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1.
AAPS PharmSciTech ; 22(2): 69, 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33565009

RESUMO

Encapsulating genetic material into biocompatible polymeric microparticles is a means to improving gene transfection while simultaneously decreasing the tendency for inflammatory responses; and can be advantageous in terms of delivering material directly to the lungs via aerosolization for applications such as vaccinations. In this study, we investigated the advantages of using polymeric microparticles carrying the luciferase reporter gene in increasing transfection efficiency in the readily transfectable HEK293 cell line and the difficult to transfect RAW264.7 cell line. The results indicated that there was a limit to the ratio of nitrogen in polyethylenimine (PEI) to phosphate in DNA (N/P ratio) beyond which further increases in transgene expression no longer, or only marginally, occurred. Microparticles encapsulating PEI:DNA nanoplexes induced cellular toxicity in a dose-dependent manner. PEGylation increased transgene expression, likely related to enhanced degradation of particles. Furthermore, intra-tracheal instillation in rats allowed us to investigate the inflammatory response in the lung as a function of PEGylation, porosity, and size. Porosity did not influence cell counts in bronchoalveolar lavage fluid in the absence of PEG, but in particles containing PEG, non-porous particles recruited fewer inflammatory cells than their porous counterparts. Finally, both 1 µm and 10 µm porous PLA-PEG particles recruited more neutrophils than 4 µm particles. Thus, we have shown that PEGylation and lack of porosity are advantageous for faster release of genetic cargo from microparticles and a reduced inflammatory response, respectively.


Assuntos
DNA/química , Inflamação/prevenção & controle , Lactatos/química , Polietilenoglicóis/química , Polietilenoimina/química , Transgenes , Animais , Células HEK293 , Humanos , Camundongos , Células RAW 264.7 , Ratos , Transfecção
2.
Food Chem ; 347: 129043, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33476919

RESUMO

In this study, the properties difference of Tilapia (Oreochromis Niloticus) skin collagen peptide chelate zinc prepared by zinc sulfate (P-Zn-S) and zinc lactate (P-Zn-L) were investigated. The results indicated that compared with P-Zn-L, P-Zn-S exhibited higher Zn-chelating capacity and different structural morphology, which may closely relate to the composition amino acid of Asp, Glu, His, Lys, Arg, Cys and Pro. FTIR and UV-Vis analysis indicated that different zinc sources could influence the metal ligands and the types of amino acid residues which were involved in chelation reaction. P-Zn-L exhibited better zinc solubility and had higher dialyzable zinc than P-Zn-S, indicating that P-Zn-L had better zinc bioaccessibility. These results suggested that P-Zn-L with a granular structure could reduced gastric stability, promoted intestinal release, and was beneficial to zinc absorption, which can be used as dietary zinc carriers.


Assuntos
Quelantes/química , Ciclídeos/metabolismo , Colágeno/química , Lactatos/química , Peptídeos/química , Sulfato de Zinco/química , Aminoácidos/análise , Aminoácidos/química , Animais , Digestão , Concentração de Íons de Hidrogênio , Peptídeos/metabolismo , Pele/metabolismo , Solubilidade
3.
J Dairy Sci ; 104(2): 1233-1250, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33309343

RESUMO

Scientific interest in cheese crystals extends back more than a century. However, starting around the 1970s, industry interest, and interest on the part of cheese scientists, grew dramatically as changes in cheesemaking technology and market changes caused the presence of crystals in the marketplace to increase; advanced analytical capabilities enabled new crystalline species to be identified, their origins and causative factors to be elucidated, and their contributions to cheese texture to be better understood. It is now evident that a host of organic- and inorganic-based crystals occur in natural cheeses. Some crystals form preferentially at the surface of rindless or rinded cheeses, others in the irregular openings or spherical eyes that occur within the body of some cheeses, and still others embedded within the cheese matrix. It is also evident that crystals may profoundly influence cheese texture, both as a direct consequence of their abundance, size, shape, and hardness, and as an indirect result of cascading physiochemical events initiated by crystal formation. Consumer response to increased incidence of crystals in the marketplace has been mixed. On the one hand, surface crystals of calcium lactate pentahydrate on Cheddar cheese came to be viewed quite negatively in some markets, often being mistaken for mold growth and spoilage. This triggered industry concern and led to considerable research to determine the underlying causes and to develop strategies to limit or prevent calcium lactate pentahydrate formation. At the same time, other forms of crystallization increasingly came to be viewed as positive features in the growing market dedicated to artisanal and traditional cheeses, giving rise to a bifurcated consumer response to cheese crystals that is evident today. Traditional artisanal cheesemakers perhaps have the most to gain from advances in cheese-crystal research. Traditional artisanal cheeses rely heavily on stories that are weaved around their identity to create uniqueness and add value. A challenge and opportunity for these cheesemakers in the United States and globally will be to translate the fascinating science of their cheese crystals into engaging narratives that capture the imagination, add value to their cheese, and enhance the enjoyment of their cheese by consumers.


Assuntos
Queijo/análise , Cristalização , Tecnologia de Alimentos , Animais , Compostos de Cálcio/química , Fenômenos Químicos , Cristalização/classificação , Manipulação de Alimentos , Lactatos/química , Sensação
4.
Comput Biol Med ; 126: 104046, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33065388

RESUMO

Coronavirus Disease 2019 (COVID-19) is an infectious illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), originally identified in Wuhan, China (December 2019) and has since expanded into a pandemic. Here, we investigate metabolites present in several common spices as possible inhibitors of COVID-19. Specifically, 32 compounds isolated from 14 cooking seasonings were examined as inhibitors for SARS-CoV-2 main protease (Mpro), which is required for viral multiplication. Using a drug discovery approach to identify possible antiviral leads, in silico molecular docking studies were performed. Docking calculations revealed a high potency of salvianolic acid A and curcumin as Mpro inhibitors with binding energies of -9.7 and -9.2 kcal/mol, respectively. Binding mode analysis demonstrated the ability of salvianolic acid A and curcumin to form nine and six hydrogen bonds, respectively with amino acids proximal to Mpro's active site. Stabilities and binding affinities of the two identified natural spices were calculated over 40 ns molecular dynamics simulations and compared to an antiviral protease inhibitor (lopinavir). Molecular mechanics-generalized Born surface area energy calculations revealed greater salvianolic acid A affinity for the enzyme over curcumin and lopinavir with energies of -44.8, -34.2 and -34.8 kcal/mol, respectively. Using a STRING database, protein-protein interactions were identified for salvianolic acid A included the biochemical signaling genes ACE, MAPK14 and ESR1; and for curcumin, EGFR and TNF. This study establishes salvianolic acid A as an in silico natural product inhibitor against the SARS-CoV-2 main protease and provides a promising inhibitor lead for in vitro enzyme testing.


Assuntos
Betacoronavirus/enzimologia , Ácidos Cafeicos/química , Infecções por Coronavirus/tratamento farmacológico , Curcumina/química , Cisteína Endopeptidases , Descoberta de Drogas , Lactatos/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/química , Proteínas não Estruturais Virais , Ácidos Cafeicos/uso terapêutico , Infecções por Coronavirus/enzimologia , Curcumina/uso terapêutico , Cisteína Endopeptidases/química , Humanos , Lactatos/uso terapêutico , Pandemias , Pneumonia Viral/enzimologia , Inibidores de Proteases/uso terapêutico , Termodinâmica , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química
5.
Sci Rep ; 10(1): 6129, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32273549

RESUMO

To eliminate the microbial infection from an injury site, various modalities have been developed such as dressings and human skin substitutes. However, the high amount of reactive oxygen species, microbial infection, and damaging extracellular matrix remain as the main challenges for the wound healing process. In this study, for the first time, green synthesized silver nanoparticles (AgNPs) using Teucrium polium extract were embedded in poly lactic acid/poly ethylene glycol (PLA/PEG) film to provide absorbable wound dressing, with antioxidant and antibacterial features. The physicochemical analysis demonstrated, production of AgNPs with size approximately 32.2 nm and confirmed the presence of phytoconstituents on their surface. The antibacterial assessments exhibited a concentration-dependent sensitivity of Staphylococcus aureus and Pseudomonas aeruginosa toward biosynthesized AgNPs, which showed a suitable safety profile in human macrophage cells. Furthermore, oxidant scavenging assays demonstrated exploitation of plant extract as a reducing agent, endows antioxidant activity to biogenic AgNPs. The formation of PLA/PEG nanofilm and entrapment of AgNPs into their matrix were clearly confirmed by scanning electron microscopy. More importantly, antibacterial examination demonstrated that the introduction of biogenic AgNPs into PLA/PEG nanofibers led to complete growth inhibition of P. aeruginosa and S. aureus. In summary, the simultaneous antioxidant activity and antimicrobial activity of the novel biogenic AgNPs/PLA/PEG nanofilm showed its potential for application as wound dressing.


Assuntos
Antibacterianos/síntese química , Antioxidantes/síntese química , Nanopartículas Metálicas/química , Cicatrização , Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Antioxidantes/efeitos adversos , Antioxidantes/farmacologia , Humanos , Lactatos/química , Macrófagos/efeitos dos fármacos , Polietilenoglicóis/química , Pseudomonas aeruginosa/efeitos dos fármacos , Prata/química , Staphylococcus aureus/efeitos dos fármacos
6.
Oxid Med Cell Longev ; 2020: 6431459, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184918

RESUMO

Oxidative stress has been recognized as the contributor to diabetic peripheral neuropathy (DPN). Antioxidant strategies have been most widely explored; nevertheless, whether antioxidants alone prevent DPN still remains inconclusive. In the present study, we established an in vitro DPN cell model for drug screening using Schwann RSC96 cells under high glucose (HG) stimulation, and we found that salvianolic acid A (SalA) mitigated HG-induced injury evidenced by cell viability and myelination. Mechanistically, SalA exhibited strong antioxidative effects by inhibiting 1,1-diphenyl-2-picrylhydrazyl (DPPH) and reducing reactive oxygen species (ROS), malondialdehyde (MDA), and oxidized glutathione (GSSG) content, as well as upregulating antioxidative enzyme mRNA expression. In addition, SalA significantly extenuated neuroinflammation with downregulated inflammatory factor mRNA expression. Furthermore, SalA improved the mitochondrial function of HG-injured Schwann cells by scavenging mitochondrial ROS, decreasing mitochondrial membrane potential (MMP), and enhancing ATP production, as well as upregulating oxidative phosphorylation gene expression. More importantly, we identified nuclear factor-E2-related factor 2 (Nrf2) as the upstream regulator which mediated protective effects of SalA on DPN. SalA directly bound to the Kelch domain of Kelch-like ECH-associated protein 1 (Keap1) and thus disrupted the interaction of Nrf2 and Keap1 predicted by LibDock of Discovery Studio. Additionally, SalA significantly inhibited Nrf2 promoter activity and downregulated Nrf2 mRNA expression but without affecting Nrf2 protein expression. Interestingly, SalA upregulated the nuclear Nrf2 expression and promoted Nrf2 nuclear translocation by high content screening assay, which was confirmed to be involved in its antiglucotoxicity effect by the knockdown of Nrf2 in RSC96 cells. In KK-Ay mice, we demonstrated that SalA could effectively improve the abnormal glucose and lipid metabolism and significantly protect against DPN by increasing the mechanical withdrawal threshold and sciatic nerve conduction velocity and restoring the ultrastructural impairment of the injured sciatic nerve induced by diabetes. Hence, SalA protected against DPN by antioxidative stress, attenuating neuroinflammation, and improving mitochondrial function via Nrf2. SalA may be prospective therapeutics for treating DPN.


Assuntos
Ácidos Cafeicos/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Lactatos/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/metabolismo , Animais , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Linhagem Celular , Neuropatias Diabéticas/patologia , Glucose/toxicidade , Inflamação/patologia , Lactatos/química , Lactatos/farmacologia , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Nervo Isquiático/ultraestrutura
7.
J Agric Food Chem ; 68(6): 1741-1749, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31964137

RESUMO

The goal of this study was to explore the regulatory mechanisms of phenyllactic acid (PLA) overaccumulation in Lactobacillus plantarum. The dynamics of PLA production revealed that 24 h was a suitable fermentation time, at which one of the largest differences in PLA content between strains S1 and YM-4-3 was 22.42 mg/L. Additionally, an optimization experiment showed that PLA production under the optimal condition (sample YM-4-3y) was up to 400.74 mg/L, 7.61-13.26 times as those of YM-4-3 and S1. Subsequently, an integrated analysis of genomic, transcriptomic and metabolomic data revealed that, YM-4-3 and YM-4-3y, compared with S1, although lacking a complete de novo biosynthetic pathway, increased PLA production by strengthening the core pathway and central carbon metabolism, and weakening the biosynthesis pathway of amino acids and their derivatives. These changes can provide sufficient precursors and compensate for or balance the energy consumed by the reinforced core pathway.


Assuntos
Lactatos/metabolismo , Lactobacillus plantarum/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Vias Biossintéticas , Fermentação , Genômica , Cinética , Lactatos/química , Lactobacillus plantarum/química , Lactobacillus plantarum/genética
8.
Food Chem ; 313: 126163, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31945702

RESUMO

The copigmentation effects of polyphenol with different structures vary greatly. Therefore, the aim of this study is to investigate possible interactions in red wine model solutions between oenin and three phenolic compounds: danshensu, caffeic acid and rosmarinic acid. Our results show that the copigmentation of rosmarinic acid is the strongest among the compounds tested. The colourimetric parameters indicate that colour intensity becomes enhanced with increasing concentration of these copigments, leading to darker and more vivid bluish colours. Thermodynamic and quantum chemical investigations are performed to interpret the absorption properties in the visible range. Fluorescence spectroscopy confirms the interaction between caffeic acid and oenin, while FTIR spectroscopic results further suggest a role for hydrogen bonds in the overall process. To our knowledge, this is the first experimentally corroborated direct evidence of hydrogen bonds in copigmentation.


Assuntos
Antocianinas/química , Ácidos Cafeicos/química , Cinamatos/química , Depsídeos/química , Lactatos/química , Vinho , Cor , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier , Termodinâmica , Vinho/análise
9.
Med Sci Monit ; 25: 9737-9751, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856143

RESUMO

BACKGROUND This study aimed to prepare doxorubicin- and tetrahydrocurcumin-loaded and transferrin-modified PEG-PLGA nanoparticles (Tf-NPs-DOX-THC) for enhanced and synergistic chemoradiotherapy. MATERIAL AND METHODS Tf-NPs-DOX-THC were prepared via the double-emulsion method. The morphologies and particle sizes of the prepared nanoparticles were examined by TEM and DLS, respectively. The in vitro MTT, apoptosis, and clone formation assays were performed to detect the proliferation and radiosensitivity of cells with various treatments. Cellular uptake assay was also conducted. The tissue distribution of Tf-NPs was investigated by ex vivo DOX fluorescence imaging. The in vivo tumor growth inhibition efficiency of various treatments was evaluated in orthotopic C6 mouse models and C6 subcutaneously grafted mouse models. RESULTS Tf-NPs-DOX-THC exhibited high drug-loading efficiency (6.56±0.32%) and desirable particle size (under 250 nm). MTT, apoptosis, and clone formation assays revealed the enhanced anti-cancer activity and favorable radiosensitizing effect of Tf-NPs-DOX-THC. Strong fluorescence was observed in the brains of mice treated with Tf-NPs-DOX. The in vitro release of drug from nanoparticles was in a pH-sensitive manner. Tf-NPs-DOX-THC in combination with radiation also achieved favorable anti-tumor efficacy in vivo. CONCLUSIONS All results suggest that a combination of Tf-NPs-DOX-THC and radiation is a promising strategy for synergistic and sensitizing chemoradiotherapy of glioma.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Glioma/tratamento farmacológico , Poliésteres/química , Polietilenoglicóis/química , Animais , Linhagem Celular Tumoral , Quimiorradioterapia/métodos , Curcumina/análogos & derivados , Curcumina/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos/farmacologia , Emulsões , Glioma/patologia , Humanos , Lactatos/química , Camundongos , Camundongos Nus , Nanopartículas/administração & dosagem , Tamanho da Partícula , Poliésteres/farmacologia , Polietilenoglicóis/farmacologia , Ratos , Distribuição Tecidual , Transferrina/química , Transferrina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Biomacromolecules ; 20(12): 4430-4436, 2019 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-31682423

RESUMO

The ability to engineer immune function has transformed modern medicine, highlighted by the success of vaccinations and recent efforts in cancer immunotherapy. Further directions in programming the immune system focus on the design of immunomodulatory biomaterials that can recruit, engage with, and program immune cells locally in vivo. Here, we synthesized shear-thinning and self-healing polymer-nanoparticle (PNP) hydrogels as a tunable and injectable biomaterial platform for local dendritic cell (DC) recruitment. PNP gels were formed from two populations of poly(ethylene glycol)-block-polylactide (PEG-b-PLA) NPs with the same diameter but different PEG brush length (2 or 5 kDa). PEG-b-PLA NPs with the longer PEG brush exhibited improved gel formation following self-assembly and faster recovery after shear-thinning. In all cases, model protein therapeutics were released via Fickian diffusion in vitro, and minor differences in the release rate between the gel formulations were observed. PNP hydrogels were loaded with the DC cytokine CCL21 and injected subcutaneously in a murine model. CCL21-loaded PNP hydrogels recruited DCs preferentially to the site of injection in vivo relative to non-CCL21-loaded hydrogels. Thus, PNP hydrogels comprise a simple and tunable platform biomaterial for in vivo immunomodulation following minimally invasive subcutaneous injection.


Assuntos
Quimiocina CCL21 , Células Dendríticas/imunologia , Hidrogéis , Lactatos , Nanopartículas/química , Polietilenoglicóis , Animais , Quimiocina CCL21/química , Quimiocina CCL21/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Células Dendríticas/citologia , Hidrogéis/química , Hidrogéis/farmacologia , Injeções Subcutâneas , Lactatos/química , Lactatos/farmacologia , Camundongos , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia
11.
Int J Pharm ; 572: 118796, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678389

RESUMO

We report preparation of theranostic nanocarriers loaded with up to 50 wt% of the anticancer drug doxorubicin that contain magnetic nanoparticles which enable Magnetic Particle Imaging (MPI), an emerging technology for quantitative and unambiguous imaging of the nanocarriers. The nanocarriers, coated with poly(ethylene glycol)-block-poly(lactic acid) (PEG4.9kD-b-PLA6kD) block copolymer for colloidal stability, are composed of a hydrophobic core of precipitated hydrolysable doxorubicin prodrug (proDox) and magnetic nanoparticles. Transmission electron microscopy (TEM) shows evidence of precipitated proDox for nanocarriers with high drug loading of up to 50 wt%. MPI measurements show that the nanocarriers can be quantitatively imaged. The nanocarriers are internalized by MDA-MB-231 cells and their IC50 value via metabolic assay is 1.1 µM, compared to 0.21 µM for free doxorubicin. The release rate from the nanocarriers was dependent on environmental pH. These nanocarriers with high drug loading and quantitative imaging are promising candidates for future applications.


Assuntos
Antibióticos Antineoplásicos/química , Meios de Contraste/química , Doxorrubicina/química , Portadores de Fármacos , Magnetismo , Nanopartículas de Magnetita/química , Imagem Molecular/métodos , Tecnologia Farmacêutica/métodos , Nanomedicina Teranóstica , Antibióticos Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Composição de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Lactatos/química , Polietilenoglicóis/química
12.
J Agric Food Chem ; 67(44): 12199-12207, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31595753

RESUMO

Salvianolic acid A (Sal A) has a wide range of pharmacological activities. To date, there have been no systematic and detailed metabolite research data of Sal A after oral administration in vitro and in vivo. In this study, a rapid and systematic method based on ultrafast liquid chromatography-quadrupole-time-of-flight mass spectrometry was developed to detect metabolites of Sal A in vitro (human liver microsome, human intestinal microbiota, artificial gastric, and intestinal juice) and in vivo (urine, plasma, feces, and various organs collected after oral administration of Sal A to normal rats and pseudo-germ-free rats). A total of 26 metabolites of Sal A were characterized. These metabolites were formed through extensive metabolic reactions, such as hydroxylation, hydrogenation, and glucuronidation reactions. This study provides novel possibility for exploring the potential biological mechanism of Sal A, and aids the promotion of clinical application.


Assuntos
Ácidos Cafeicos/química , Ácidos Cafeicos/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Lactatos/química , Lactatos/metabolismo , Espectrometria de Massas/métodos , Salvia miltiorrhiza/química , Adulto , Animais , Feminino , Humanos , Masculino , Metaboloma , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Adulto Jovem
13.
Mater Sci Eng C Mater Biol Appl ; 104: 109957, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31500028

RESUMO

The present work concerns the surface modification of The Ti-13Nb-13Zr alloy by electropolishing and plasma electrolytic oxidation (PEO) process in Ca-containing electrolytes: calcium formate and calcium lactate solutions (0.1-1.0 mol dm-3) under voltages of 200 and 400 V. As a result of the PEO process, a porous oxide layer containing incorporated calcium compounds was formed on the Ti-13Nb-13Zr alloy surface. The morphology and chemical composition of the modified Ti-13Nb-13Zr alloy were investigated using scanning electron microscopy (SEM + EDS), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). An increase in the applied voltage caused an increase in the number of pores and an increase in the amount of calcium incorporated in the oxide layer. Analysis showed that all samples were covered by titanium oxide, which was present in the form of anatase and/or rutile. In course of the experiments, it was showed that the proposed procedure has a positive effect on the overall bioactivity of the Ti-13Nb-13Zr alloy. Bioactivity investigations using simulated body fluid (SBF) confirmed the formation of apatite on the anodized surfaces. The cell adhesion results obtained by the use of human bone marrow mesenchymal stem cells (hBMSC) demonstrated that the PEO coatings on the Ti-13Nb-13Zr alloy remarkably enhanced the cytocompatibility of the substrate, indicating a potential application in orthopedic surgeries. The incorporation of Ca into the oxide layer proceeded to a higher extent when the PEO treatment was performed in the calcium lactate bath. The oxide layers formed in the calcium lactate solution exhibited also superior biological behavior towards hBMSC. This can be ascribed to the presence of carboxylic groups onto coatings' surface (as identified by XPS), which facilitated the anchoring of cells and tissues.


Assuntos
Ligas/química , Materiais Biocompatíveis/química , Cálcio/química , Íons/química , Óxidos/química , Titânio/química , Adulto , Idoso , Apatitas/química , Compostos de Cálcio/química , Eletrodos , Feminino , Humanos , Lactatos/química , Masculino , Teste de Materiais , Microscopia Eletrônica de Varredura/métodos , Pessoa de Meia-Idade , Oxirredução , Porosidade , Propriedades de Superfície , Difração de Raios X/métodos
14.
Biochem Biophys Res Commun ; 519(2): 351-357, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31514995

RESUMO

Phenyllactate (PLA) is found in a variety of fermented foods and is a promising antibacterial agent, drug and plastic synthetic precursor. Previous studies have shown that PLA is a product of Phe catabolism in lactic acid bacteria (LAB), and PLA biosynthesis is mainly related to lactate dehydrogenases (LDHs). Here, the genome, transcriptome and fermentation characteristics of PLA-producing Lactobacillus plantarum LY-78 were studied. The fermentation experiments demonstrated that L. plantarum LY-78 possesses the ability to synthesize PLA de novo. Secondly, the genome and transcriptome analyses revealed candidate pathways, operons and key genes for PLA biosynthesis in the strain. Finally, genome-wide transcriptome analysis revealed significant changes in the expression profile of strain LY-78 in the absence and presence of PPA. Overall, this work demonstrates for the first time that PLA can be a by-product of Phe anabolism in LAB, provides new insights and evidence for elucidating the mechanism of PLA biosynthesis in LAB, and may provide new candidate genes and research strategies for future PLA biosynthesis applications.


Assuntos
Fermentação , Lactatos/metabolismo , Lactobacillales/química , Lactobacillus plantarum/genética , Lactobacillus plantarum/metabolismo , Lactatos/química , Lactobacillales/metabolismo , Estrutura Molecular , Transcriptoma
15.
Phytomedicine ; 63: 153055, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377585

RESUMO

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1), an important intracellular rate-limiting enzyme in the development of Hepatic fibrosis (HF), and has been proposed as a hallmark of HF. Danshensu (DSS) is a major bioactive component that isolated from a edible traditional Chinese medicinal herb Salviae Miltiorrhizae Radix et Rhizoma (Danshen), while, the anti-HF mode and mechanism of action of DSS have not been fully elucidated. METHODS: Carbon tetrachloride (CCl4)-induced rat HF model and TGF-ß1-induced hepatic stellate cell (HSC) model were employed to assess the in vivo and in vitro anti-HF effects of DSS. HSC-T6 cells stably expressing IDO1, a constitutively active IDO1 mutant, was used to determine the role of JAK2-STAT3 signaling in the DSS's anti-HF effects. RESULTS: We found that intragastric administration of DSS potently reduced fibrosis, inhibited IDO1 expression and STAT3 activity both in vitro and in vivo. Using molecular docking and molecular dynamics analysis, DSS was identified as a novel IDO1 inhibitor. Mechanistic studies indicated that DSS inhibited JAK2-STAT3 signaling, it reduced IDO1 expression, STAT3 phosphorylation and STAT3 nuclear localization. More importantly, overexpression of IDO1 diminished DSS's anti-HF effects. CONCLUSION: Our findings provide a pharmacological justification for the clinical use of DSS in treating HF, and suggest that DSS has the potential to be developed as a modern alternative and/or complimentary agent for HF treatment and prevention.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Janus Quinase 2/metabolismo , Lactatos/farmacologia , Cirrose Hepática Experimental/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Linhagem Celular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Janus Quinase 2/antagonistas & inibidores , Lactatos/química , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Masculino , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
16.
Biomacromolecules ; 20(9): 3435-3444, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31361468

RESUMO

Stimuli-responsive polymersomes formed by amphiphilic block copolymers have attracted substantial attention as smart and robust containers for drug delivery and nano/microreactors. Biosourced amphiphilic diblock copolypeptoids were developed that can self-assemble into oxidation-responsive unilamellar vesicles. These vesicles can burst under the action of reactive oxygen species which can be the hydrogen peroxide or the singlet oxygen produced by light-activation of a photosensitizer with spatiotemporal control. Polysarcosine (PSar, also called poly(N-methyl glycine)) was selected as the hydrophilic block because of its resistance to protein adsorption and low toxicity, similar to poly(ethylene glycol) (PEG). We designed and synthesized poly(N-3-(methylthio)propyl glycine) as the hydrophobic block. Its polyglycine backbone is the same as that of PSar, and especially, its hydrophobic N-substituents, thioether side chains, can be oxidized to hydrophilic sulfoxides. These oxidation-responsive polymersomes entirely based on N-substituted poly(amino acid)s were biocompatible as confirmed by cell viability tests and may find applications in drug delivery, biosensing, biodetection, and nano/microreactors.


Assuntos
Sistemas de Liberação de Medicamentos , Peptídeos/química , Sarcosina/análogos & derivados , Tensoativos/farmacologia , Adsorção/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/química , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Lactatos/química , Oxirredução/efeitos dos fármacos , Peptídeos/síntese química , Peptídeos/farmacologia , Polietilenoglicóis/química , Polímeros/química , Polímeros/farmacologia , Sarcosina/síntese química , Sarcosina/química , Sarcosina/farmacologia , Tensoativos/síntese química , Tensoativos/química
17.
Biomed Res Int ; 2019: 1395480, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341887

RESUMO

In peach orchards, birds severely damage flowers during blossom season, decreasing the fruit yield potential. However, the wild peach species Prunus mira shows intraspecific variations of bird damage, indicating that some of the wild trees have developed strategies to avert bird foraging. Motivated by this observation, we formulated the present study to identify the potential flower metabolites mediating the bird's selective feeding behavior in P. mira flowers. The birds' preferred (FG) and avoided (BFT) flowers were collected from wild P. mira trees at three different locations, and their metabolite contents were detected, quantified, and compared. The widely-targeted metabolomics approach was employed to detect a diverse set of 603 compounds, predominantly, organic acids, amino acid derivatives, nucleotide and its derivatives, and flavones. By quantitatively comparing the metabolite contents between FG and BFT, three candidate metabolites, including Eriodictiol 6-C-hexoside 8-C-hexoside-O-hexoside, Luteolin O-hexosyl-O-hexosyl-O-hexoside, and Salvianolic acid A, were differentially accumulated and showed the same pattern across the three sampling locations. Distinctly, Salvianolic acid A was abundantly accumulated in FG but absent in BFT, implying that it may be the potential metabolite attracting birds in some P. mira flowers. Overall, this study sheds light on the diversity of the floral metabolome in P. mira and suggests that the bird's selective feeding behavior may be mediated by variations in floral metabolite contents.


Assuntos
Aves/fisiologia , Comportamento Alimentar , Flores/química , Prunus persica/metabolismo , Animais , Ácidos Cafeicos/química , Ácidos Cafeicos/metabolismo , Flavanonas/química , Flavanonas/metabolismo , Flores/metabolismo , Lactatos/química , Lactatos/metabolismo , Luteolina/química , Luteolina/metabolismo , Metaboloma , Prunus persica/química
18.
Drug Deliv ; 26(1): 595-603, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31195837

RESUMO

With high morbidity and death rates, liver cancer has become one of the most common cancers in the world. But, most chemotherapeutic anticancer drugs have high toxicity as well as low specificity. To improve the treatment modalities and enhance the therapeutic effect of liver cancer, a brand new liver-targeting nanoparticle (NP), Ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic acid (5 F)-loaded cholic acid (CA)-functionalized star-shaped poly (lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-lactobionic acid (LA) (5 F-loaded CA-PLGA-PEG-LA), was developed. The particle size, zeta potential, size distribution, surface morphology, drug loading content, drug encapsulation efficiency and drug release of 5 F-loaded NPs were characterized. Confocal microscopy and flow cytometry showed that the prepared NPs could be internalized by HepG2 cells. Furthermore, the cellular uptake efficiency of coumarin 6-loaded CA-PLGA-PEG-LA NPs was much better in compare with that of CA-PLGA-PEG and CA-PLGA NPs. Moreover, LA-conjugated NPs (CA-PLGA-PEG-LA NPs) enhanced fluorescence of HepG2 cells via ligand-mediated endocytosis. The antitumor effects of 5 F-loaded NPs were evaluated by the MTT assay in vitro and by a xenograft tumor model in vivo, demonstrating that targeted 5 F-loaded CA-PLGA-PEG-LA NPs were significantly superior to free 5 F and 5 F-loaded CA-PLGA-PEG NPs. All the results indicated the 5 F-loaded CA-PLGA-PEG-LA NPs can be employed as a novel potentially targeting drug delivery system for liver cancer therapy.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Neoplasias Hepáticas/tratamento farmacológico , Fígado/efeitos dos fármacos , Nanopartículas/administração & dosagem , Nanopartículas/química , Polímeros/química , Animais , Linhagem Celular Tumoral , Ácido Cólico/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Feminino , Células Hep G2 , Humanos , Lactatos/química , Ácido Láctico/química , Camundongos , Camundongos Nus , Tamanho da Partícula , Polietilenoglicóis/química , Ácido Poliglicólico/química
19.
Br J Pharmacol ; 176(17): 3143-3160, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31116880

RESUMO

BACKGROUND AND PURPOSE: Tanshinol borneol ester (DBZ) is a novel synthetic compound derived from Dantonic® , a botanical drug approved in 26 countries outside the United States for angina pectoris and currently undergoing FDA Phase III clinical trial. Here, we investigated the angiogenic effects of (S)-DBZ and (R)-DBZ isomers in vitro and in vivo. EXPERIMENTAL APPROACH: A network pharmacology approach was used to predict molecular targets of DBZ. The effects of DBZ isomers on proliferation, migration, and tube formation of human endothelial cells were assessed. For in vivo approaches, the transgenic Tg (vegfr2:GFP) zebrafish and C57BL/6 mouse Matrigel plug models were used. ELISA and western blots were used to quantitate the release and expression of relevant target molecules and signalling pathways. KEY RESULTS: DBZ produced a biphasic modulation on proliferation and migration of three types of human endothelial cells. Both DBZ isomers induced tube formation in Matrigel assay and a 12-day co-culture model in vitro. Moreover, DBZ promoted Matrigel neovascularization in mice and partially reversed the vascular disruption in zebrafish induced by PTK787. Mechanistically, DBZ enhanced the cellular levels of VEGF, VEGFR2, and MMP-9, as well as activating Akt and MAPK signalling in endothelial cells. Selective inhibition of PI3K and MEK significantly attenuated its angiogenic effects. CONCLUSIONS AND IMPLICATIONS: These data reveal, for the first time, that DBZ promotes multiple key steps of angiogenesis, at least in part through Akt and MAPK signalling pathways, and suggest it may be potentially developed further for treating myocardial infarction and other cardiovascular diseases.


Assuntos
Angina Pectoris/tratamento farmacológico , Canfanos/farmacologia , Lactatos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Angina Pectoris/metabolismo , Animais , Canfanos/síntese química , Canfanos/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Composição de Medicamentos , Humanos , Lactatos/síntese química , Lactatos/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Estrutura Molecular , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Estereoisomerismo , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacos , Peixe-Zebra
20.
Nucl Med Biol ; 71: 11-18, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31108463

RESUMO

BACKGROUND: [166Ho]Ho-acetylacetonate-poly(L-lactic acid) microspheres were used in radioembolization of liver malignancies by intra-arterial administration. The primary aim of this study was to assess the stability and biodistribution of these microspheres. MATERIALS AND METHODS: Peripheral blood and urine samples were obtained from two clinical studies. Patient and in vitro experiment samples were analyzed using inductively coupled plasma mass spectrometry (ICP-MS), gamma-ray spectroscopy, light microscopy, Coulter particle counting, and high performance liquid chromatography (HPLC). RESULTS: The median percentage holmium compared to the total amount injected into the hepatic artery was 0.19% (range 0.08-2.8%) and 0.32% (range 0.03-1.8%) in the 1 h blood plasma and 24 h urine, respectively. Both the blood plasma and urine were correlated with the neutron irradiation exposure required for [166Ho]Ho-AcAc-PLLA microsphere production (ρ = 0.616, p = 0.002). After a temporary interruption of the phase 2 clinical study, the resuspension medium was replaced to precipitate [166Ho]Ho3+ pre-administration using phosphate. The in vitro near-maximum neutron irradiation experiments showed significant [166Ho]Ho-AcAc-PLLA microsphere damage. CONCLUSION: The amount of holmium in the peripheral blood and urine samples after [166Ho]Ho-AcAc-PLLA microsphere intrahepatic infusion was low. A further decrease was observed after reformulation of the resuspension solution but minimization of production damage is necessary.


Assuntos
Embolização Terapêutica , Hidroxibutiratos/química , Hidroxibutiratos/uso terapêutico , Lactatos/química , Lactatos/uso terapêutico , Ácido Láctico/química , Ácido Láctico/uso terapêutico , Neoplasias Hepáticas/radioterapia , Microesferas , Pentanonas/química , Pentanonas/uso terapêutico , Estabilidade de Medicamentos , Humanos , Hidroxibutiratos/farmacocinética , Lactatos/farmacocinética , Ácido Láctico/farmacocinética , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/urina , Pentanonas/farmacocinética , Distribuição Tecidual
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