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1.
Int J Mol Sci ; 21(3)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973146

RESUMO

In the current study, we identified a transcription factor, MYB14, from Chinese wild grape, Vitis quinquangularis-Pingyi (V. quinquangularis-PY), which could enhance the main stilbene contents and expression of stilbene biosynthesis genes (StSy/RS) by overexpression of VqMYB14. The promoter of VqMYB14 (pVqMYB14) was shown to be induced as part of both basal immunity (also called pathogen-associated molecular pattern (PAMP)-triggered immunity, PTI) and effector-triggered immunity (ETI), triggered by the elicitors flg22 and harpin, respectively. This was demonstrated by expression of pVqMYB14 in Nicotiana benthamiana and Vitis. We identified sequence differences, notably an 11 bp segment in pVqMYB14 that is important for the PTI/ETI, and particularly for the harpin-induced ETI response. In addition, we showed that activation of the MYB14 promoter correlates with differences in the expression of MYB14 and stilbene pattern induced by flg22 and harpin. An experimental model of upstream signaling in V. quinquangularis-PY is presented, where early defense responses triggered by flg22 and harpin partially overlap, but where the timing and levels differ. This translates into a qualitative difference with respect to patterns of stilbene accumulation.

2.
Eur J Pharmacol ; 872: 172944, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31978424

RESUMO

Salvianolate has been widely used for the treatment of cerebrovascular diseases. However, the detailed molecular mechanism of how it alleviates cerebral ischaemia-reperfusion injury is not well understood. In the present study, we investigated the neuroprotective effects of salvianolate in acute cerebral infarction using the PC12 cell oxygen-glucose deprivation (OGD) model in vitro and the rat transient middle cerebral artery occlusion (MCAO) model in vivo. The results showed that the salvianolate significantly reduced the level of reactive oxygen species and inhibited the Caspase-3 signalling pathway in vitro; at the same time, in vivo experiments showed that salvianolate obviously reduced the infarct area (12.9%) and repaired cognitive function compared with the model group (28.28%). In conclusion, our data demonstrated that the salvianolate effectively alleviated cerebral ischaemia-reperfusion injury via suppressing the Caspase-3 signalling pathway.

3.
J Org Chem ; 85(2): 622-632, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31799847

RESUMO

An efficient Pd-catalyzed arylation of alkylpyridine based on the pyridinium activation strategy has been developed for synthesis of mixed aryl alkylpyridines. It was found that (1) the N-methyl group in the pyridinium salts acted as a transient activator and could be automatically departed after the reaction, (2) CuBr was an indispensable additive for achieving the C6-selective arylation, (3) the α-branched alkyl chain on the alkylpyridine greatly increased the yield of the product. Deuterium labelling experiment revealed that in the case of the α-branched alkylpyridine, the presence of CuBr completely inhibited the H/D exchange at the benzylic position and thus enabled the selective arylation at the C6 position. This protocol demonstrates a broad substrate scope, and with respect to both the aryl iodides and the α-branched alkylpyridine, the desired mixed aryl alkylpyridines were obtained in generally good to excellent yields.

4.
Org Lett ; 21(23): 9425-9429, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31810112

RESUMO

A simple and efficient method for the synthesis of isoquinolone and isocoumarin derivatives is reported. The method for the first time provides a one-step divergent synthesis of important isoquinolone and isocoumarin skeletons from benzoic acid by switching the coupling partners. In addition, a reliable mechanism has been proposed on the basis of experimental investigations, including kinetic isotope effect experiments, 13C labeling experiments, time-tracking experiments, and competitive experiments, as well as DFT calculation studies.

5.
Chem Commun (Camb) ; 55(82): 12384-12387, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31559990

RESUMO

Herein, we report the first example of synthesis of N-substituted lactams via an acceptorless dehydrogenative coupling of diols with primary amines in one step, which was enabled by combining Ru3(CO)12 with a hybrid N-heterocyclic carbene-phosphine-phosphine ligand as the catalyst.

6.
Acta Pharm Sin B ; 9(4): 843-857, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31384543

RESUMO

Chemotherapy outcomes for the treatment of glioma remains unsatisfactory due to the inefficient drug transport across the blood-brain barrier (BBB) and insufficient drug accumulation in the tumor region. Although many approaches, including various nanosystems, have been developed to promote the distribution of chemotherapeutics in the brain tumor, the delivery efficiency and the possible damage to the normal brain function still greatly restrict the clinical application of the nanocarriers. Therefore, it is urgent and necessary to discover more safe and effective BBB penetration and glioma-targeting strategies. In the present study, menthol, one of the strongest BBB penetration enhancers screened from traditional Chinese medicine, was conjugated to casein, a natural food protein with brain targeting capability. Then the conjugate self-assembled into the nanoparticles to load anti-cancer drugs. The nanoparticles were characterized to have appropriate size, spheroid shape and high loading drug capacity. Tumor spheroid penetration experiments demonstrated that penetration ability of menthol-modified casein nanoparticles (M-CA-NP) into the tumor were much deeper than that of unmodified nanoparticles. In vivo imaging further verified that M-CA-NPs exhibited higher brain tumor distribution than unmodified nanoparticles. The median survival time of glioma-bearing mice treated with HCPT-M-CA-NPs was significantly prolonged than those treated with free HCPT or HCPT-CA-NPs. HE staining of the organs indicated the safety of the nanoparticles. Therefore, the study combined the advantages of traditional Chinese medicine strategy with modern delivery technology for brain targeting, and provide a safe and effective approach for glioma therapy.

7.
J Org Chem ; 84(14): 9151-9160, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31273988

RESUMO

A selective catalytic system for the dehydrogenation of primary alcohols to carboxylic acids using a facial ruthenium complex generated in situ from the [Ru(COD)Cl2]n and a hybrid N-heterocyclic carbene (NHC)-phosphine-phosphine ligand (CPP) has been first reported. The facial coordination model was unveiled by NMR analysis of the reaction mixture. Such a fac-ruthenium catalyst system exhibited high catalytic activity and stability, and a high turnover number of 20 000 could be achieved with catalyst loading as low as 0.002 mol %. The exceedingly high catalyst stability was tentatively attributed to both the anchoring role of NHC and the hemi-lability of phosphines. The catalytic system also features a wide substrate scope. In particular, the facial coordination of CPP ligands was found to be beneficial for sterically hindered alcohols, and ortho-substituted benzylic alcohols and bulky adamantanyl methanol as well as cholesterol were all found to be viable dehydrogenation substrates.

8.
Water Res ; 159: 77-86, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078754

RESUMO

Biochars are low-cost and environmental-friendly materials, which are promising in wastewater treatment. In this study, biochars were manufactured from C-phycocyanin extracted (C-CP) Spirulina residue (SDBC) via thermal pyrolysis. Simultaneously, N-doping was also achieved from the protein in the algae for obtaining a high-performance carbocatalyst for peroxydisulfate (PDS) activation. The SDBC yielded large specific surface areas, nitrogen loading, and good conductivity, which demonstrated excellent oxidation efficiencies toward a wide array of aqueous microcontaminants. An in-depth mechanistic study was performed by integrating selective radical scavenging, solvent exchange (H2O to D2O), diverse organic probes, and electrochemical measurement, unveiling that SDBC/PDS did not rely on free radicals or singlet oxygen but a nonradical pathway. PDS intimately was bonded with a biochar (SDBC 900-acid, pyrolysis at 900 °C) to form a surface reactive complex that subsequently attacked an organic sulfamethoxazole (SMX) adsorbed on the biochar via an electron-transfer regime. During this process, the SDBC 900-acid played versatile roles in PDS activation, organic accumulation and mediating the electron shuttle from SMX to PDS. This nonradical system can maintain a superior oxidation efficiency in complicated water matrix and long-term stable operation. More importantly, the nonradical species in SDBC 900-acid/PDS system were capable of inactivating the bacteria (Escherichia coli) in wastewater. Therefore, the biochar based nonradical system can provide a mild and high-efficiency strategy for disinfection in waste and drinking water by green carbocatalysis. This study provides not only a value-added biochar catalyst for wastewater purification but also the first insight into the bacteria inactivation via nonradical oxidation.


Assuntos
Grafite , Spirulina , Carvão Vegetal , Desinfecção , Ficocianina
9.
ACS Nano ; 13(4): 4148-4159, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30855941

RESUMO

Pore-forming toxins (PFTs) are the most common bacterial virulence proteins and play a significant role in the pathogenesis of bacterial infections; thus, PFTs are an attractive therapeutic target in bacterial infections. Inspired by the pore-forming process and mechanism of PFTs, we designed an integrated hybrid nanovesicle-the erythroliposome (called the RM-PL)-for PFT detoxification by fusing natural red blood cell (RBC) membranes with artificial lipid membranes. The lipid and RBC membranes were mutually beneficial when integrated into a hybrid nanovesicle structure. The RBC membrane endowed RM-PLs with the capacity for detoxification, while the PEGylated lipid membrane stabilized the RM-PLs and greatly improved the detoxification capacity of the RBC membrane. With α-hemolysin (Hlα) as a model PFT, we demonstrated that RM-PLs could not only significantly reduce the toxicity of Hlα to erythrocytes in vitro but also effectively sponge Hlα in vivo and rescue mice from Hlα-induced damage. Moreover, the high detoxification capacity of RM-PLs was shown to be partly related to the expression of the Hlα receptor protein, a disintegrin and metalloproteinase domain-containing protein 10 on the RBC membrane. Consequently, as a component integrating natural and artificial materials, the erythroliposome nanoplatform inspires potential strategies for antivirulence therapy.

10.
Environ Int ; 126: 302-308, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30825749

RESUMO

Regulated disposal or re-utilization of dewatered sludge is of economic benefits and can avoid secondary contamination to the environment; however, feasible and effective management strategies are still lacking. In this study, a peroxydisulfate/zero-valent iron (PDS-ZVI) system is proposed to destroy proteins in soluble extracellular polymeric substances (S-EPS) and loosely bound EPS (LB-EPS) in anaerobic digested sludge (ADS) to improve the dewaterability. Moreover, ADS derived biochars supported via iron oxides (Fe-ADSBC) were generated by dewatering and thermal annealing. Intriguingly, the iron species was discovered to gradually transform from Fe3O4 to FeO with increased pyrolysis temperatures from 600 to 1000 °C. The manipulated iron species on the biochar can remarkably impact the catalytic activity in PDS activation and degradation of sulfamethazine (SMT). The in situ radical scavenging and capturing tests revealed that the principal reactive oxygen species (ROS) in Fe-ADSBC/PDS system experienced a variation from OH into SO4- at higher annealing temperature (1000 °C). In addition, the carbonaceous ADSBC can promote the catalytic activity of iron oxides by synergistically facilitating the adsorption of reactants and charge transfer through COFe bonds at the interfaces. This study enables the first insights into the properties and catalytic performance of Fe-ADSBC, meanwhile unveils the mechanism, reaction pathways, and environmental impacts of the ultimate transformation products (TPs) from SMT degradation in the Fe-ADSBC/PDS system. The study also contributes to developing value-added green biochar catalysts from bio-wastes towards environmental purification.


Assuntos
Carvão Vegetal/química , Esgotos/química , Anaerobiose , Catálise , Meio Ambiente , Ferro/química , Fenômenos Magnéticos , Oxirredução , Óxidos/química , Compostos de Potássio/química , Sulfatos/química
11.
Planta ; 249(6): 1889-1902, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30864013

RESUMO

MAIN CONCLUSION: MYB15 promoter of Vitis quinquangularis has potential as a target for disease resistance breeding, and its involvement in PTI is associated with a range of defense mechanisms. China is a center of origin for Vitis and is home to diverse wild Vitis genotypes, some of which show superior pathogen resistance, although the underlying molecular basis for this has not yet been elucidated. In the current study, we identified a transcription factor, MYB15, from the Chinese wild grape, Vitis quinquangularis, whose promoter region (pVqMYB15) was shown to be induced by basal immunity (also called PAMP-triggered immunity, PTI) triggered by flg22, following heterologous expression in Nicotiana benthamiana and homologous expression in grapevine. By analyzing the promoter structure and activity, we identified a unique 283 bp sequence that plays a key role in the activation of basal immunity. In addition, we showed that activation of the MYB15 promoter correlates with differences in the expression of MYB15 and RESVERATROL SYNTHASE (RS) induced by the flg22 elicitor. We further tested whether the MYB15 induction triggered by flg22 was consistent with MYB15 and RS expression following inoculation with Plasmopara viticola in grape (V. quinquangularis and Vitis vinifera) leaves. Mapping upstream signals, we found that calcium influx, an RboH-dependent oxidative burst, an MAPK cascade, and jasmonate and salicylic acid co-contributed to flg22-triggered pVqMYB15 activation. Our data suggest that the MYB15 promoter has potential as a target for disease resistance breeding, and its involvement in PTI is associated with a range of defense mechanisms.


Assuntos
Resistência à Doença/genética , Oomicetos/fisiologia , Doenças das Plantas/imunologia , Reguladores de Crescimento de Planta/metabolismo , Fatores de Transcrição/metabolismo , Vitis/genética , China , Ciclopentanos/metabolismo , Oxilipinas/metabolismo , Melhoramento Vegetal , Doenças das Plantas/microbiologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regiões Promotoras Genéticas/genética , Ácido Salicílico/metabolismo , Fatores de Transcrição/genética , Vitis/imunologia , Vitis/fisiologia
12.
Org Lett ; 21(4): 1002-1006, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30730151

RESUMO

The first iridium-catalyzed oxidative alkeynylation of benzylamines with acrylates enabled by a new directing group pentafluorobenzoyl has been developed. The reaction proceeded efficiently in the presence of silver acetate as oxidant and chlorobenzene as solvent. A good range of benzylamines could be selectively monoalkenylated without interfering with further aza-Michael addition. The kinetic isotope effect experiments showed that C-H activation is not the rate-limiting step. In addition, a five-membered iridacycle species was isolated and established as the possible key intermediate.

13.
J Org Chem ; 84(4): 2158-2168, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30676029

RESUMO

Herein, an efficient and green method for the selective synthesis of tertiary amines has been developed that involves iridium-catalyzed alkylation of various primary amines with aromatic or aliphatic alcohols. Notably, the catalytic protocol enables this transformation in the absence of additional base and solvent. Furthermore, the alkylation of nitrobenzene with primary alcohol to tertiary amine has also been achieved by the same catalytic system. Deuterium-labeling experiments and a series of control experiments were conducted, and the results suggested that an intermolecular borrowing hydrogen pathway might exist in the alkylation process.

14.
Nano Lett ; 19(1): 124-134, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30521345

RESUMO

The targeted delivery of therapeutics to sites of rheumatoid arthritis (RA) has been a long-standing challenge. Inspired by the intrinsic inflammation-targeting capacity of macrophages, a macrophage-derived microvesicle (MMV)-coated nanoparticle (MNP) was developed for targeting RA. The MMV was efficiently produced through a novel method. Cytochalasin B (CB) was applied to relax the interaction between the cytoskeleton and membrane of macrophages, thus stimulating MMV secretion. The proteomic profile of the MMV was analyzed by iTRAQ (isobaric tags for relative and absolute quantitation). The MMV membrane proteins were similar to those of macrophages, indicating that the MMV could exhibit bioactivity similar to that of RA-targeting macrophages. A poly(lactic- co-glycolic acid) (PLGA) nanoparticle was subsequently coated with MMV, and the inflammation-mediated targeting capacity of the MNP was evaluated both in vitro and in vivo. The in vitro binding of MNP to inflamed HUVECs was significantly stronger than that of the red blood cell membrane-coated nanoparticle (RNP). Compared with bare NP and RNP, MNP showed a significantly enhanced targeting effect in vivo in a collagen-induced arthritis (CIA) mouse model. The targeting mechanism was subsequently revealed according to the proteomic analysis, indicating that Mac-1 and CD44 contributed to the outstanding targeting effect of the MNP. A model drug, tacrolimus, was encapsulated in MNP (T-RNP) and significantly suppressed the progression of RA in mice. The present study demonstrates MMV as a promising and rich material, with which to mimic macrophages, and demonstrates that MNP is an efficient biomimetic vehicle for RA targeting and treatment.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Nanopartículas/administração & dosagem , Proteômica , Animais , Artrite Reumatoide/patologia , Citocalasina B/química , Modelos Animais de Doenças , Eritrócitos/química , Eritrócitos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Receptores de Hialuronatos/genética , Antígeno de Macrófago 1/genética , Macrófagos/química , Camundongos , Nanopartículas/química , Poliésteres/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Tacrolimo
15.
Org Lett ; 20(21): 6755-6759, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30346794

RESUMO

An efficient rhodium(III)-catalyzed self-annulation of N-vinylarylamide has been developed. This reaction features a simple system and good reactivity with complete regioselectivity. The protocol provides easy access to an aminal incorporated dihydroisoquinolinone, which proved to be a versatile synthetic synthon. The kinetic isotope effect experiments showed that C-H activation is the rate-limiting step, and competition studies revealed the annulation exhibits a strong self-recognition mode. In addition, a seven-membered rhodacycle species was isolated and established as the key reaction intermediate.

16.
J Org Chem ; 83(17): 10389-10397, 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30037224

RESUMO

Recently, we realized the highly selective one-pot synthesis of 2,6-diarylpyridines by using a Pd-catalyzed direct C-H arylation approach via a transient activator strategy. Although methylation reagent as a transient activator and Cu(I) salt or oxide were found to be prerequisites, details regarding the mechanism remained unclear. In this paper, DFT calculations combined with experimental investigations were carried out to elucidate the principle features of this transformation. The results reveal (1) the origin of the exquisite diarylating selectivity of the pyridine under the transient strategy; (2) the possible demethylating reagent as the counteranion of the pyridinium salt; (3) the reason why Cu2O is a better Cu(I) resource than others.

17.
Acta Pharm Sin B ; 8(1): 14-22, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29872619

RESUMO

Taking inspiration from nature, the biomimetic concept has been integrated into drug delivery systems in cancer therapy. Disguised with cell membranes, the nanoparticles can acquire various functions of natural cells. The cell membrane-coating technology has pushed the limits of common nano-systems (fast elimination in circulation) to more effectively navigate within the body. Moreover, because of the various functional molecules on the surface, cell membrane-based nanoparticles (CMBNPs) are capable of interacting with the complex biological microenvironment of the tumor. Various sources of cell membranes have been explored to camouflage CMBNPs and different tumor-targeting strategies have been developed to enhance the anti-tumor drug delivery therapy. In this review article we highlight the most recent advances in CMBNP-based cancer targeting systems and address the challenges and opportunities in this field.

18.
Molecules ; 23(3)2018 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-29498696

RESUMO

Ischemic stroke (IS) is characterized by the sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. It has been a worldwide critical disease threatening to the health and life of human beings. Despite significant progresses achieved, effective treatment still remains a formidable challenge due to the complexity of the disease. Salvianolic acid B (Sal-B) and Puerarin (Pue) are two active neuroprotectants isolated from traditional Chinese herbs, Salvia miltiorrhiza and Kudzu root respectively, which have been used for the prevention and treatment of IS for thousands of years in China. The activities of two compounds against cerebral ischemia reperfusion injury have been confirmed via various pathways. However, the therapeutic efficacy of any of the two components is still unsatisfied. In the present study, the effect of the combination of Sal-B and Pue on IS was evaluated and validated in vitro and in vivo. The ratio of two compounds was firstly optimized based on the results of CoCl2 damaged PC12 cells model. The co-administration exhibited significantly protective effect in CoCl2 induced PC12 cells injury model by reducing ROS, inhibiting apoptosis and improving mitochondrial membrane potential in vitro. Moreover, Sal-B + Pue significantly relieved neurological deficit scores and infarct area than Sal-B or Pue alone in vivo. The results indicated that neuroprotection mechanism of Sal-B + Pue was related to TLR4/MyD88 and SIRT1 activation signaling pathway to achieve synergistic effect, due to the inhibition of NF-κB transcriptional activity and expression of pro-inflammatory cytokine (TNF-α, IL-1ß, IL-6). In conclusion, the combination of Sal-B and Pue exerted much stronger neuroprotective effect than Sal-B or Pue alone, which provides a potential new drug and has great significance for the treatment of IS.


Assuntos
Benzofuranos/farmacologia , Isquemia Encefálica/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Isoflavonas/farmacologia , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/genética , Isquemia Encefálica/imunologia , Isquemia Encefálica/patologia , Transtornos Cerebrovasculares/cirurgia , Cobalto/farmacologia , Combinação de Medicamentos , Sinergismo Farmacológico , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Artéria Cerebral Média/cirurgia , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Células PC12 , Ratos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
19.
J Org Chem ; 83(8): 4441-4454, 2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29595260

RESUMO

The first Pd-catalyzed multicomponent reaction of aryl iodides, alkenyl bromides, and strained alkenes has been developed, which allowed us to synthesize a variety of multisubsituted olefins in yields of 45-96% with excellent stereoselectivity. The configuration of the product was controlled by the configuration of the alkenyl bromides. Moreover, this practical methodology employing readily available substrates was found to be tolerant to a wide range of functional groups. Fifty six examples of highly stereoselective tri- or tetrasubstituted olefins have been successfully synthesized via this methodology. Most of the synthesized tetrasubstituted olefins are good aggregation-induced emission (AIE) luminogens.

20.
Theranostics ; 8(4): 878-893, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29463988

RESUMO

The outcome of scaffold-based stem cell transplantation remains unsatisfied due to the poor survival of transplanted cells. One of the major hurdles associated with the stem cell survival is the immune rejection, which can be effectively reduced by the use of immunosuppressant. However, ideal localized and sustained release of immunosuppressant is difficult to be realized, because it is arduous to hold the drug delivery system within scaffold for a long period of time. In the present study, the sustained release of immunosuppressant for the purpose of improving the survival of stem cells was successfully realized by a nanoparticle-anchoring hydrogel scaffold we developed. Methods: Poly (lactic-co-glycolic acid) (PLGA) nanoparticles were modified with RADA16 (RNPs), a self-assembling peptide, and then anchored to a RADA16 hydrogel (RNPs + Gel). The immobilization of RNPs in hydrogel was measured in vitro and in vivo, including the Brownian motion and cumulative leakage of RNPs and the in vivo retention of injected RNPs with hydrogel. Tacrolimus, as a typical immunosuppressant, was encapsulated in RNPs (T-RNPs) that were anchored to the hydrogel and its release behavior were studied. Endothelial progenitor cells (EPCs), as model stem cells, were cultured in the T-RNPs-anchoring hydrogel to test the immune-suppressing effect. The cytotoxicity of the scaffold against EPCs was also measured compared with free tacrolimus-loaded hydrogel. The therapeutic efficacy of the scaffold laden with EPCs on the hind limb ischemia was further evaluated in mice. Results: The Brownian motion and cumulative leakage of RNPs were significantly decreased compared with the un-modified nanoparticles (NPs). The in vivo retention of injected RNPs with hydrogel was obviously longer than that of NPs with hydrogel. The release of tacrolimus from T-RNPs + Gel could be sustained for 28 days. Compared with free tacrolimus-loaded hydrogel, the immune responses were significantly reduced and the survival of EPCs was greatly improved both in vitro and in vivo. The results of histological evaluation, including accumulation of immune cells and deposition of anti-graft antibodies, further revealed significantly lessened immune rejection in T-RNPs-anchoring hydrogel group compared with other groups. In pharmacodynamics study, the scaffold laden with EPCs was applied to treat hind limb ischemia in mice and significantly promoted the blood perfusion (~91 % versus ~36 % in control group). Conclusion: The nanoparticle-anchoring hydrogel scaffold is promising for localized immunosuppressant release, thereby can enhance the survival of transplanted cells and finally lead to successful tissue regeneration.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Células Progenitoras Endoteliais/fisiologia , Regeneração Tecidual Guiada/métodos , Hidrogel de Polietilenoglicol-Dimetacrilato/administração & dosagem , Imunossupressores/administração & dosagem , Nanopartículas/administração & dosagem , Animais , Sobrevivência Celular , Modelos Animais de Doenças , Isquemia/terapia , Camundongos Endogâmicos BALB C , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Tacrolimo/administração & dosagem , Resultado do Tratamento
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