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1.
Mol Med Rep ; 22(1): 209-218, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32377693

RESUMO

Toll-like receptor 2 (TLR2)-mediated myocardial inflammation serves an important role in promoting myocardial ischemic/reperfusion (I/R) injury. Previous studies have shown that miR­499 is critical for cardioprotection after ischemic postconditioning (IPostC). Therefore, the present study evaluated the protective effect of IPostC on the myocardium by inhibiting TLR2, and also assessed the involvement of microRNA (miR)­499. Rat hearts were subjected to 30 min of ischemia and 2 h of reperfusion. The IPostC was 3 cycles of 30 sec of reperfusion and 30 sec of re­occlusion prior to reperfusion. In total, 90 rats were randomly divided into six groups (n=15 per group): Sham; I/R; IPostC; miR­499 negative control adeno­associated virus (AAV) vectors + IPostC; miR­499 inhibitor AAV vectors + IPostC; and miR­499 mimic AAV vectors + IPostC. It was identified that IPostC significantly decreased the I/R­induced cardiomyocyte apoptotic index (29.4±2.03% in IPostC vs. 42.64±2.27% in I/R; P<0.05) and myocardial infarct size (48.53±2.49% in IPostC vs. 66.52±3.1% in I/R; P<0.05). Moreover, these beneficial effects were accompanied by increased miR­499 expression levels (as demonstrated by reverse transcription­quantitative PCR) in the myocardial tissue and decreased TLR2, protein kinase C (PKC), interleukin (IL)­1ß and IL­6 expression levels (as demonstrated by western blotting and ELISA) in the myocardium and serum. The results indicated that IPostC + miR­499 mimics significantly inhibited inflammation and the PKC signaling pathway and enhanced the anti­inflammatory and anti­apoptotic effects of IPostC. However, IPostC + miR­499 inhibitors had the opposite effect. Therefore, it was speculated that IPostC may have a miR­499­dependent cardioprotective effect. The present results suggested that miR­499 may be involved in IPostC­mediated ischemic cardioprotection, which may occur via local and systemic TLR2 inhibition, subsequent inhibition of the PKC signaling pathway and a decrease in inflammatory cytokine release, including IL­1ß and IL­6. Moreover, these effects will ultimately lead to a decrease in the myocardial apoptotic index and myocardial infarct size via the induction of the anti­apoptotic protein Bcl­2, and inhibition of the pro­apoptotic protein Bax in myocardium.

2.
Acta Cir Bras ; 35(1): e202000105, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215465

RESUMO

PURPOSE: To investigate whether heat shock protein 90 (HSP90) is involved in complement regulation in ischemic postconditioning (IPC). METHODS: The left coronary artery of rats underwent 30 min of occlusion, followed by 120 min of reperfusion and treatment with IPC via 3 cycles of 30s reperfusion and 30s occlusion. The rats were injected intraperitoneally with 1 mg/kg HSP90 inhibitor geldanamycin (GA) after anesthesia. Eighty rats were randomly divided into four groups: sham, ischemia-reperfusion (I/R), IPC and IPC + GA. Myocardial infarct size, apoptosis index and the expression of HSP90, C3, C5a, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1ß and c-Jun N-terminal kinase (JNK) were assessed. RESULTS: Compared with the I/R injury, the IPC treatment significantly reduced infarct size, release of troponin T, creatine kinase-MB, and lactate dehydrogenase, and cardiomyocyte apoptosis. These beneficial effects were accompanied by a decrease in TNF-α, IL-1ß, C3, C5a and JNK expression levels. However, all these effects were abrogated by administration of the HSP90 inhibitor GA. CONCLUSION: HSP90 exerts a profound effect on IPC cardioprotection, and may be linked to the inhibition of the complement system and JNK, ultimately attenuating I/R-induced myocardial injury and apoptosis.


Assuntos
Benzoquinonas/farmacologia , Proteínas do Sistema Complemento/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lactamas Macrocíclicas/farmacologia , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Animais , Creatina Quinase Forma MB/metabolismo , Mediadores da Inflamação , Pós-Condicionamento Isquêmico/métodos , Masculino , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
3.
Ther Innov Regul Sci ; 54(1): 32-41, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32008241

RESUMO

BACKGROUND: Computerized detection is a promising method for monitoring adverse drug events (ADEs); however, this method is currently in its infancy and is a new area of exploration in China. This study aimed to develop a computerized ADE alarm and assessment system to help pharmacists effectively detect, assess, and analyze possible ADEs in patients in China. METHODS: Based on the clinical characteristics of these adverse drug events, we designed combined multiparameters as ADE alert rules to be assembled into detection configurations. We also developed system function modules by extracting data from the People's Liberation Army (PLA) general hospital information system (electronic medical records). Positive predictive values were calculated for the alert. RESULTS: Five function modules were created in this platform: automatic screening, assisted evaluation, risk characteristic analysis, report generation into SRS (spontaneous reporting system), and a dictionary database. Four ADE alert configurations were set in our ADE alarm and assessment system: drug-related thrombocytopenia, anemia, liver injury, and kidney injury. The positive predictive values of the 4 monitored ADEs were approximately 44.4% to 95.8%. CONCLUSIONS: An automatic ADE screening system was established for hospitalized patients in Chinese medical institutions. Compared with previous studies, combined drug-event alerts and a system-assisted assessment interface performed better than alerts based only on laboratory values. Furthermore, this platform's assisted-layered evaluation and risk factor analysis functions could save considerable time for professionals and improve early prevention of potentially serious ADEs. To date, this system has been applied in 10 large-scale medical institutions.

4.
Sci Total Environ ; 710: 136335, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-31926415

RESUMO

The concentrations of persistent organic pollutants (POPs) in sediments from the Eastern Indian Ocean were analyzed by GC-MS/MS to explore the status of contamination, distribution and their potential sources and risk. The average (±SD) concentrations of total polycyclic aromatic hydrocarbons (∑16PAHs), polybrominated diphenyl ethers (∑10PBDEs), dechlorane plus (∑2DP), organochlorine pesticides (∑22OCPs) and polychlorinated biphenyls (∑31PCBs) in sediments were 79,900 ± 31,400, 173 ± 62, 42 ± 24, 1051 ± 305 and 147 ± 24 pg g-1 dw (or 11,200 ± 7200, 28 ± 26, 6 ± 6, 168 ± 121 and 24 ± 17 ng g-1 organic carbon), respectively. The concentrations of POPs in sediments were generally at low to median levels compared to those recorded in other ocean sediments. Composition analyses suggest that PAHs originate from both petrogenic and pyrogenic sources, while dichlorodiphenyltrichloroethane (DDT) mainly comes from technical-DDT, hexachlorocyclohexane (HCH) from lindane, and chlordane from fresh inputs. The risk assessments show that the targeted chemicals except for chlordane and naphthalene in sediments do not pose potential biological effects to the organisms in the Eastern Indian Ocean. The present study contributes to the very rare data on PAHs, PBDEs, DP, OCPs and PCBs in the vast deep-ocean and will deepen our knowledge of the fate of POPs in ocean environments.

5.
Acta cir. bras ; 35(1): e202000105, 2020. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-1088523

RESUMO

Abstract Purpose To investigate whether heat shock protein 90 (HSP90) is involved in complement regulation in ischemic postconditioning (IPC). Methods The left coronary artery of rats underwent 30 min of occlusion, followed by 120 min of reperfusion and treatment with IPC via 3 cycles of 30s reperfusion and 30s occlusion. The rats were injected intraperitoneally with 1 mg/kg HSP90 inhibitor geldanamycin (GA) after anesthesia. Eighty rats were randomly divided into four groups: sham, ischemia-reperfusion (I/R), IPC and IPC + GA. Myocardial infarct size, apoptosis index and the expression of HSP90, C3, C5a, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1β and c-Jun N-terminal kinase (JNK) were assessed. Results Compared with the I/R injury, the IPC treatment significantly reduced infarct size, release of troponin T, creatine kinase-MB, and lactate dehydrogenase, and cardiomyocyte apoptosis. These beneficial effects were accompanied by a decrease in TNF-α, IL-1β, C3, C5a and JNK expression levels. However, all these effects were abrogated by administration of the HSP90 inhibitor GA. Conclusion HSP90 exerts a profound effect on IPC cardioprotection, and may be linked to the inhibition of the complement system and JNK, ultimately attenuating I/R-induced myocardial injury and apoptosis.

6.
Oncol Lett ; 18(3): 2316-2321, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31402937

RESUMO

Diagnostic value of fine-needle aspiration (FNA) combined with ultrasound for thyroid cancer was evaluated. A retrospective analysis was performed on the preoperative FNA and ultrasound data of 165 thyroid nodule patients, were divided into group A (≤1 cm group) and group B (>1 cm group) based on the maximum diameter line of the thyroid nodule. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of FNA, ultrasound and FNA combined with ultrasound in the diagnosis of thyroid cancer were analyzed and compared. In group A (≤1 cm group), the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of FNA in the diagnosis of thyroid cancer were 93.33, 71.43, 91.04, 96.55 and 55.56%, respectively, those of ultrasound were 86.67, 28.57, 80.60, 91.23 and 20%, respectively, and those of FNA combined with ultrasound were 100, 28.57, 92.54, 92.6 and 100%, respectively, with statistically significant differences in the sensitivity, specificity, accuracy, positive predictive value and negative predictive value between FNA, ultrasound and FNA combined with ultrasound (P<0.05). In group B, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of FNA in the diagnosis of thyroid cancer were 100, 54.55, 94.90, 94.57 and 100%, respectively, those of ultrasound were 96.55, 72.73, 93.88, 96.55 and 72.73%, respectively, and those of FNA combined with ultrasound were 100, 63.64, 97.96, 95.92 and 100%, respectively, without statistically significant differences in the sensitivity, specificity, accuracy, positive predictive value and negative predictive value between FNA, ultrasound and FNA combined with ultrasound (P>0.05). FNA combined with ultrasound significantly improved the sensitivity and accuracy in the diagnosis of the thyroid nodule in group A, but it did not significantly improve the accuracy, sensitivity and specificity in the diagnosis of the thyroid nodule in group B.

7.
Iran J Public Health ; 48(3): 435-443, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31223570

RESUMO

Background: To survey the prevalence of potential drug-drug interactions (DDIs) between anticancer drugs and non-anticancer drugs and evaluate the risk factors associated with these drug-drug interactions in China. Methods: All discharged patients in the Department of Oncology were collected from Jun to Dec in 2016 with the Hospital Information System of the Chinese people's Liberation Army General Hospital. Drugs were screened for interactions by Micromedex solutions database. Descriptive statistics were generated and logistic regression was used to identify the associated factors. Results: Among 6578 eligible patients, 1979 potential drug interactions were found in 1830 patients (27.82%). The most common drug-drug interaction was cisplatin and furosemide. Erlotinib was most likely to interact with various non-anticancer drugs. Most interactions were classified as pharmacodynamics (71.60%), major severity (97.02%) and were supported by fair documentation evidence (86.21%). In multivariate analysis, increasing number of medications, lung cancer and patients with stage IV had a higher risk for potential drug-drug interactions. Conclusion: Potential drug-drug interactions between antineoplastic drugs and non-antineoplastic drugs occur frequently in cancer patients of Chinese hospitals. Doctors should fully consider potential risk associated with DDIs. Further research should be performed to evaluate real clinical significance of these drug-drug interactions.

8.
Nat Commun ; 10(1): 298, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30655541

RESUMO

In March 2017, sea surface temperatures off Peru rose above 28 °C, causing torrential rains that affected the lives of millions of people. This coastal warming is highly unusual in that it took place with a weak La Niña state. Observations and ocean model experiments show that the downwelling Kelvin waves caused by strong westerly wind events over the equatorial Pacific, together with anomalous northerly coastal winds, are important. Atmospheric model experiments further show the anomalous coastal winds are forced by the coastal warming. Taken together, these results indicate a positive feedback off Peru between the coastal warming, atmospheric deep convection, and the coastal winds. These coupled processes provide predictability. Indeed, initialized on as early as 1 February 2017, seasonal prediction models captured the extreme rainfall event. Climate model projections indicate that the frequency of extreme coastal El Niño will increase under global warming.

9.
J Tradit Chin Med ; 39(3): 324-331, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-32186004

RESUMO

OBJECTIVE: To investigate the radioprotective effect of tea polyphenols (TP 50) against radiation-induced organ and tissue damage. METHODS: Beagle dogs were exposed to a single acute dose of whole-body γ-radiation (3 Gy) and orally administered TP 50 (80 or 240 mg·kg-1·d-1) for 28 consecutive days. A hemogram was obtained from experimental dogs every other day for 42 d. At the end of the experiment, enzyme activities of the antioxidants superoxide-dismutase andglutathione peroxidase, serum levels of inflamma- tory cytokines (tumor necrosis factor-α, interleukin-1ß, and interleukin-6), colony-forming units of bone marrow hematopoietic progenitor cells, andorgan coefficients were measured. RESULTS: Dogs exposed to γ-radiation alone exhibited typical hematopoietic syndrome. In contrast, irradiated dogs that received TP 50 exhibited an improved blood profile with reduced leucopenia, thrombocytopenia (platelet counts), and reticulocyte levels. TP 50 also significantly elevated levels of the endogenous antioxidant enzyme superoxide-dismutase, reduced the increased levels of serum cytokine in response to radiation-induced toxicity, and increased colony-forming units of bone marrow hematopoietic progenitor cells. In addition, TP 50 repaired radiation-induced organ damage. CONCLUSION: The current findings suggest that oral administration of TP 50 to beagle dogs effectively alleviated hematopoietic bone marrow dam- age induced by γ-radiation.

10.
Ther Innov Regul Sci ; : 2168479018810193, 2018 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-30449145

RESUMO

BACKGROUND:: Computerized detection is a promising method for monitoring adverse drug events (ADEs); however, this method is currently in its infancy and is a new area of exploration in China. This study aimed to develop a computerized ADE alarm and assessment system to help pharmacists effectively detect, assess, and analyze possible ADEs in patients in China. METHODS:: Based on the clinical characteristics of these adverse drug events, we designed combined multiparameters as ADE alert rules to be assembled into detection configurations. We also developed system function modules by extracting data from the People's Liberation Army (PLA) general hospital information system (electronic medical records). Positive predictive values were calculated for the alert. RESULTS:: Five function modules were created in this platform: automatic screening, assisted evaluation, risk characteristic analysis, report generation into SRS (spontaneous reporting system), and a dictionary database. Four ADE alert configurations were set in our ADE alarm and assessment system: drug-related thrombocytopenia, anemia, liver injury, and kidney injury. The positive predictive values of the 4 monitored ADEs were approximately 44.4% to 95.8%. CONCLUSIONS:: An automatic ADE screening system was established for hospitalized patients in Chinese medical institutions. Compared with previous studies, combined drug-event alerts and a system-assisted assessment interface performed better than alerts based only on laboratory values. Furthermore, this platform's assisted-layered evaluation and risk factor analysis functions could save considerable time for professionals and improve early prevention of potentially serious ADEs. To date, this system has been applied in 10 large-scale medical institutions.

11.
Sci Rep ; 8(1): 12488, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30131499

RESUMO

We studied the biodiversity of autotrophic calcareous coccolithophore assemblages at 30 locations in the Eastern Equatorial Indian Ocean (EEIO) (80°-94°E, 6°N-5°S) and evaluated the importance of regional hydrology. We documented 26 species based on the identification of coccospheres and coccoliths, respectively. The coccolithophore community was dominated by Gephyrocapsa oceanica, Emiliania huxleyi, Florisphaera profunda, Umbilicosphaera sibogae, and Helicosphaera carteri. The abundance of coccoliths and coccospheres ranged from 0.2 × 103 to 160 × 103 coccoliths l-1 and 0.2 × 103 to 68 × 103 cells l-1, averaged 23 × 103 coccoliths l-1 and 9.4 × 103 cells l-1, respectively. Biogenic PIC, POC, and rain ratio mean values were 0.50 µgC l-1, 1.047 µgC l-1, and 0.10 respectively. High abundances of both coccoliths and coccospheres in the surface ocean layer occurred on the north of the equator. Vertically, the great majority of coccoliths and coccospheres were concentrated in water taken from depths of <75 m. The ratios between the number of coccospheres and free coccoliths indicated that coccoliths experience different levels of dissolution when transported to deep water. Abundant coccolithophores mainly occurred at the west of 90°E, which is in accordance with the presence of Wyrtki jets. Patterns of coccolithosphores and of coccoliths have been reflected in hydrological processes.


Assuntos
Clorofila A/análise , Haptófitas/classificação , Haptófitas/fisiologia , Processos Autotróficos , Biodiversidade , Carbonato de Cálcio/análise , Sedimentos Geológicos , Haptófitas/metabolismo , Oceano Índico , Temperatura
12.
Sci Rep ; 8(1): 11791, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30087355

RESUMO

Thirty conductivity-temperature-depth profiler casts in the Challenger Deep were conducted during four cruises from December 2015 to February 2017. Two cruises took place in the summer, and two in the winter. The results demonstrated that water characteristics varied seasonally. The temperature minimum values were the same between the four cruises, but its depth was noticeably shallower in the winter than that in the summer. The θ-S diagram indicated that deep water is more saline in the summer than that in winter at the same potential temperature. Mixing is more intense between 5000 and 6800 m in the summer than that in the winter. The dissipation rate and eddy diffusivity vertically averaged between 5000 and 6800 m in the summer were εT = 3.277 × 10-8 m2s-3 and KzT = 2.58 × 10-2 m2s-1, respectively. The geostrophic flows below the reference level of 3000 dbar were cyclonic in the summer, travelling westwards in the northern and eastwards in the southern areas of the Challenger Deep.

13.
Adv Sci (Weinh) ; 5(4): 1700744, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29721421

RESUMO

As a promising candidate for low-cost and environmentally friendly thin-film photovoltaics, the emerging kesterite-based Cu2ZnSn(S,Se)4 (CZTSSe) solar cells have experienced rapid advances over the past decade. However, the record efficiency of CZTSSe solar cells (12.6%) is still significantly lower than those of its predecessors Cu(In,Ga)Se2 (CIGS) and CdTe thin-film solar cells. This record has remained for several years. The main obstacle for this stagnation is unanimously attributed to the large open-circuit voltage (VOC) deficit. In addition to cation disordering and the associated band tailing, unpassivated interface defects and undesirable energy band alignment are two other culprits that account for the large VOC deficit in kesterite solar cells. To capture the great potential of kesterite solar cells as prospective earth-abundant photovoltaic technology, current research focuses on cation substitution for CZTSSe-based materials. The aim here is to examine recent efforts to overcome the VOC limit of kesterite solar cells by cation substitution and to further illuminate several emerging prospective strategies, including: i) suppressing the cation disordering by distant isoelectronic cation substitution, ii) optimizing the junction band alignment and constructing a graded bandgap in absorber, and iii) engineering the interface defects and enhancing the junction band bending.

14.
Ultrasonics ; 87: 82-90, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29475016

RESUMO

The application of microbubble (MB)-assisted ultrasound (US) can combine the advantages of real-time imaging and targeted drug delivery. However, the drug loading capacity of MB is limited restricting its application in antitumor procedure. In contrast, nanoparticles (NPs) can carry drugs more efficiently, but adverse side effect induced by unspecific accumulation can not be ignored. Herein, we developed a dual-functionalized NP loaded MB to investigate its potential feasibility for tumor-targeted drug delivery. Firstly, we prepared NPs using heparin as backbone. Targeting ligand folate and cell-penetrating ligand Tat peptide were conjugated to the backbone to deliver paclitaxel (H-F-Tat-P NPs). Subsequently, the dual-functionalized NPs were incorporated with MBs via avidin-biotin linkage to fabricate H-F-Tat-P NPs loaded MBs (NPs-loaded MBs). The combined strategy can take profit of dual functionalities from NPs and sonoporation effect from MBs triggered by US. The prepared NPs have been characterized. The excellent cellular uptake of NPs were qualitative and quantitative analysis by flow cytometry and confocal microscope, the results indicated that it was attributed to not only dual functionalities but also US effect. Foremost, the NPs-loaded MBs combined with US exhibited significant cytotoxicity on both folate receptor (FR) overexpressing and deficiency cells. The combination of dual-functionalized NPs and MBs with US is expected to be a promising strategy for targeted anticancer drug delivery and ultrasound imaging simultaneously.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Microbolhas , Nanopartículas , Ultrassom
15.
Oncotarget ; 8(59): 99312-99322, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29245903

RESUMO

The T cell receptor (TCR) ß repertoire directly reflects the status of T cell function. Meanwhile, the immune/inflammatory responses regulated by T cells are the critical determinants of atherosclerosis development. However, due to technical limitations, the composition and molecular characteristics of the TCR repertoire in atherosclerotic patients have not been fully elucidated. In the present study, we use powerful immune repertoire sequencing technology to study this issue. Results show that the utilization of V and/or J genes and the diversity of TCRß repertoire in atherosclerotic plaques are significantly reduced compared to those in the peripheral blood of normal subjects and atherosclerotic patients. The frequencies of the common T cell clones with certain lengths of the complement determining region 3 regions are notably different among all groups. The high-frequency common clones are also increased in the atherosclerotic plaques compared to that in the other two groups. The expansion of several T cell clonotypes (V29-1J2-1, V20-1J1-6, V6-3J2-7 and V11-2J2-2) is validated in atherosclerotic patients. In short, this study reveals that the diversity of TCR ß repertoire significantly decreases in atherosclerotic plaques, probably because of the reduced utilization of VJ genes and marked expansion of some T cell subclones. It provides the basis for understanding the roles of T lymphocytes in the pathogenesis of atherosclerosis.

16.
Front Pharmacol ; 8: 15, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28184196

RESUMO

AG36 is the biotransformation product of triterpenoid saponin from Ardisia gigantifolia stapf. In this study, the antitumor activity and underlying molecular mechanisms of AG36 against human breast MCF-7, MDA-MB-231, and SK-BR-3 cancer cells were investigated. AG36 inhibited the viability of MCF-7, MDA-MB-231, and SK-BR-3 cells in a dose and time-dependent manner, with an IC50 of approximately 0.73, 18.1, and 23.4 µM at 48 h, respectively. AG36 obviously induced apoptosis and G2/M arrest of all the three breast cancer cells. Moreover, AG36 decreased the protein expression of cycle regulatory proteins cyclin B1 or cyclin D1. In MCF-7 and MDA-MB-231 cells, AG36 strongly increased the cleaved caspase-3 and -8 protein expressions, while in SK-BR-3 cells, AG36 only increased the protein expression of cleaved caspase-3. In all the three breast cancer cells, the ratio of Bax/Bcl-2 and cytosolic cytochrome c content increased significantly compared with control group. The death receptor-related proteins Fas/FasL, TNFR1, and DR5 were detected by Western blot, it showed that different breast cancer cells activated the death receptor-mediated extrinsic caspase-8 pathway through different receptors. In addition, the caspase-8 inhibitor z-IETD-fmk could significantly block AG36-triggered MCF-7 cells apoptosis. The in vivo studies showed that AG36 significantly inhibited the growth of MCF-7 xenograft tumors in BALB/c nude mice comparing with control. In conclusion, AG36 inhibited MCF-7, MDA-MB-231, and SK-BR-3 cells proliferation by the intrinsic mitochondrial and the extrinsic death receptor pathways and AG36 might be a potential breast cancer therapeutic agent.

17.
Ultrason Sonochem ; 34: 448-457, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27773267

RESUMO

We have fabricated a negative-charged nanoparticle (Heparin-Folate-Tat-Taxol NP, H-F-Tat-T NP) with dual ligands, tumor targeting ligand folate and cell-penetrating peptide Tat, to deliver taxol presenting great anticancer activity for sensitive cancer cells, while it fails to overcome multidrug resistance (MDR) in MCF-7/T cells (taxol-resistant breast cancer cells). Ultrasound (US) can increase the sensitivity of positive-charged NPs thereby making it possible to reverse MDR through inducing NPs' drug release. However, compared with the negative-charged NPs, positive-charged NPs may cause higher toxic effect. Hence, the combination of negative-charged NPs and US may be an efficient strategy for overcoming MDR. The conventional procedure to treat with NPs followed by US exposure possibly destruct multifunctional NPs resulting in its bioactivity inhibition. Herein, we have further improved the operating approach to eliminate US mechanical damage and keep the integrity of negative-charged NPs: cells are exposed to US with microbubbles (MBs) prior to the treatment of H-F-Tat-T NPs. Superior to the conventional method, US sonoporation affects the physiological property of cancer cells while preventing direct promotion of drug release from NPs. The results of the present study displayed that US in condition (1MHz, 10% duty cycle, duration of 80s, US intensity of 0.6W/cm2 and volume ratio of medium to MBs 20:1) combined with H-F-T-Tat-T NPs can achieve optimal reversal MDR effect in MCF-7/T cells. Mechanism study further disclosed that the individual effect of US was responsible for the enhancement of cell membrane permeability, inhibition of cell proliferation rate and down-regulation of MDR-related genes and proteins. Simultaneously, US sonoporation on resistant cancer cells indirectly increased the accumulation of NPs by inducing endosomal escape of negative-charged NPs. Taken together, the overcoming MDR ability for the combined strategy was achieved by the synergistic effect from individual function of NPs, physiological changes of resistant cancer cells and behavior changes of NPs caused by US.


Assuntos
Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Nanopartículas , Fenótipo , Ondas Ultrassônicas , Proliferação de Células/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/metabolismo , Peptídeos Penetradores de Células/farmacologia , Endocitose , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7
18.
Exp Ther Med ; 12(5): 3308-3314, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27882154

RESUMO

Kai-Xin-San (KXS) is a traditional Chinese medicine that has been widely used for the treatment of emotion-related disease. However, the underlying mechanism remains largely unknown. The present study aimed to examine whether phospho-cAMP response element-binding protein (pCREB) and upstream components, such as extracellular signal-regulated kinase (ERK), phospho-ERK (pERK), phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase 3ß (GSK3ß) and pGSK3ß are associated with the antidepressive effect of KXS. In total, 24 male Wistar rats were randomly divided into three groups, including control (n=8, no treatment), induced with chronic unpredictable mild stress (CMS) (n=8), and CMS rats treated with KXS at dosage of 370 mg/kg/day orally. Primary hippocampal neuronal cultures were prepared from Wistar rats for cell survival and proliferation assays. In KXS rats, increased protein expression levels of pCREB, BDNF and tyrosine receptor kinase B (TrkB) were observed in the hippocampus and prefrontal cortex, compared with the CMS model group. Furthermore, increased expression levels of ERK, pERK, PI3K, Akt, and GSK3ß were also detected in the hippocampus and prefrontal cortex of KXS-treated rats compared with CMS model rats and in primary hippocampal neuronal cells treated with KXS. These results suggest that pCREB and upstream components, including TrkB/ERK/CREB and TrkB/PI3 K/CREB, may contribute to the antidepressive effect induced by KXS. Further studies are required to confirm these findings.

19.
Front Pharmacol ; 7: 337, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27729863

RESUMO

As two natural oligosaccharide esters, 3,6'-Disinapoyl sucrose (DISS) and tenuifolisideA (TFSA) are originating from the root of Polygala tenuifolia Willd, a traditional Chinese medicine used in treatment of mental disorders. Previous reports have shown that both of them possess in vitro neuroprotective effects by stimulating different upstream pathways related with cyclic AMP-responsive element-binding protein (CREB). In the present study, we investigated the additive neuroprotective effects of DISS and TFSA on Glu-induced damage of SY5Y cells and purposed the possible underlying mechanism. The interaction between DISS and TFSA showed a clear-cut synergistic effect as evidenced by combination index (CI). Additional evidence from biochemical (NOS activity) assays confirmed their additive inhibition on the Glu-induced NOS hyperactivation. Moreover, we showed that co-treatment of DISS and TFSA resulted in an additively up-regulated phosphorylation of CREB as well as increased expressions of CRTC1 and BDNF. Neuroprotective effects of DISS and TFSA on Glu-induced decrease in cell viability were blocked by MAPK/ERK1/2 inhibitor (U0126) and PI3-K inhibitor (LY290042). Nevertheless, the CRTC1 or BDNF expression induced by these two compounds was significantly reduced in the presence of either ERK or PI3-K inhibitor, indicating that the two oligosaccharide esters shared some common pathways in the regulation of CREB-BDNF pathway. Taken together, we, for the first time, showed that DISS and TFSA exerted the additive neuroprotective effects on CREB-BDNF signaling pathway through complementary mechanisms.

20.
Nanomedicine ; 12(7): 2127-2137, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27262932

RESUMO

Heterogenous cancer cells possess cancer multidrug resistance (MDR) due to their relative quiescence and ABC-transporter expression. Heterogenous cancer cells can be detected by an Rh123 exclusion assay for identifying Rh123low population. In the present study, we fabricated targeted nanoparticles entrapped with Rh123 (Rh123 NPs) to investigate the effect of these targeted nanoparticles on an Rh123low population. The Rh123low population stained by Rh123 NPs exhibited similar heterogeneity to that stained by Rh123. In addition, the ABC-transporters did not contribute to the uptake of Rh123 or Rh123 NPs. Interestingly, ABC-transporters in the Rh123low population stained by Rh123 were possibly responsible for Rh123 efflux, while Rh123 NPs were not susceptible to ABC-transporters in the Rh123low population. It is plausible that the synergistic effect of NPs caused a targeted and endocytic effect which promoted the cellular uptake of Rh123 NPs, and the targeted effect played a more important role.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Resistencia a Medicamentos Antineoplásicos , Nanopartículas , Rodamina 123/farmacocinética , Resistência a Múltiplos Medicamentos , Humanos , Neoplasias
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