 3 (STAT3) were significantly reduced in CKAP2 knockdown cells. The expression of downstream targets of JAK2/STAT3 signaling, Cyclin D1, Bcl-2 and survivin, was also decreased in CKAP2 knockdown cells. Such aberrations can be rescued by re-expression of RNAi-resistant CKAP2. Collectively, the present study indicates that CKAP2 is a potential oncogene by targeting JAK2/STAT3 signaling, and that CKAP2 may serve as a novel target for osteosarcoma therapy.


Assuntos
Apoptose , Neoplasias Ósseas/genética , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Proteínas do Citoesqueleto/genética , Osteossarcoma/genética , Interferência de RNA , Adolescente , Animais , Cistos Ósseos/genética , Cistos Ósseos/metabolismo , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular , Proteínas do Citoesqueleto/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Janus Quinase 2/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fosforilação , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Fatores de Tempo , Carga Tumoral
20.
J Vis Exp ; (137)2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-30035772

RESUMO

Budding yeast has been widely used as a model in studying proteins associated with human diseases. Genome-wide genetic screening is a powerful tool commonly used in yeast studies. The expression of a number of neurodegenerative disease-associated proteins in yeast causes cytotoxicity and aggregate formation, recapitulating findings seen in patients with these disorders. Here, we describe a method for screening a yeast model of the Amyotrophic Lateral Sclerosis-associated protein FUS for modifiers of its toxicity. Instead of using transformation, this new screening platform relies on the mating of yeast to introduce an arrayed library of plasmids into the yeast model. The mating method has two clear advantages: first, it is highly efficient; second, the pre-transformed arrayed library of plasmids can be stored for long-term as a glycerol stock, and quickly applied to other screens without the labor-intensive step of transformation into the yeast model each time. We demonstrate how this method can successfully be used to screen for genes that modify the toxicity of FUS.


Assuntos
Biblioteca Gênica , Doenças Neurodegenerativas/diagnóstico , Proteínas/metabolismo , Deficiências na Proteostase/diagnóstico , Saccharomyces cerevisiae/patogenicidade , Humanos
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