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1.
ACS Nano ; 13(10): 10887-10917, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31538764

RESUMO

Gas-involving cancer theranostics have attracted considerable attention in recent years due to their high therapeutic efficacy and biosafety. We have reviewed the recent significant advances in the development of stimuli-responsive gas releasing molecules (GRMs) and gas nanogenerators for cancer bioimaging, targeted and controlled gas therapy, and gas-sensitized synergistic therapy. We have focused on gases with known anticancer effects, such as oxygen (O2), carbon monoxide (CO), nitric oxide (NO), hydrogen sulfide (H2S), hydrogen (H2), sulfur dioxide (SO2), carbon dioxide (CO2), and heavy gases that act via the gas-generating process. The GRMs and gas nanogenerators for each gas have been described in terms of the stimulation method, followed by their applications in ultrasound and multimodal imaging, and finally their primary and synergistic actions with other cancer therapeutic modalities. The current challenges and future possibilities of gas therapy and imaging vis-à-vis clinical translation have also been discussed.

2.
Analyst ; 144(14): 4188-4193, 2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31184646

RESUMO

In this study, catalase-linked immunosorbent pressure assay with a gas-generation reaction was established for quantitative detection of disease biomarker C-reactive protein (CRP) by a portable pressuremeter. The pressure-based detection system recognizes, transduces, and amplifies the target signal to a convenient target-correlated pressure signal reading in a closed chamber. Biotin molecules were modified on the surface of catalase in order to incorporate catalase into the pressure immunoassay by the streptavidin-biotin interaction. To improve the assay performance, the modification ratios of biotin molecules to catalase, and the concentrations of capture and detection antibodies were further optimized. The catalase-linked immunosorbent pressure assay allows portable and quantitation analysis of CRP with a limit of detection of 1.8 nM, which can satisfy the clinical needs for determining the risk of cardiovascular disease. The catalase-linked immunosorbent pressure assay also shows superior specificity and good accuracy. Compared to the previously reported assay catalyzed by PtNP nanozyme, catalase is not easily deactivated during storage and operation. With the merits of enzymatic efficiency, biocompatibility, low non-specific adsorption and facile modification, catalase can be reasonably used for reproducible, stable, simple quantitative detection of disease markers using a portable pressure-based assay in resource-limited settings.

3.
Talanta ; 202: 452-459, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31171207

RESUMO

Despite the success in long-term storage of food and dietary products using antibiotics as supplements, enormous levels of their residues have remained as a significant health concern, leading to severe toxicity issues on consumption. Herein, we report an ultrasensitive and highly selective aptasensor based on carbon nanoparticles (CNPs) through a fluorescence-based aptamer-linked immunosorbent assay (FALIA) for rapid detection of kanamycin (KAA) residue. The fabricated CNP-aptasensor exhibited superior selectivity with exceptional photoluminescence properties. Under the optimal conditions, the linear equation of standard KAA solution was Y = -0.2279LogX+1.3648 (R = -0.9893) ranged from 10-4 to 10-7 ppb with excellent relative standard deviations (RSD) between 3.12 and 5.59 % (n = 3). Moreover, the limit of detection (LOD) was lower than 5.0 × 10-8 ppb. Together, the excellent recovery and significant efficacy in the rapid detection of antibiotics at a low level in milk indicate that this fabricated CNP-aptasensor has a great potential in the establishment of an efficient antibiotic detector system in food and other nutraceutical industries.


Assuntos
Aptâmeros de Nucleotídeos/química , Carbono/química , Técnicas de Imunoadsorção , Canamicina/análise , Luminescência , Pontos Quânticos/química
4.
Molecules ; 24(11)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159343

RESUMO

In this work, with the drug oxytetracycline (OTC) released, cell cytotoxicity and antimicrobial studies of dual-responsive sodium alginate and N-Isopropylacrylamide hydrogels (SA/pNIPAAm) with enclosed OTC were investigated. The molecular OTC release was explored with different acid-base conditions and temperature conditions. In order to characterize cell cytotoxicity and antimicrobial efficacy, time-dependent OTC release analysis of different acid-base conditions was performed in SA/pNIPAAm hydrogels. OTC@SA/pNIPAAm hydrogels showed excellent time-dependent antimicrobial efficacy, in which the IC50 values were 50.11 µg mL-1, 34.27 µg mL-1, and 22.39 µg mL-1 among three consecutive days, respectively. Meanwhile, the human cells showed excellent viability at the IC50 dosage of OTC@SA/pNIPAAm (50.11 µg mL-1). OTC@SA/pNIPAAm performed in this study indicated that SA/pNIPAAm may serve as drug carriers for sustainable release at a specific concentration and for being employed as substrates for decreasing drug toxicity. Besides, pH-responsive and thermos-responsive SA/pNIPAAm may lead to the better selectivity of drug release in the ideal location or site. Finally, the results demonstrate that the designed, dual-responsive, biocompatible OTC@SA/pNIPAAm hydrogels showed excellent antimicrobial efficacy and may potentially be found to have enormous applicability in the field of pharmaceutics.

5.
Sensors (Basel) ; 19(10)2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31091745

RESUMO

In this work, we have developed a simple and rapid colorimetric assay for the detection of immunoglobulin E (IgE) using functional nucleic acids (FNAs) and a solid-phase competition enzyme-linked immunosorbent assay (ELISA). The FNAs including aptamer of recombinant IgE, G-quadruplex and its complementary fragments were immobilized on 96-well microplates to achieve recognition and detection of IgE in biological samples. The G-quadruplex DNAzyme catalyzed 2,2'-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS)-hemin-H2O2 system was used to improve the sensitivity of colorimetric assay. In the presence of IgE, the hairpin structure and G-quadruplex would be destroyed, resulting in the inactivation of DNAzyme and subsequent reduction of its absorbance. This cost-effective approach detected IgE in the linear range from 5.0 pg/mL to 500 ng/mL, with the limit of detection (LOD) of 2.0 pg/mL, under optimal conditions. Moreover, the developed method was successfully applied to the rapid detection of IgE in human urine, indicating a great potentiality of this approach in clinical diagnosis and other biomedical applications.


Assuntos
Técnicas Biossensoriais , Colorimetria , Imunoglobulina E/isolamento & purificação , Benzotiazóis/química , DNA Catalítico/química , Quadruplex G , Humanos , Peróxido de Hidrogênio/química , Imunoglobulina E/química , Limite de Detecção , Técnicas de Amplificação de Ácido Nucleico , Ácidos Sulfônicos/química
6.
Sci Rep ; 9(1): 3489, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837641

RESUMO

Carbon nanoparticles (CNPs) have been combined with aptamer, providing a broad application in small molecule. CNPs can be quenched by small molecules and are usually applied as luminescent probes because of their photophysical characteristics. In this work, we developed a competitive analysis for antibiotic residues detection based on carbon nanoparticles (CNPs) and oligonucleotide probes. Oligonucleotide probes including oxytetracycline (OTC) aptamer was exploited for recognition OTC and was used to restore the luminescence. Tetracycline (TC), as a competitor of OTC, was utilized to quench the luminescence of CNPs and reduce the sample matrix effect. Under optimal conditions, the linear rang of OTC was 0.010~1.0 ng/mL with the relative standard deviations (RSDs) from 2.91% to 11.3%, and the limit of detection (LOD) was low to 0.002 ng/mL. Moreover, the proposal was successfully applied to analyze OTC from drink water, indicating that this approach has great potential for other small molecule analysis.

7.
J Cancer ; 9(12): 2061-2071, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29937924

RESUMO

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, but the overall prognosis remains disappointing especially in the advanced-stage patients. Aberration expression of Aurora kinases is tumorigenic and thus it has attracted interests as therapeutic targets in cancer treatment. Here, we investigated the proteomic response of HCC Hep3B cells to danusertib (Danu), a pan-Aurora kinase inhibitor, and then validated the proteomic results based on stable-isotope labeling by amino acids in cell culture (SILAC). The proteomic data identified that Danu modulated the expression of 542 protein molecules (279 up-regulated; 260 down-regulated; 3 stable). Ingenuity pathway analysis (IPA) and KEGG pathway analysis identified 107 and 24 signaling pathways were regulated by Danu, respectively. IPA analysis showed cellular growth and proliferation, and cell death and survival were among the top five molecular and cellular functions regulated by Danu. The verification experiments showed that Danu inhibited the proliferation of Hep3B cells with a 24-hr IC50 value of 22.03 µM. Danu treatment also arrested Hep3B cells in G2/M phase via regulating the expression of key cell cycle regulators and induced apoptosis via mitochondria-dependent pathway in a dose-dependent manner. Besides, Danu induced a marked autophagy, and inhibition of autophagy enhanced the anticancer effects of Danu, indicating a cyto-protective role of Danu-induced autophagy. Our proteomic data and Western blotting assays showed the PI3K/Akt/mTOR signaling pathway was involved in the inducing effect of Danu on apoptosis and autophagy. Collectively, our findings have demonstrated that the Aurora kinases inhibition with danusertib results in global proteomic response and exerts anticancer effects in Hep3B cells involving regulation of cell cycle, apoptosis and autophagy and associated signaling pathways.

8.
Theranostics ; 7(17): 4071-4086, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29158811

RESUMO

Chemotherapy-resistant cancer stem cells (CSCs) are a major obstacle to the effective treatment of many forms of cancer. To overcome CSC chemo-resistance, we developed a novel system by conjugating a CSC-targeting EpCAM aptamer with doxorubicin (Apt-DOX) to eliminate CSCs. Incubation of Apt-DOX with colorectal cancer cells resulted in high concentration and prolonged retention of DOX in the nuclei. Treatment of tumour-bearing xenograft mice with Apt-DOX resulted in at least 3-fold more inhibition of tumour growth and longer survival as well as a 30-fold lower frequency of CSC and a prolonged longer tumourigenic latency compared with those receiving the same dose of free DOX. Our data demonstrate that a CSC-targeting aptamer is able to transform a conventional chemotherapeutic agent into a CSC-killer to overcome drug resistance in solid tumours.


Assuntos
Aptâmeros de Nucleotídeos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Molécula de Adesão da Célula Epitelial/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Relação Dose-Resposta a Droga , Doxorrubicina/química , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Feminino , Células HT29 , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos SCID , Polietilenoglicóis/química , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Am J Transl Res ; 9(10): 4652-4672, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29118925

RESUMO

Chronic myeloid leukemia (CML) treatment remains a challenge due to drug resistance and severe side effect, rendering the need on the development of novel therapeutics. CDDO-Me (Bardoxolone methyl), a potent Nrf2 activator and NF-κB inhibitor, is a promising candidate for cancer treatment including leukemia. However, the underlying mechanism for CDDO-Me in CML treatment is unclear. This study aimed to evaluate the molecular interactome of CDDO-Me in K562 cells using the quantitative proteomics approach stable-isotope labeling by amino acids in cell culture (SILAC) and explore the underlying mechanisms using cell-based functional assays. A total of 1,555 proteins responded to CDDO-Me exposure, including FANCI, SRPK2, XPO5, HP1BP3, NELFCD, Na+,K+-ATPase 1, etc. in K562 cells. A total of 246 signaling pathways and 25 networks regulating cell survival and death, cellular function and maintenance, energy production, protein synthesis, response to oxidative stress, and nucleic acid metabolism were involved. Our verification experiments confirmed that CDDO-Me down-regulated Na+,K+-ATPase α1 in K562 cells, and significantly arrested cells in G2/M and S phases, accompanied by remarkable alterations in the expression of key cell cycle regulators. CDDO-Me caused mitochondria-, death receptor-dependent and ER stress-mediated apoptosis in K562 cells, also induced autophagy with the suppression of PI3K/Akt/mTOR signaling pathway. p38 MAPK/Erk1/2 signaling pathways contributed to both apoptosis- and autophagy-inducing effects of CDDO-Me in K562 cells. Taken together, these data demonstrate that CDDO-Me is a potential anti-cancer agent that targets cell cycle, apoptosis, and autophagy in the treatment of CML.

10.
Biofactors ; 43(6): 812-820, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28817203

RESUMO

Digoxin is a member of cardiac glycosides and recent studies show that digoxin plays anticancer role in several types of cancer. However, the anticancer effects and mechanism of digoxin in leukemia is largely unknown. Her, our data show that digoxin treatment significantly inhibits leukemia cell viability. In addition, digoxin treatment significantly induced apoptosis and G2/M cell cycle arrest in leukemia cells. Furthermore, we demonstrated that digoxin treatment inactivate that oncogenic pathway Akt/mTOR signaling in leukemia cells. In addition, our data show that digoxin treatment induces activation of unfolded protein response (UPR) signaling in leukemia cells. Interestingly, our in vitro and in vivo experiments show that combination treatment of digoxin and UPR inhibitor can synergistically suppress leukemia growth and induces apoptosis and cell cycle arrest compared to single drug treatment. In summary, our findings indicate that digoxin has potential anticancer effects on leukemia. The combination of digoxin and UPR signaling inhibitor can exerts synergistic anticancer activity against leukemia. © 2017 BioFactors, 43(6):812-820, 2017.


Assuntos
Adenina/análogos & derivados , Antineoplásicos/farmacologia , Digoxina/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Indóis/farmacologia , Leucemia Eritroblástica Aguda/tratamento farmacológico , Adenina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Humanos , Células K562 , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Eritroblástica Aguda/patologia , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células THP-1 , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Behav Neurol ; 2017: 6261479, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28720981

RESUMO

BACKGROUND: Functional magnetic resonance imaging (fMRI) is a promising method for quantifying brain recovery and investigating the intervention-induced changes in corticomotor excitability after stroke. This study aimed to evaluate cortical reorganization subsequent to virtual reality-enhanced treadmill (VRET) training in subacute stroke survivors. METHODS: Eight participants with ischemic stroke underwent VRET for 5 sections per week and for 3 weeks. fMRI was conducted to quantify the activity of selected brain regions when the subject performed ankle dorsiflexion. Gait speed and clinical scales were also measured before and after intervention. RESULTS: Increased activation in the primary sensorimotor cortex of the lesioned hemisphere and supplementary motor areas of both sides for the paretic foot (p < 0.01) was observed postintervention. Statistically significant improvements were observed in gait velocity (p < 0.05). The change in voxel counts in the primary sensorimotor cortex of the lesioned hemisphere is significantly correlated with improvement of 10 m walk time after VRET (r = -0.719). CONCLUSIONS: We observed improved walking and increased activation in cortical regions of stroke survivors after VRET training. Moreover, the cortical recruitment was associated with better walking function. Our study suggests that cortical networks could be a site of plasticity, and their recruitment may be one mechanism of training-induced recovery of gait function in stroke. This trial is registered with ChiCTR-IOC-15006064.


Assuntos
Córtex Motor/fisiopatologia , Reabilitação do Acidente Vascular Cerebral/métodos , Adulto , Idoso , Encéfalo/patologia , Isquemia Encefálica/complicações , Mapeamento Encefálico/métodos , Feminino , Marcha/fisiologia , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Plasticidade Neuronal/fisiologia , Projetos Piloto , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/fisiopatologia , Sobreviventes/psicologia , Realidade Virtual
12.
Sci Rep ; 7(1): 5898, 2017 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-28724889

RESUMO

The development of chemoresistance and inability in elimination of cancer stem cells are among the key limitations of cancer chemotherapy. Novel molecular therapeutic strategies able to overcome such limitations are urgently needed for future effective management of cancer. In this report, we show that EpCAM-aptamer-guided survivin RNAi effectively downregulated survivin both in colorectal cancer cells in vitro and in a mouse xenograft model for colorectal cancer. When combined with the conventional chemotherapeutic agents, the aptamer-guided survivin RNAi was able to enhance the sensitivity towards 5-FU or oxaliplatin in colorectal cancer stem cells, increase apoptosis, inhibit tumour growth and improve the overall survival of mice bearing xenograft colorectal cancer. Our results indicate that survivin is one of the key players responsible for the innate chemoresistance of colorectal cancer stem cells. Thus, aptamer-mediated targeting of survivin in cancer stem cells in combination with chemotherapeutic drugs constitutes a new avenue to improve treatment outcome in oncologic clinics.

13.
J Laparoendosc Adv Surg Tech A ; 27(11): 1145-1150, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28586262

RESUMO

BACKGROUND: Severe acute pancreatitis (SAP), one severe and fatal disease, the therapy of which is pretty hard. This study aimed to study the effect of laparoscopic peritoneal lavage and drainage (LPLD) and continuous venovenous diahemofiltration (CVVDH) on SAP. MATERIALS AND METHODS: Two hundred forty-five patients with SAP in total were randomly assigned into four groups according to the therapeutic plan: basic treatment; LPLD; CVVDH; or LPLD+CVVDH. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, the ratios of multiple organ dysfunction syndrome (MODS), mortality, hospitalization time, hospitalization cost, ratios of complications, the abdominal distention relief time, abdominal pain relief time, plasma concentration of endotoxin, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-8 were evaluated. RESULTS: Ratios of MODS, mortality, hospitalization time, hospitalization cost, the abdominal distention relief time, abdominal pain relief time, concentration of endotoxin, TNF-α, IL-6, IL-8, and APACHE II scores were significantly decreased in the CVVDH, LPLD, and CVVDH+LPLD groups, while ratios of recovery were significantly increased in the CVVDH, LPLD, and CVVDH+LPLD groups, especially in the CVVDH+LPLD group. CONCLUSIONS: LPLD and CVVDH are effective in the treatment of SAP by eliminating endotoxin, TNF-α, IL-6, and IL-8. The combination of CVVDH and LPLD can further improve the treatment effect.


Assuntos
Pancreatite/terapia , APACHE , Doença Aguda , Adulto , Terapia Combinada , Drenagem , Feminino , Hemofiltração , Humanos , Interleucina-6/sangue , Laparoscopia , Masculino , Pessoa de Meia-Idade , Pancreatite/sangue , Pancreatite/patologia , Lavagem Peritoneal , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue
14.
Am J Transl Res ; 9(3): 845-873, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28386317

RESUMO

Glioblastoma (GBM) is the most common brain tumor with poor response to current therapeutics. Alisertib (ALS), a second-generation selective Aurora kinase A (AURKA) inhibitor, has shown potent anticancer effects on solid tumors in animal studies. This study aimed to investigate the killing effect of ALS on GBM cell line DAOY and the possible underlying mechanisms using both bioinformatic and cell-based approaches. Our molecular docking showed that ALS preferentially bound AURKA over AURKB via hydrogen bond formation, charge interaction, and π-π stacking. ALS also bound key regulating proteins of cell cycle, apoptosis and autophagy, such as cyclin-dependent kinase 1 (CDK1/CDC2), CDK2, cyclin B1, p27 Kip1, p53, cytochrome C, cleaved caspase 3, Bax, Bcl-2, Bcl-xl, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), 5'-adenosine monophosphate-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (MAPK), beclin 1, phosphatase and tensin homolog (PTEN), and microtubule-associated protein light chain 3 (LC3). ALS exhibited potent growth-inhibitory, pro-apoptotic, and pro-autophagic effects on DAOY cells in a concentration-dependent manner. Notably, ALS remarkably induced G2/M arrest mainlyvia regulating the expression of CDK1/CDC2, CDK2, cyclin B1, p27 Kip1, and p53 in DAOY cells. ALS significantly induced the expression of mitochondria-mediated pro-apoptotic proteins such as Baxbut inhibited the expression of anti-apoptotic proteins such as Bcl-2 and Bcl-xl, with a significant increase in the release of cytochrome C and the activation of caspases 3 and 9. ALS also induced PI3K/Akt/mTOR and p38 MAPK signaling pathways while activating the AMPK signaling pathway. Taken together, these findings indicate that ALS exerts a potent inhibitory effect on cell proliferation and induces mitochondria-dependent apoptosis and autophagy with the involvement of PI3K/Akt/mTOR- and p38 MAPK-mediated signaling pathways in DAOY cells. ALS is a promising anticancer agent for GBM treatment.

15.
J Cancer ; 8(2): 220-226, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28243326

RESUMO

Cutaneous squamous cell carcinoma (cSCC) contributes to one of most common types of skin cancer. Epidermal growth factor receptor (EGFR) activation has been investigated to be associated with the development of cSCC. Lapatinib is an inhibitor targeting HER2/neu and EGFR pathway. We found that lapatinib can inhibit proliferation by enhancing apoptosis of human cSCC cell lines. The cSCC cell cycle distribution could be arrested in G2/M phase after lapatinib treatment. In the in vitro experiment, we found that lapatinib interrupted PI3K/AKT/mTOR signaling pathway in human cSCC cells. Furthermore, lapatinib could suppress epithelial to mesenchymal transition (EMT) via Wnt/ErK/PI3K-AKT signaling pathway to represent a promising anticancer drug for cSCC treatment.

17.
Lipids Health Dis ; 16(1): 8, 2017 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-28086886

RESUMO

BACKGROUND: It has been demonstrated that acute oral administration of schisandrin B (Sch B), an active dibenzocyclooctadiene isolated from Schisandrae Fructus (a commonly used traditional Chinese herb), increased serum and hepatic triglyceride (TG) levels and hepatic mass in mice. The present study aimed to investigate the biochemical mechanism underlying the Sch B-induced hypertriglyceridemia, hepatic steatosis and hepatomegaly. METHODS: Male ICR mice were given a single oral dose of Sch B (0.25-2 g/kg). Sch B-induced changes in serum levels of biomarkers, such as TG, total cholesterol (TC), apolipoprotein B48 (ApoB 48), very-low-density lipoprotein (VLDL), non-esterified fatty acid (NEFA) and hepatic growth factor (HGF), as well as hepatic lipids and mass, epididymal adipose tissue (EAT) and adipocyte size, and histological changes of the liver and EAT were examined over a period of 12-120 h after Sch B treatment. RESULTS: Serum and hepatic TG levels were increased by 1.0-4.3 fold and 40-158% at 12-72 h and 12-96 h, respectively, after Sch B administration. Sch B treatment elevated serum ApoB 48 level (up to 12%), a marker of exogenous TG, but not VLDL, as compared with the vehicle treatment. Treatment with Sch B caused a time-/dose-dependent reduction in EAT index (up to 39%) and adipocyte size (up to 67%) and elevation in serum NEFA level (up to 55%). Sch B treatment induced hepatic steatosis in a time-/dose-dependent manner, as indicated by increases in total vacuole area (up to 3.2 fold vs. the vehicle control) and lipid positive staining area (up to 17.5 × 103 µm2) in liver tissue. Hepatic index and serum HGF levels were increased by 18-60% and 42-71% at 12-120 h and 24-72 h post-Sch B dosing, respectively. In addition, ultrastructural changes, such as increase in size and disruption of cristae, in hepatic mitochondria were observed in Sch B-treated mice. CONCLUSION: Our findings suggest that exogenous sources of TG and the breakdown of fat storage in the body contribute to Sch B-induced hypertriglyceridemia and hepatic steatosis in mice. Hepatomegaly (a probable hepatotoxic action) caused by Sch B may result from the fat accumulation and mitochondrial damage in liver tissue.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Fígado Gorduroso/metabolismo , Hepatomegalia/metabolismo , Hipertrigliceridemia/metabolismo , Lignanas/efeitos adversos , Fígado/efeitos dos fármacos , Compostos Policíclicos/efeitos adversos , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Apolipoproteína B-48/sangue , Tamanho Celular , Colesterol/sangue , VLDL-Colesterol/sangue , Ciclo-Octanos/efeitos adversos , Ácidos Graxos não Esterificados/sangue , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/patologia , Fator de Crescimento de Hepatócito/sangue , Hepatomegalia/induzido quimicamente , Hepatomegalia/patologia , Hipertrigliceridemia/induzido quimicamente , Hipertrigliceridemia/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Schisandra/química , Triglicerídeos/sangue
18.
Am J Physiol Renal Physiol ; 312(2): F245-F253, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27122543

RESUMO

The (pro)renin receptor (PRR) is abundantly expressed in the collecting duct (CD) and the expression is further induced by angiotensin II (ANG II). The present study was conducted to investigate the role of CD PRR during ANG II-induced hypertension and to further explore the underlying mechanism. Radiotelemetry demonstrated that a 1-wk ANG II infusion gradually and significantly induced hypertensive response in floxed mice and this response was significantly attenuated in mice lacking PRR in the CD (termed CD PRR KO). ANG II infusion in floxed mice increased urinary renin activity and selectively induced renal medullary α-epithelial sodium channel (α-ENaC) mRNA and protein expression, all of which were blunted in the null mice. In cultured mpkCCD cells grown in Transwells, transepithelial Na+ transport as measured by using a volt-ohmmeter was transiently stimulated by acute ANG II treatment, which was abolished by a PRR antagonist, PRO20. In a chronic setting, ANG II treatment induced α-ENaC mRNA expression in mpkCCD cells, which was similarly blocked by PRO20. Chronic intramedullary infusion of an ENaC inhibitor amiloride in rats significantly attenuated ANG II-induced hypertension. Overall, the present study suggests that CD PRR contributes to ANG II-induced hypertension at least partially via activation of renal medullary ENaC.


Assuntos
Pressão Sanguínea/fisiologia , Canais Epiteliais de Sódio/metabolismo , Hipertensão/metabolismo , Túbulos Renais Coletores/metabolismo , Receptores de Superfície Celular/metabolismo , Angiotensina II , Animais , Células Cultivadas , Hipertensão/induzido quimicamente , Túbulos Renais Coletores/efeitos dos fármacos , Camundongos , Camundongos Knockout , Fragmentos de Peptídeos/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/genética , Renina/farmacologia
19.
Cancer Lett ; 387: 77-83, 2017 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-27045474

RESUMO

As one of the life-threatening diseases involving multi-step genetic and epigenetic disorders, cancer has long been a dynamic research area for siRNA-based therapy as half of the current siRNA-based clinical trials are involved in oncology. However, despite consistent enthusiasm in the academic world, siRNA-based cancer treatment still faces obstacles and difficulties in clinical development. In this article, we discuss key challenges facing siRNA-based cancer treatment revealed from recent clinical and preclinical studies, including chemical modification, tumour penetration, endosomal escape, target selection and off-target effects. In addition, opportunities and avenues for translating siRNA technology from bench to oncologic clinics are explored.


Assuntos
Inativação Gênica , Terapia Genética , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/terapia , RNA Interferente Pequeno/genética , Animais , Humanos , Proteínas de Neoplasias/genética , Neoplasias/genética
20.
Curr Cancer Drug Targets ; 17(4): 386-401, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27396604

RESUMO

BACKGROUND: Aurora A kinase represent a feasible target in cancer therapy. OBJECTIVE: To evaluate the proteomic response of human liver carcinoma cells to alisertib (ALS) and identify the molecular targets of ALS, we examined the effects of ALS on the proliferation, cell cycle, autophagy, apoptosis, and chemosensitivity in HepG2 cells. METHOD: The stable-isotope labeling by amino acids in cell culture (SILAC) based quantitative proteomic study was performed to evaluate the proteomic response to ALS. Cell cycle distribution and apoptosis were assessed using flow cytometry and autophagy was determined using flow cytometry and confocal microscopy. RESULTS: Our SILAC proteomic study showed that ALS regulated the expression of 914 proteins, with 407 molecules being up-regulated and 507 molecules being down-regulated in HepG2 cells. Ingenuity pathway analysis (IPA) and KEGG pathway analysis identified 146 and 32 signaling pathways were regulated by ALS, respectively, which were associated with cell survival, programmed cell death, and nutrition-energy metabolism. Subsequently, the verification experiments showed that ALS remarkably arrested HepG2 cells in G2/M phase and led to an accumulation of aneuploidy via regulating the expression of key cell cycle regulators. ALS induced a marked autophagy in a concentration- and time-dependent manner via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Autophagy inhibition promoted the pro-apoptotic effect of ALS, indicating a cyto-protective role of ALS-induced autophagy. ALS increased the chemosensitivity of HepG2 cells to cisplatin and doxorubicin. CONCLUSION: Taken together, ALS induces autophagy and cell cycle arrest in HepG2 cells via PI3K/Akt/mTOR-mediated pathway. Autophagy inhibition may promote the anticancer effect of ALS and sensitize the chemotherapy in HepG2 cells.


Assuntos
Aurora Quinase A/antagonistas & inibidores , Autofagia/efeitos dos fármacos , Azepinas/farmacologia , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Pirimidinas/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Citometria de Fluxo , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/metabolismo , Proteômica
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