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1.
J Cell Biochem ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31571264

RESUMO

Acute coronary syndrome (ACS) is characterized by atherosclerotic plaque rupture with a high incidence of recurrent ischemic events. Several microRNAs are found to be aberrantly expressed in atherosclerotic plaques. This study aims to investigate the effects of microRNA-9 (miR-9) on vulnerable atherosclerotic plaque and vascular remodeling in ACS and underlying mechanisms. Microarray-based gene expression profiling was used to identify differentially expressed genes related to ACS and regulatory miRNAs. Oxidized low-density lipoprotein (lectin-like) receptor 1 (OLR1) was identified to be aberrantly activated in ACS and regulated by miR-9. OLR1 was verified as a target gene of miR-9 by bioinformatics prediction and dual luciferase reporter gene assay. The atherosclerotic models were induced in ApoE-/- mice, in which the agomir or antagomir of miR-9, or small interfering RNA (siRNA) against OLR1 were separately introduced. Serum lipid levels and expression of vascular remodeling and inflammatory response-related factors were determined, respectively. On the basis of the obtained results, in the atherosclerosis mice treated with the agomir of miR-9 and siRNA against OLR1, the p38-mitogen-activated protein kinase (p38MAPK) pathway was inhibited; levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol, tumor necrosis factor-α, interleukin-6, and vascular endothelial growth factor were reduced, but the high-density lipoprotein cholesterol level was increased, along with decreased vulnerable atherosclerotic plaque area and enhanced vascular remodeling. Taken together, these findings suggested an inhibitory role miR-9 acts in the formation of vulnerable atherosclerotic plaques in ACS mice, along with a promoted vascular remodeling, via a negative feedback regulation of OLR1-mediated p38MAPK pathway.

2.
Phys Rev E ; 100(2-1): 022318, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31574598

RESUMO

Edge dynamics is relevant to various real-world systems with complex network topological features. An edge dynamical system is controllable if it can be driven from any initial state to any desired state in finite time with appropriate control inputs. Here a framework is proposed to study the impact of correlation between in- and out-degrees on controlling the edge dynamics in complex networks. We use the maximum matching and direct acquisition methods to determine the controllability limit, i.e., the limit of acceptable change of the edge controllability by adjusting the degree correlation only. Applying the framework to plenty complex networks, we find that the controllability limits are ubiquitous in model and real networks. Arbitrary edge controllability in between the limits can be achieved by properly adjusting the degree correlation. Moreover, a nonsmooth phenomenon occurs in the upper limits, and exponential and power-law scaling behaviors are widespread in the approach or separation speed between the upper and lower limits.

3.
Chin J Nat Med ; 17(9): 698-706, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31526505

RESUMO

Seven new isoquinoline alkaloids, 9-(2'-formyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy dehydroaporphine (1), 9-(2'-formyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy oxoaporphine (2), 3-methoxy-2'-formyl oxohernandalin (3), (-)-9-(2'-methoxycarbonyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy aporphine (4), (-)-2'-methoxycarbonyl thaliadin (5), (-)-9-(2'-methoxyethyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy aporphine (6), (-)-3-methoxy hydroxyhernandalinol (7), together with six known isoquinoline alkaloids (8-13) were isolated from the roots of Thalictrum foetidum. Their structures were elucidated by extensive spectroscopic measurements. Compounds 1 and 2 showed significant selective cytotoxicity against glioma stem cells (GSC-3# and GSC-18#) with IC50 values ranging from 2.36 to 5.37 µg·mL-1.

4.
Theranostics ; 9(18): 5282-5297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410215

RESUMO

Purpose: Methotrexate (MTX) is a first-line drug for rheumatoid arthritis (RA)therapy. However, MTX monotherapy often results in irreversible joint damage due to its slow onset of action and long duration. microRNA-124 (miR-124) has shown direct bone protection activity against RA. A co-delivery system for MTX and microRNA combination may provide therapeutic synergy. Methods: Methotrexate-conjugated polymer hybrid micelles (M-PHMs) were prepared by self-assembly of two functional amphiphilic polymers (MTX-PEI-LA and mPEG-LA) at an optimized weight ratio. Incorporation of microRNA was achieved through electrostatic interactions between microRNA and cationic polymer MTX-PEI-LA. Cellular uptake, endosome escape, biodistribution, and therapeutic efficacy of M-PHMs/miR-124 complexes were investigated and evaluated in RAW264.7 cells and a rat adjuvant-induced arthritis (AIA) model. Results: M-PHMs/miR-124 complexes exhibited folate receptor-mediated uptake in activated RAW264.7 cells. miR-124 was able to escape from the endosome and down-regulate nuclear factor of activated T cells cytoplasmic1 (NFATc1). M-PHMs/miR-124 complexes accumulated in inflamed joints of AIA rats and showed superior therapeutic efficacy through both anti-inflammatory effect and direct bone protective effect. Combination of miR-124 and MTX in these micelles induced disease remission. Conclusions: M-PHMs/miR-124 was highly effective against RA through therapeutic synergy. Additional studies are warranted to further investigate its therapeutic potential and delineate its mechanisms of action.

5.
Poult Sci ; 98(10): 4384-4390, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31329963

RESUMO

The present study aims to investigate the similarities and differences between the host cells apoptosis induced by virulent line of Eimeria tenella (Tsx) and precocious line (PTsx), which can provide a theoretical basis for the study of drugs and vaccines against coccidiosis. HE staining, Hoechst 33342/AnnexinV-FITC/PI composite staining, and ELISA were used to detect the infection rate, apoptosis rate, and Caspase-3 enzyme activity of host cells infected by PTsx or Tsx, respectively. The apoptotic rates and Caspase-3 absorbance of the inoculation groups were lower (P < 0.05 or P < 0.01) than those of the control group at 4 h, whereas the apoptotic rates and Caspase-3 absorbance of the inoculation groups were higher (P < 0.05 or P < 0.01) than those of the control groups at 24 to 120 h. At the same inoculation dose, there was no significant difference in the infection rate, apoptosis rate or Caspase-3 absorbance between Tsx groups and PTsx groups after E. tenella inoculation for 4 to 72 h (P > 0.05). However, these indicators of PTsx groups were lower (P < 0.01) than those of the same dose inoculated Tsx groups at 120 h. The apoptosis rates of cecal and glandular epithelial cells in the inoculated groups were higher (P < 0.01) than those in the control group after inoculated E. tenella 5 D in vivo, and the apoptosis rates of cecal and glandular epithelial cells in PTsx group was lower (P < 0.01) than that in the same dose inoculated Tsx group. These observations indicate that both Tsx and PTsx inhibit host cell apoptosis in the early development of E. tenella, induce host cell apoptosis in the middle and late stages, and the apoptosis-inducing effect on host cells increases with increasing dose. However, when the same dose of oocysts was inoculated, the amount of apoptosis induced by PTsx in late development was less than Tsx.

6.
Int J Biol Sci ; 15(8): 1743-1754, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360116

RESUMO

The cashmere goat breed is known to provide excellent quality cashmere. Here, we attempted to breed high-yielding cashmere goats by specifically inserting the Tß4 gene into the goat CCR5 locus and provided an animal model for future research. We successfully obtained Tß4 knock-in goat without any screening and fluorescent markers using CRISPR/Cas9 technology. A series of experiments were performed to examine physical conditions and characteristics of the Tß4 knock-in goat. The goat exhibited an increase in cashmere yield by 74.5% without affecting the fineness and quality. Additionally, RNA-seq analysis indicated that Tß4 may promote hair growth by affecting processes such as vasoconstriction, angiogenesis, and vascular permeability around secondary hair follicles. Together, our study can significantly improve the breeding of cashmere goat and thereby increase economic efficiency.

7.
Microb Pathog ; 134: 103569, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31163247

RESUMO

Caprine parainfluenza virus type 3 (CPIV3) is one of the important viral respiratory tract agents in goats. The pathogenicity of CPIV3 has been examined in goats but it has not been explored in other laboratory animals. In the present study, an experimental infection of guinea pigs with CPIV3 was performed. The virus-inoculated guinea pigs displayed clinical signs related to the respiratory disease at 2-12 days post inoculation (dpi). Five infected guinea pigs died during 2 and 7 dpi. Apparent gross pneumonic lesions including consolidation and congestion in one or more lung lobes were observed in necropsied and dead animals. Histo-pathological changes in lungs including expansions of the alveolar interstitium, congestion, macrophage infiltration and compensatory emphysema were also observed. Virus was detectable at 2-10 dpi, 2-10 dpi and 2-7 dpi, as detected by virus isolation, real-time RT-PCR and immunohistochemistry staining, respectively. Viremia was also confirmed after CPIV3 infection during 3-7 dpi. The severe pathological lesions and highest viral load were observed before 7 dpi. Viral specific hemagglutination inhibition and neutralizing antibodies were produced from 7 dpi and 10 dpi, respectively, which related to the clearance of virus. The results present here indicated that guinea pig could be an ideal laboratory animal model for CPIV3 studies in the future.

8.
BMC Genomics ; 20(1): 516, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31226933

RESUMO

BACKGROUND: Bovine viral diarrhea virus (BVDV) is an economically important viral pathogen of domestic and wild ruminants. Apart from cattle, small ruminants (goats and sheep) are also the susceptible hosts for BVDV. BVDV infection could interfere both of the innate and adaptive immunity of the host, while the genes and mechanisms responsible for these effects have not yet been fully understood. Peripheral blood mononuclear cells (PBMCs) play a pivotal role in the immune responses to viral infection, and these cells were the target of BVDV infection. In the present study, the transcriptome of goat peripheral blood mononuclear cells (PBMCs) infected with BVDV-2 was explored by using RNA-Seq technology. RESULTS: Goat PBMCs were successfully infected by BVDV-2, as determined by RT-PCR and quantitative real-time RT-PCR (qRT-PCR). RNA-Seq analysis results at 12 h post-infection (hpi) revealed 499 differentially expressed genes (DEGs, fold-change ≥ ± 2, p < 0.05) between infected and mock-infected PBMCs. Of these genes, 97 were up-regulated and the remaining 352 genes were down-regulated. The identified DEGs were found to be significantly enriched for locomotion/ localization, immune response, inflammatory response, defense response, regulation of cytokine production, etc., under GO enrichment analysis. Cytokine-cytokine receptor interaction, TNF signaling pathway, chemokine signaling pathway, etc., were found to be significantly enriched in KEGG pathway database. Protein-protein interaction (PPI) network analysis indicated most of the DEGs related to innate or adaptive immune responses, inflammatory response, and cytokine/chemokine-mediated signaling pathway. TNF, IL-6, IL-10, IL-12B, GM-CSF, ICAM1, EDN1, CCL5, CCL20, CXCL10, CCL2, MAPK11, MAPK13, CSF1R and LRRK1 were located in the core of the network and highly connected with other DGEs. CONCLUSIONS: BVDV-2 infection of goat PBMCs causes the transcription changes of a series of DEGs related to host immune responses, including inflammation, defense response, cell locomotion, cytokine/chemokine-mediated signaling, etc. The results will be useful for exploring and further understanding the host responses to BVDV-2 infection in goats.

9.
Science ; 364(6446)2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31221830

RESUMO

Ruminants are the only extant mammalian group possessing bony (osseous) headgear. We obtained 221 transcriptomes from bovids and cervids and sequenced three genomes representing the only two pecoran lineages that convergently lack headgear. Comparative analyses reveal that bovid horns and cervid antlers share similar gene expression profiles and a common cellular basis developed from neural crest stem cells. The rapid regenerative properties of antler tissue involve exploitation of oncogenetic pathways, and at the same time some tumor suppressor genes are under strong selection in deer. These results provide insights into the evolutionary origin of ruminant headgear as well as mammalian organ regeneration and oncogenesis.

10.
Clin Dermatol ; 37(3): 192-199, 2019 May - Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31178102

RESUMO

Tuberculosis (TB) is still prevalent in many developing countries and can pose a new potential threat to global health due to international migration. As an uncommon form of extrapulmonary TB, cutaneous TB is complicated in its clinical manifestation, pathogenesis, and classification. Cutaneous TB can be divided into two major categories, true cutaneous TB and tuberculid, depending on the source of infection, the route of transmission, the amount of bacteria, and the immune state of the host. Clinical manifestations may include patches and plaques (lupus vulgaris, TB verrucosa cutis), macules and papules (acute miliary TB, papulonecrotid tuberculid, lichen scrofulosorum), nodules, and abscesses (erythema induratum of Bazin, tuberculous gumma), erosions, and ulcers (tuberculous chancre, orificial TB, scrofuloderma), mimicking diverse skin diseases. Uncommon localizations such as external genitalia, unusual presentations such as nodular granulomatous phlebitis, and coexistence with other morbidities such as Behçet disease and acne inversa or hidradenitis suppurativa deserve special attention. Treatment of both true and tuberculid cutaneous TB follows the same drug regimens of the World Health Organization's recommendation for treatment of new cases of pulmonary TB. Erythema induratum of Bazin may need longer treatment duration and adjuvants such as dapsone, potassium iodide, doxycycline, and corticosteroids to tackle inflammation. Misdiagnosis and undertreatment in daily practice are likely, and contemplation of this classic great imitator in dermatology is warranted.

11.
Adv Healthc Mater ; 8(8): e1900015, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30868753

RESUMO

Two principal methods for cancer drug testing are widely used, namely, in vitro 2D cell monolayers and in vivo animal models. In vitro 2D culture systems are simple and convenient but are unable to capture the complexity of biological processes. Animal models are costly, time-consuming, and often fail to replicate human activity. Here a microfluidic tumor-on-a-chip (TOC) model designed for assessing multifunctional liposome cancer targeting and efficacy is presented. The TOC device contains three sets of hemispheric wells with different sizes for tumor spheroid formation and evaluation of liposomes under a controlled flow condition. There is good agreement between time-elapsed tumor targeting of fluorescent liposomes in the TOC model and in in vivo mouse models. Evaluation of the anticancer efficacy of four PTX-loaded liposome formulations shows that compared to 2D cell monolayers and 3D tumor spheroid models, the TOC model better predicts the in vivo anticancer efficacy of targeted liposomes. Lastly, the TOC model is used to assess the effects of flow rates and tumor size on treatment outcome. This study demonstrates that the TOC model provides a convenient and powerful platform for rapid and reliable cancer drug evaluation.

12.
Anticancer Res ; 39(3): 1169-1178, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30842146

RESUMO

BACKGROUND/AIM: Effective and targeted delivery of siRNA to tumor cells is a prerequisite to achieving their therapeutic effects. Survivin is up-regulated in tumor cells and is associated with resistance to therapy. Therefore, siRNA-mediated silencing of survivin is a potential therapeutic strategy for cancer. The aim of the study was to examine whether polymeric hybrid micelles can be used to effectively deliver siRNAs into cells. MATERIALS AND METHODS: First, linoleic acid (LA) was conjugated to polyethylenimine (PEI) and methoxy-polyethyleneglycol (mPEG) and two amphiphilic polymers (PEI-LA and mPEG-LA) were obtained. Polymeric hybrid micelle (PHM) was then prepared and characterized by self-assembly of PEI-LA and mPEG-LA at different percentages of the two amphiphilic polymers. A PHM/siRNA complex with optimized composition and good biocompatibility was then prepared and its cellular uptake, biodistribution, and antitumor effects were investigated. RESULTS: Survivin siRNA was efficiently delivered to the cells. It reduced survivin protein expression and greatly suppressed tumor growth. Moreover, siRNA loaded in PHM gathered in a solid tumor in mice and achieved an improved anticancer effect compared to naked siRNA. CONCLUSION: PHM is a promising and safe vehicle for siRNA delivery and may find utility in cancer therapy.


Assuntos
Micelas , Neoplasias/terapia , RNA Interferente Pequeno/administração & dosagem , Células A549 , Animais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Ácido Linoleico/administração & dosagem , Ácido Linoleico/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Polietilenoimina/administração & dosagem , Polietilenoimina/química , RNA Interferente Pequeno/farmacocinética , Survivina/genética , Survivina/metabolismo , Carga Tumoral
13.
Interv Neuroradiol ; 25(4): 454-459, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30803339

RESUMO

BACKGROUND: Rupture of cerebral aneurysm is an inevitable complication during embolization, followed by subsequent acute subarachnoid hemorrhage or intracranial hematoma, and results in the aggravation of a patient's condition. In particular, for patients who have had a ruptured aneurysm, urgent treatment strategies are required during operation. The most common hemostatic methods seen in clinical practices are as follows: after lowering the blood pressure, we continue to embolize the aneurysms with detachable coils as soon as possible or inject with Glubran/Onyx embolization liquids, as well as use a balloon catheter to temporarily block the blood supply. If the conditions are permissible, a balloon guiding catheter may even be used to restrict the proximal blood flow. At times, due to limitations of these methods, neurosurgeons are requested to perform craniotomy to treat the hemostasis. However, the delayed transition often leads to rapid deterioration of the patient's condition and even death due to cerebral hernia. CASE DESCRIPTION: We herein presented two cases of ruptured cerebral aneurysms to provide an alternative method for hemostasis and to save the lives of patients as much as possible. In an extremely urgent situation (conventional treatment is ineffective), we successfully saved the patient's life by injecting lyophilizing thrombin powder (LTP) solution into the aneurysmal sac and the parent artery through a microcatheter. CONCLUSIONS: To our knowledge, this is the first report of successful hemostasis during coil embolization of ruptured cerebral aneurysm with LTP. Further prospective studies are needed to confirm the safety and efficacy of LTP in cerebrovascular interventional therapy.

14.
Environ Pollut ; 247: 595-606, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30708322

RESUMO

Graphene family nanomaterials (GFNs) have attracted significant attention due to their unique characteristics and applications in the fields of biomedicine and nanotechnology. However, previous studies highlighted the in vitro and in vivo toxicity of GFNs with size and oxidation state differences are still elusive. Therefore, we prepared graphene (G) and graphene oxide (GO) of three different sizes (S-small, M-medium, and L-large), and characterized them using multiple surface-sensitive analytical techniques. In vitro assays using HEK 293T cells revealed that the small and large sizes of G and GO significantly reduced the cell viability and increased DNA damage, accompanying with activated reactive oxygen species (ROS) generation and induced various expressions of associated critical genetic markers. Moreover, the bacterial assays highlighted that G and GO caused strong acute toxicity on Tox2 bacteria. Effects of G were higher than GO and showed size dependent effect: L > M > S, while the medium size of GO induced mild genetic toxicity on RecA bacteria. In vivo assays revealed that exposure to G and GO caused the developmental toxicity, induced ROS generation, and activated related pathways (specifically GO) in zebrafish. Taken together, G showed stronger ability to decrease the survival rate and induce the acute toxicity, while GO showed obvious toxicity in terms of DNA damages, ROS generation, and abnormal gene expressions. Our findings highlighted that G and GO differentially induced toxicity based on their varying physical characteristics, especially sizes and oxidation state, and exposure concentrations and sensitivity of the employed in vitro and in vivo models. In short, this study provided deep insights on the negative effects of GFNs exposure.


Assuntos
Grafite/toxicidade , Nanoestruturas/toxicidade , Óxidos/química , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Proteínas HMGB , Humanos , Oxirredução
15.
Biomed Eng Online ; 18(1): 11, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30704488

RESUMO

BACKGROUND: Docetaxel (DTX) is an anticancer drug that is currently formulated with polysorbate 80 and ethanol (50:50, v/v) in clinical use. Unfortunately, this formulation causes hypersensitivity reactions, leading to severe side-effects, which have been primarily attributed to polysorbate 80. METHODS: In this study, a DTX-loaded human serum albumin (HSA) nanoparticle (DTX-NP) was designed to overcome the hypersensitivity reactions that are induced by polysorbate 80. The methods of preparing the DTX-NPs have been optimized based on factors including the drug-to-HSA weight ratio, the duration of HSA incubation, and the choice of using a stabilizer. Synthesized DTX-NPs were characterized with regard to their particle diameters, drug loading capacities, and drug release kinetics. The morphology of the DTX-NPs was observed via scanning electron microscopy (SEM) and the successful preparation of DTX-NPs was confirmed via differential scanning calorimetry (DSC). The cytotoxicity and cellular uptake of DTX-NPs were investigated in the non-small cell lung cancer cell line A549 and the maximum tolerated dose (MTD) of DTX-NPs was evaluated via investigations with BALB/c mice. RESULTS: The study showed that the loading capacity and the encapsulation efficiency of DTX-NPs prepared under the optimal conditions was 11.2 wt% and 63.1 wt%, respectively and the mean diameter was less than 200 nm, resulting in higher permeability and controlled release. Similar cytotoxicity against A549 cells was exhibited by the DTX-NPs in comparison to DTX alone while higher maximum tolerated dose (MTD) with the DTX-NPs (75 mg/kg) than with DTX (30 mg/kg) was demonstrated in mice, suggesting that the DTX-NPs prepared with HSA yielded similar anti-tumor activity but were accompanied by less systemic toxicity than solvent formulated DTX. CONCLUSIONS: DTX-NPs warrant further investigation and are promising candidates for clinical applications.


Assuntos
Docetaxel/química , Portadores de Fármacos/química , Nanopartículas/química , Albumina Sérica Humana/química , Células A549 , Transporte Biológico , Técnicas de Química Sintética , Docetaxel/farmacologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Humanos , Nanotecnologia , Albumina Sérica Humana/síntese química , Albumina Sérica Humana/metabolismo
16.
Int J Nanomedicine ; 14: 135-148, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30613142

RESUMO

Background: We previously developed cabazitaxel (CTX)-loaded human serum albumin nanoparticles (NPs-CTX) via a self-assembly method, and these NPs showed efficacy in prostate cancer therapy. Many studies have shown that the levels of folic acid (FA) receptor on the surface of various tumor cells are high. Therefore, FA-modified NPs-CTX may have enhanced antitumor effects compared with unmodified NPs-CTX. Methods: NPs-CTX were first prepared via self-assembly, and FA was conjugated on the surface of NPs-CTX through the -NH2 groups of the NPs to produce FA-NPs-CTX. The FA-NPs-CTX were evaluated in tumor cells with high FA receptor (FR) expression in vitro and in vivo. Results: Both NPs-CTX and FA-NPs-CTX exhibited good stability and morphology. Drug release from the NPs was not affected by FA conjugation. Compared with CTX dissolved in a mixture of Tween 80 and 13% ethanol (w/w) at a ratio of 1:4 (v/v) (Tween-CTX), the two nanoformulations had lower lytic activity against normal red blood cells. However, FA-NPs-CTX showed greater inhibition of tumor cells with overexpressed FR, compared with NPs-CTX, in the cytotoxicity experiments. Moreover, the cellular uptake of FA-NPs-CTX was enhanced through FR-mediated endocytosis in HeLa cells in vitro and HeLa xenograft tumors in vivo. Although Tween-CTX exhibited tumor growth inhibition similar to FA-NPs-CTX in vivo, this inhibition also caused adverse side effects; the median lethal dose (LD50) of Tween-CTX to mice was 5.68 mg/kg, while FA-NPs-CTX-treated mice survived at doses exceeding 400 mg/kg. Conclusion: The results showed that FA-NPs-CTX caused inhibition of tumor growth in a manner similar to that of Tween-CTX; however, the safety and tolerability of CTX were greatly improved by FA conjugation compared with those of Tween-CTX. In summary, FA-NPs-CTX have great potential in CTX delivery, and this formulation is a promising candidate for the treatment of cancers with high FR levels.


Assuntos
Sistemas de Liberação de Medicamentos , Receptor 2 de Folato/metabolismo , Nanopartículas/química , Neoplasias/tratamento farmacológico , Albumina Sérica Humana/metabolismo , Taxoides/uso terapêutico , Células A549 , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Endocitose , Feminino , Ácido Fólico/metabolismo , Células HeLa , Hemólise/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/ultraestrutura , Neoplasias/patologia , Taxoides/farmacologia , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Anticancer Res ; 39(1): 237-243, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30591464

RESUMO

BACKGROUND/AIM: Glioma is a deadly form of brain cancer. Doxorubicin is cytotoxic against glioma cells. However, the blood-brain barrier (BBB) limits its ability to be delivered to the brain. MATERIALS AND METHODS: Liposomes (R8PLP) formed from, 1,2-dioleoyl-3-trimethylammonium-propane chloride (DOTAP), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-(polyethylene glycol)-2000] (PEG-DSPE), cholesterol and egg phosphatidylcholine (ePC) were modified by cell-penetrating peptide R8 conjugated with oleic acid as a novel method for delivering doxorubicin. The antitumor effect of R8PLP was evaluated by uptake, cytotoxicity and brain accumulation. RESULTS: The size of R8PLP was 95 nm. Doxorubicin was loaded into R8PLP by active loading with more than 95% encapsulation efficiency. Cellular uptake of R8PLP by U87-MG cells was 8.6-fold higher than that of unmodified liposomes. R8PLP reduced cell viability by 16.18% and 18.11% compared to cholesterol-ePC-liposomes and free doxorubicin, respectively, at 3.6 µM after 24 h treatment. The biodistribution of doxorubicin in the brain was significantly improved by R8PLP. The area under the concentration-time curve (AUC0.5-12 h) of R8PLP was 2.4-times higher than that of cholesterol-ePC-PEG-DSPE-liposomes. CONCLUSION: These results suggest that R8-conjugated oleic acid-modified liposomes are effective delivery vehicles for glioma.


Assuntos
Peptídeos Penetradores de Células/administração & dosagem , Sistemas de Liberação de Medicamentos , Glioma/tratamento farmacológico , Nanopartículas/administração & dosagem , Barreira Hematoencefálica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Colesterol/química , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Ácidos Graxos Monoinsaturados/química , Glioma/patologia , Humanos , Lipossomos/administração & dosagem , Lipossomos/química , Nanopartículas/química , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Compostos de Amônio Quaternário/química , Distribuição Tecidual/efeitos dos fármacos
18.
Curr Med Chem ; 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30378483

RESUMO

Polyethylenimine (PEI) is well-known as the non-viral gene delivery vector, especially for the oligonucleotides delivery. However, its clinical applications are significantly limited due to its high cationic charge, low cell recognition, and interaction with the proteins and non-target cells in the biological fluids, resulting in high cytotoxicity, poor stability and low transfection efficiency for oligonucleotides transporting. Many researchers have concluded that the molecular weight (MW) of PEI, degree of branched or linear structure, N/P ratio, buffer capacity, oligonucleotides structure, culture medium pH, serum, and different types of PEI-based particles including preparation methods make a great difference in the cell toxicity, stability, transfection efficiency for the PEI-based oligonucleotides delivery systems. Ligands, small molecules, peptides targeting conjugation, hydrophobic, hydrophilic, and amphiphilic modification of PEI are also deeply investigated to reduce the cell toxicity and improve the stability, transfection efficiency, and therapeutic effect. Moreover, various intelligent modifications of PEI such as pH responsive bond (hydrazone bond) and redox sensitive bond (disulfide bond) could accurately control oligonucleotides release and have attracted attention for efficient oligonucleotides delivery. In general, the efficient oligonucleotides delivery could be achieved by the different modifications of PEI with optimized parameters of PEI or PEI-based formulations.

19.
ACS Nano ; 12(11): 11600-11609, 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30380832

RESUMO

Nanoparticle tumor accumulation relies on a key mechanism, the enhanced permeability and retention (EPR) effect, but it remains challenging to decipher the exact impact of the EPR effect. Animal models in combination with imaging modalities are useful, but it is impossible to delineate the roles of multiple biological barriers involved in nanoparticle tumor accumulation. Here we report a microfluidic tumor-vasculature-on-a-chip (TVOC) mimicking two key biological barriers, namely, tumor leaky vasculature and 3D tumor tissue with dense extracellular matrix (ECM), to study nanoparticle extravasation through leaky vasculature and the following accumulation in tumor tissues. Intact 3D tumor vasculature was developed with selective permeability of small molecules (20 kDa) but not large ones (70 kDa). The permeability was further tuned by cytokine stimulation, demonstrating the independent control of the leaky tumor vasculature. Combined with tumor spheroids in dense ECM, our TVOC model is capable of predicting nanoparticles' in vivo tumor accumulation, thus providing a powerful platform for nanoparticle evaluation.

20.
Vet Microbiol ; 224: 58-65, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30269791

RESUMO

Caprine parainfluenza virus type 3 (CPIV3) is an important respiratory pathogen in the goat industry and was detected in China in 2014. Numerous studies have shown that microRNAs (miRNAs) play critical roles in viral infections, but the involvement of miRNAs during CPIV3 infection is poorly understood. In this study, we showed by deep sequencing that a panel of miRNAs, including bta-miR-222, were significantly downregulated in Madin-Darby bovine kidney (MDBK) cells infected with CPIV3 strain JS2013 compared with uninfected MDBK cells. Overexpression of bta-miR-222 significantly reduced CPIV3 replication in vitro, while inhibition of endogenous bta-miR-222 enhanced CPIV3 replication. Bta-miR-222 enhanced type I interferon expression and suppressed CPIV3 replication in MDBK cells. Moreover, we showed using luciferase reporter assays that bta-miR-222 directly targeted the 3'-untranslated region of interferon regulatory factor 2 (IRF2). Transfection of cells with bta-miR-222 mimics resulted in decreased IRF2 mRNA and protein levels, with a consequent increase in type I interferon levels and potentiation of antiviral responses. Together, these data demonstrate the important role of bta-miR-222 in restricting CPIV3 replication and suggest potential antiviral strategies against CPIV3.

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