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1.
ACS Appl Mater Interfaces ; 13(33): 38979-38989, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433249

RESUMO

Chronic infections caused by Pseudomonas aeruginosa pose severe threats to human health. Traditional antibiotic therapy has lost its total supremacy in this battle. Here, nanoplatforms activated by the clinical microenvironment are developed to treat P. aeruginosa infection on the basis of dynamic borate ester bonds. In this design, the nanoplatforms expose targeted groups for bacterial capture after activation by an acidic infection microenvironment, resulting in directional transport delivery of the payload to bacteria. Subsequently, the production of hyperpyrexia and reactive oxygen species enhances antibacterial efficacy without systemic toxicity. Such a formulation with a diameter less than 200 nm can eliminate biofilm up to 75%, downregulate the level of cytokines, and finally promote lung repair. Collectively, the biomimetic design with phototherapy killing capability has the potential to be an alternative strategy against chronic infections caused by P. aeruginosa.


Assuntos
Antibacterianos/química , Verde de Indocianina/química , Nanocápsulas/química , Fármacos Fotossensibilizantes/química , Polímeros/química , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/radioterapia , Células A549 , Animais , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Humanos , Verde de Indocianina/farmacologia , Raios Infravermelhos , Masculino , Metacrilatos/química , Camundongos Endogâmicos BALB C , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Polietilenoglicóis/química , Pseudomonas aeruginosa/efeitos dos fármacos
2.
Am J Physiol Endocrinol Metab ; 321(4): E509-E520, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34423682

RESUMO

Impaired wound healing is a major complication of diabetes and involves sustained inflammation and oxidative stress at the wound site. Here, we investigated the potential involvement of ferroptosis, a newly discovered form of cell death characterized by iron-dependent accumulation of lipid peroxides in the pathogenesis of diabetic wound healing. Fibroblasts and vascular endothelial cells exposed to high glucose concentrations in vitro contained elevated levels of reactive oxygen species (ROS), lipid peroxidation products, and ferroptosis-associated proteins and displayed reduced survival and migration. These effects of high glucose were all significantly reduced by treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1). Similarly, in a rat model of diabetes, direct application of Fer-1 to the wound site reduced the expression of oxidative stress and inflammation markers and accelerated wound healing via activation of the anti-inflammatory phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. Our results implicate ferroptosis in wound healing and identify a potential new therapeutic target for difficult-to-treat diabetic wounds.NEW & NOTEWORTHY Ferroptosis-related characteristic changes were found in diabetic wound models. Inhibition of ferroptosis improved inflammatory infiltration of diabetic wounds. PI3K/AKT signal pathway was rescued by restraining of ferroptosis. Mitigation of ferroptosis in diabetic wound promoted the wound healing.

3.
Biomacromolecules ; 22(9): 3704-3717, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34380309

RESUMO

Bacterial keratitis is a serious bacterial infection of the cornea that can cause sight loss in severe cases because of the sharp decline of efficacious antibiotics. Herein, a targeted photosensitizer based on BODIPY severing as a photobactericidal agent was developed for treating bacterial keratitis. The water solubility of the material was as high as 10 mg/mL, which was attributable to the introduction of pathogen-targeting galactose and fucose. The photosensitizer was able to preferentially bind Pseudomonas aeruginosa instead of mammalian cells and trigger the aggregation of bacteria, which ultimately facilitated effective pathogen ablation upon the generation of reactive oxygen species (ROS) via laser irradiation. Photoexcited targeted photosensitizers can promote wound healing by eradicating P. aeruginosa in rat eyes and reducing the inflammatory response, thus exhibiting the significant therapeutic effect on bacterial keratitis. We also performed molecular level mechanistic studies using the unique field-induced droplet ionization mass spectrometry methodology and confirmed that the generated ROS were mainly singlet oxygen that caused lipid peroxidation (Type II mechanism). We anticipate that the targeted photosensitizer will have great potential in the application of clinical photodynamic therapy to ocular infection.


Assuntos
Ceratite , Fotoquimioterapia , Animais , Ceratite/tratamento farmacológico , Luz , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Pseudomonas aeruginosa
4.
ACS Appl Mater Interfaces ; 13(29): 33790-33801, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34254513

RESUMO

Hypoxia, a common characteristic of bacterial infections, is known to be closely associated with the emergence of multidrug-resistant bacteria, which hastens the need to develop advanced microbicides and antibacterial techniques. Photodynamic therapy is a promising strategy to reduce bacterial antibiotic resistance and employs photosensitizers, excitation light sources, and sufficient oxygen to generate toxic reactive oxygen species (ROS). The inherent limitation of PDT is that the generation of ROS is restricted by the hypoxic microenvironment in infection sites. Here, an oxygen self-supplying nanotherapeutic is developed to enhance antibacterial activity against multidrug-resistant bacteria on the basis of fluorinated boron dipyrromethene (BODIPY)-based glycomimetics. The nanotherapeutic not only could capture the bacteria efficiently but also was able to act as an oxygen carrier to relieve the hypoxic microenvironment of bacterial infections, thus achieving enhanced PDT efficacy. In a Pseudomonas aeruginosa infection of a rat cornea, typical administration of the nanotherapeutic decreased the infiltrate and showed a faster healing capacity in comparison with BODIPY-based glycomimetics. Self-supplying oxygen nanotherapeutics that relieve the hypoxic microenvironment and interfere with bacterial colonization have been shown to be a promising candidate for the management of drug-resistant microbial keratitis.

5.
J Mater Chem B ; 9(20): 4190-4200, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-33997882

RESUMO

Eye-drop formulations as conventional regimens to tackle ocular diseases are far from efficient due to the rapid clearance by eye tears and the blockage of the corneal epithelium barrier. Here, we describe a bioadhesive glycosylated nanoplatform with boric acid pendants as a drug carrier for noninvasive trans-corneal delivery of drugs to treat corneal neovascularization (CNV), a serious corneal disease resulting in significant vision impairment. This biocompatible nanoplatform is formulated from a synthetic amphiphilic boric acid-based copolymer self-assembling to form highly stable micelles with a high loading capacity for dexamethasone (DEX). The nanoplatform is demonstrated to be in contact with the corneal epithelium for a long period under the bioadhesive function of boric acid modules and releases the drug over 96 h in a controlled manner. Our results also suggest that the nanoplatform can be efficiently internalized by corneal epithelial cells in vitro and realize transcytosis in vivo to greatly enhance the transcorneal penetration of the loaded drugs into the pathological corneal stroma. On topical application against rat corneal alkali burn, the nanoformulation presents more robust efficacy on neovascularization suppression and inflammation elimination than free DEX with a negligible effect on normal tissues. This bioadhesive strategy which focuses on extending ocular drug retention and improving trans-corneal drug delivery not only highlights an approach for alternative noninvasive therapy of CNV but also provides a versatile paradigm for other biomedical applications by overcoming protective barriers.


Assuntos
Materiais Biocompatíveis/química , Ácidos Borônicos/química , Neovascularização da Córnea/tratamento farmacológico , Dexametasona/farmacologia , Sistemas de Liberação de Medicamentos , Animais , Materiais Biocompatíveis/síntese química , Ácidos Borônicos/síntese química , Sobrevivência Celular/efeitos dos fármacos , Córnea/efeitos dos fármacos , Dexametasona/química , Portadores de Fármacos/química , Composição de Medicamentos , Glicosilação , Humanos , Masculino , Nanopartículas/química , Ratos , Ratos Sprague-Dawley
6.
Biomacromolecules ; 22(5): 2020-2032, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33880923

RESUMO

A standardized regimen for addressing the adverse effects of bacterial keratitis on vision remains an intractable challenge due to poor epithelial penetration and a short corneal retention time. In this study, a new strategy is proposed to implement the direct transport of antibiotics to bacteria-infected corneas via topical administration of an epithelium-penetrable biodriven nanoplatform, thereby enabling the efficacious treatment of bacterial keratitis. The nanoplatforms were composed of amphiphilic glycopolymers containing boron dipyrromethene and boronic acid moieties with stable fluorescence characteristics and the ability to potentiate epithelial penetration deep into the cornea. The boronic acid-derived nanoplatforms enabled efficient cellular internalization through the high affinity of boric acid groups for the diol-containing bacterial cell wall, resulting in enhanced drug penetration and retention inside the pathogenic bacteria. The bacterial cells formed agglomerations after incorporating the nanoplatforms along with a special mechanism to release the encapsulated cargo in response to in situ bacteria. Compared with the drug alone, this smart system achieved enhanced bacterial mortality and attenuated inflammation associated with Staphylococcus aureus-induced keratitis in rats, demonstrating a paradigm for targeted ocular drug delivery and an alternative strategy for managing bacterial keratitis or other bacterial infections by heightening corneal permeability and transcorneal bioavailability.


Assuntos
Infecções Oculares Bacterianas , Ceratite , Infecções Estafilocócicas , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Córnea , Epitélio , Infecções Oculares Bacterianas/tratamento farmacológico , Ceratite/tratamento farmacológico , Ratos , Infecções Estafilocócicas/tratamento farmacológico
7.
Free Radic Biol Med ; 162: 435-449, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152439

RESUMO

Diabetic nephropathy (DN) is now considered the leading cause of end-stage renal disease. In diabetes, the accumulation of reactive oxygen species (ROS) and iron overload are important determinants that promote the occurrence of DN. However, the underlying mechanism of how they cause diabetic kidney damage remains unclear. Ferroptosis, characterized by iron-dependent lipid peroxidation, provided us with a new idea to explore the progression of DN. Iron overload, reduced antioxidant capability, massive ROS and lipid peroxidation were detected in the kidneys of streptozotocin-induced DBA/2J diabetic mice and high-glucose cultured human renal proximal tubular (HK-2) cells, which were the symbolic changes of ferroptosis. Furthermore, the characteristic mitochondrial morphological changes of ferroptosis were observed in high glucose cultured cells. Additional treatment of Ferrostatin-1 (Fer-1) in DN models significantly rescued these changes and alleviated the renal pathological injuries in diabetic mice. Besides, the decreased NFE2-related factor 2 (Nrf2) was observed in DN models. The specific knockdown of Nrf2 increased the sensitivity of cells to ferroptosis in the high glucose condition. In Nrf2 knockdown cells, up-regulating Nrf2 by treating with fenofibrate improved the situation of ferroptosis, which was verified in RSL-3 induced cells. Moreover, the ferroptosis-related changes were inhibited by increasing Nrf2 in fenofibrate treated diabetic mice, which delayed the progression of DN. Collectively, we demonstrated that ferroptosis was involved in the development of DN, and up-regulating Nrf2 by treating with fenofibrate inhibited diabetes-related ferroptosis, delaying the progression of DN. Our research revealed the development mechanism of DN from a new perspective, and provide a new approach delaying the progression of DN.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Ferroptose , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/genética , Camundongos , Camundongos Endogâmicos DBA , Fator 2 Relacionado a NF-E2/genética
9.
J Clin Lab Anal ; 34(12): e23546, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33047841

RESUMO

BACKGROUND: Indirect immunofluorescence assay (IIFA) is viewed as a preliminary standard to assess antinuclear antibodies (ANAs). Our aim was to explore ANA positivity rate, titers, and patterns in patients with systemic autoimmune rheumatic diseases (SARD), including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), systemic sclerosis (SSc), and mixed connective tissue disease (MCTD), compared with healthy controls (HC). METHODS: Assess antinuclear antibody titers and patterns were retrospectively identified and compared by IIFA using human epithelial cells (HEp-2) and primate liver tissue substrate according to international consensus in SARD. Serum complement 3 (C3), C4, and immunoglobulin G were compared among subgroups with different ANA titers. The positive predictive values (PPV) for different ANA titers were calculated. RESULTS: There were a total of 3510 samples, including 2034 SLE, 973 RA, 155 SSc, 309 pSS, and 39 MCTD cases. There was no difference in age between HC and SARD, excluding RA. ANA positivity rate in SARD and HC was 78.7% and 12.2%, respectively. A titer of ≥1:320 revealed a PPV of 84.0% in SARD. SLE patients with ANA titers ≥1:320 had significantly lower levels of C3 and C4. AC-4 (31.2%) was the major pattern in patients with SARD, followed by AC-5 (23.9%) and AC-1 (18.8%). SLE mostly presented with AC-4 (30.3%). Several mixed patterns provided a significant hint for SSc and SLE. The major pattern in HC was AC-2 (12.2%). CONCLUSIONS: Assess antinuclear antibody positivity, titers, and patterns display differences in various SARD, contributing to the classification of SARD.

10.
J Mater Chem B ; 8(21): 4627-4641, 2020 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-32373901

RESUMO

Frequent subcutaneous insulin injection and islet transplantation are promising therapeutic options for type 1 diabetes mellitus. However, poor patient compliance, insufficient appropriate islet ß cell donors and body immune rejection limit their clinical applications. The design of a platform capable of encapsulating insulin-secreting cells and achieving real-time blood glucose regulation, is a so far unmet need. Herein, inspired by the natural processes of regulating blood glucose in pancreatic islet ß cells, we developed a poly(N-isopropylacrylamide-co-dextran-maleic acid-co-3-acrylamidophenylboronic acid) (P(AAPBA-Dex-NIPAM)) hydrogel as a cell platform with glucose responsiveness and thermo-responsiveness for the therapy of diabetes. This platform showed good biocompatibility against insulin-secreting cells and presented glucose-dependent insulin release behaviour. The bioinspired P(AAPBA6-Dex-NIPAM64) hydrogel had a positive effect on real-time glycaemic regulation, as observed by intraperitoneal glucose tolerance tests. The non-fasting blood glucose of diabetic rats was restored to a normal level during the period of treatment. Additionally, the inflammatory response did not occur after administration of the platform. Collectively, we expected that the bio-mimetic platform combined with an insulin-secreting capability could be a new diabetic treatment strategy.


Assuntos
Glicemia/metabolismo , Dextranos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hidrogéis/farmacologia , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dextranos/administração & dosagem , Dextranos/química , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Teste de Tolerância a Glucose , Hidrogéis/administração & dosagem , Hidrogéis/química , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Estrutura Molecular , Células NIH 3T3 , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Estreptozocina , Propriedades de Superfície , Fatores de Tempo
11.
Clin Rheumatol ; 39(8): 2425-2432, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32103375

RESUMO

INTRODUCTION: Antinuclear antibody (ANA) testing using indirect immunofluorescence assay (IIFA) is a common and economical method which contributes to detect systemic autoimmune diseases (SARD) and autoimmune liver diseases (AILD). The primary aim of our study was to investigate ANA positivity and their patterns in multiple liver diseases, including primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), hepatitis B virus infection (HBV), hepatitis C virus infection (HCV), and hepatic carcinoma (HCC). Besides, we also compared the ANA titers and patterns in patients with liver disease, SARD, and healthy controls (HC). METHODS: A total of 2537 patients with SARD, 137 PBC cases, 57 AIH cases, 3420 HBV cases, 769 HCV cases, 268 HCC cases, and 1073 HC were retrospectively assessed. The titers and patterns of ANA were detected with the IIFA method. RESULTS: ANA positivity rate was considerably discernible between these diseases, which is 90.1% in SARD, 93.4% in PBC, 49.1% in AIH, 19.1% in HBV, 13.9% in HCV, and 23.5% in HCC. Moreover, only 4.9% of HCC cases, 2.5% of HBV patients, and 1.6% of HCV patients had an ANA titer ≥ 1:320. The mixed pattern which composed of at least two patterns majorly lied in PBC. AC-15 and AC-21 was frequently related to liver diseases; the former pattern was more frequently found in AIH (84.2%) and PBC (8.8%), and the latter pattern was easily seen in PBC (62.2%) and HCC (22.6%). The positive rate of ANA in HC was 12.2%, and its major pattern was AC-2. CONCLUSIONS: There are differences in ANA positivity among patients with SARD and various liver diseases. Some mixed patterns may provide important evidence for the diagnosis of PBC. Clinicians should pay attention to ANA patterns and titer during the interpretation of this test. Key Points • Defining the clinical relevance of antinuclear antibody (ANA) using indirect immunofluorescence assay in the context of diseases can be an important tool for the clinician in the diagnostic work-up of patients with liver diseases. • The mixed pattern of ANA is majorly found in primary biliary cirrhosis (PBC). ANA patterns including AC-15 and AC-21 are frequently related to liver diseases. AC-15 is more often found in autoimmune hepatitis (AIH) (84.2%) and PBC (8.8%), and AC-21 is easily found in PBC (62.2%, and hepatic carcinoma (HCC) (22.6%). • ANA positivity can be seen in 19.1% of hepatitis B virus infection (HBV) cases, 13.9% of hepatitis C virus infection (HCV) cases, and 23.5% of HCC cases. Only 2.5% of HBV patients, 1.6% of HCV patients, and 4.9% of HCC cases have an ANA titer ≥ 1:320.


Assuntos
Anticorpos Antinucleares/análise , Autoanticorpos/análise , Doenças Autoimunes/imunologia , Hepatopatias/imunologia , Adulto , Idoso , China , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/imunologia , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
12.
Scand J Immunol ; 91(3): e12849, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31899559

RESUMO

The aim of study was to detect antinuclear antibodies (ANA) using indirect immunofluorescence assay (IIFA), linear immunoassay (LIA), chemiluminescence microparticle immunoassay (CMIA), multiple microbead immunoassay (MBI) and to compare these four methods in the performance of diagnosing systemic lupus erythematosus (SLE). Serum ANA were detected in 147 SLE cases and 42 healthy controls (HCs). The sensitivity, specificity, accuracy, positive predictive value and agreement, the area under the curve of four methods in diagnosing were calculated. Finally, a diagnostic model through logistic regression was constructed. The sensitivity of CMIA and IIFA in diagnosing SLE was 89.08% and 89.12%, higher than other two methods (P < .01), while highest specificity lied in CMIA (95.24%) and LIA (95.24%). The accuracy was highest in CMIA (91.01%), and lowest in LIA (83.07%). CMIA and the other three methods had good agreement, especially with LIA (κ = .798, 95% CI, 0.708-0.88). ANA-IIFA (OR = 1.016, P < .001) and anti-SSA antibodies (OR = 1.017, P = .043) were finally included in the SLE diagnostic model, with AUC value of 0.964 (95% CI, 0.936-0.991). SLE patients exhibited 14 various ANA patterns, especially AC-1, AC-4, and AC-5. Antibodies against SSA and dsDNA were mostly seen with AC-1 and AC-4 patterns, while antibodies against RNP, Sm, SSA, dsDNA, nucleosome and PO were most frequently observed with AC-5 pattern in SLE. CMIA method is a reliable screening test for detections of antibodies related to SLE. Using ANA-IIFA and anti-SSA antibodies by CMIA can discriminate SLE patients from HCs effectively.


Assuntos
Autoanticorpos/imunologia , Imunoensaio , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Idoso , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Área Sob a Curva , Autoanticorpos/sangue , Estudos de Casos e Controles , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Imunoensaio/métodos , Imunoensaio/normas , Medições Luminescentes/métodos , Medições Luminescentes/normas , Lúpus Eritematoso Sistêmico/sangue , Masculino , Pessoa de Meia-Idade , Razão de Chances , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
13.
Sci Total Environ ; 697: 133945, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31473551

RESUMO

The strength of methane (CH4) source of mangroves is not well understood, especially when including all CH4 pathways in consideration. This study measured CH4 fluxes by five pathways (sediments, pneumatophores, water surface, leaves, and stems) from four typical mangrove forests, including Kandelia candel without pneumatophores and three species with pneumatophores: Sonneratia apetala, Laguncularia racemosa and Bruguiera gymnorhiza-Bruguiera sexangula. The CH4 fluxes from sediments were 4.82±1.46mgCH4m-2h-1 for K. candel and 1.36±0.17mgCH4m-2h-1 for the other three with pneumatophores. Among the three communities with pneumatophores, S. apetala community had significantly greater emission rate than the other two (P<0.05). Pneumatophores in S. apetala were found to significantly decrease CH4 emission from sediments (P<0.01), while those in B. gymnorhiza-B. sexangula were significantly increase it (P<0.05). CH4 fluxes from waters were 3.48±1.11mgCH4m-2h-1, with the highest emission rate in the K. candel community for the duck farming. Leaves of mangroves except for those of K. candel were a weak CH4 daytime sink, but stems were a weak source. The total 72ha of mangroves in the Changning river basin emitted about 8.10Gg CH4 per year, with a weighted emission rate of about 1.29mgCH4m-2h-1. Our results suggested that mangroves are only a small methane source to atmosphere with great contribution from sediments and waters, only slight contribution from leaves and stems. Pneumatophores of different mangrove species played different roles in CH4 fluxes from sediments.


Assuntos
Poluentes Atmosféricos/análise , Espécies Introduzidas , Metano/análise , Áreas Alagadas , China , Monitoramento Ambiental , Rhizophoraceae
14.
Langmuir ; 35(5): 1837-1845, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30086636

RESUMO

Patients with diabetic wounds have deficient local and systemic cellular immunity. Herein, a new silver nanoparticle-containing hydrogel with antifouling properties was developed for enhancing the immune response in diabetic wound healing. The antifouling property was obtained by adjusting the composition of cationic chitosan and anionic dextran to approach zero charge. Furthermore, this hybrid hydrogel showed long-lasting and broad-spectrum antibacterial activity. Rapid wound contraction was observed after the treatment with the hydrogel, which suggested its superior healing activity to promote fibroblast migration, granulation tissue formation, and angiogenesis. The upregulation of CD68+ and CD3+ expression levels demonstrated that the hydrogel could trigger immune responses in the treatment of wound healing. These results show that this antifouling hybrid hydrogel as a wound dressing provided a promising strategy for the treatment of diabetic ulcers.


Assuntos
Antibacterianos/uso terapêutico , Hidrogéis/química , Nanopartículas Metálicas/uso terapêutico , Prata/uso terapêutico , Úlcera Cutânea/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , Quitosana/síntese química , Quitosana/química , Quitosana/toxicidade , Doença Crônica , Derme/patologia , Dextranos/síntese química , Dextranos/uso terapêutico , Dextranos/toxicidade , Diabetes Mellitus Experimental/complicações , Hidrogéis/síntese química , Hidrogéis/toxicidade , Masculino , Nanopartículas Metálicas/química , Nanopartículas Metálicas/toxicidade , Camundongos , Células NIH 3T3 , Pseudomonas aeruginosa/efeitos dos fármacos , Ratos Sprague-Dawley , Prata/química , Prata/toxicidade , Úlcera Cutânea/etiologia , Staphylococcus aureus/efeitos dos fármacos , Linfócitos T/metabolismo
15.
Carbohydr Polym ; 197: 57-65, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30007649

RESUMO

Overweight and obesity, which contribute to various chronic diseases, are increasingly common conditions around the world. For the purpose of weight loss in patients with overweight and obesity, we developed a series of ß-cyclodextrin functionalized cationic branched polyethylenimine as oral pharmaceutical agents to inhibit digestion and absorption of dietary lipids in vivo. Tuning the structural configuration, molecular weight, and side-chain length of the cationic polymers provided the polymer with effective inhibition of lipid absorption. Importantly, the cationic polymer significantly increased fecal elimination of bile acids, triglycerides and cholesterol by 6.3-, 4.8- and 5.0-fold higher than those of the control with high fat diet, respectively. Moreover, the polymer could reduce the plasma lipids and liver lipid level in mice. The cationic polymer exhibited low cytotoxicity and did not cause observable histological changes for normal tissue. Therefore, the cationic polymer showed effective and safe characteristics as an oral pharmaceutical agent for inhibiting lipid absorption. This work offers a new promising venue to control weight for patients with overweight and obesity.


Assuntos
Lipídeos/antagonistas & inibidores , Polietilenoimina/farmacologia , Polissacarídeos/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dieta , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Polietilenoimina/administração & dosagem , Polietilenoimina/química , Polissacarídeos/administração & dosagem , Polissacarídeos/química , Ratos
16.
Med Sci Monit ; 24: 1241-1250, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29491345

RESUMO

BACKGROUND Diabetes mellitus (DM) is characterized by a decreased blood level of glutamine (Gln), which may contribute to the disturbance in the effect of insulin on skeletal muscle. Therefore, it is crucial to study how to improve the effect of insulin on skeletal muscle by increasing Gln. In the present study, we investigated the effect of Gln on the hypoglycemic action of insulin in skeletal muscle L6 cells at high glucose levels through the insulin signaling pathway and glycogen synthesis pathway. MATERIAL AND METHODS The L6 cells were cultured in and stimulated by Gln and insulin. The glutamine analogue, L-Gamma-Glutamyl-p-nitroanilide (GPNA), was used for verifying the effect of Gln. The expression of insulin signaling molecules, including phosphatidylinositol-3-kinase (PI3K), 3-phosphoinositide-dependent protein kinase-1 (PDK1), protein kinase B (AKT), protein kinase C zeta (PKCz), and glucose transporter 4 (GLUT4), were detected by real-time PCR and Western blot analysis, GLUT4 translocation was observed by immunofluorescence staining, glycogen synthase kinase (GSK) was analyzed by Western blotting, and glucose uptake was measured by glucose oxidase method (GOD). RESULTS The results demonstrated that Gln combined with insulin remarkably up-regulated PI3K and PDK1 and also increased AKT and PKCz phosphorylation. The present study shows that Gln enhanced the impact of insulin on GLUT4 and its translocation. The results of glucose uptake and GSK phosphorylation further confirmed the hypoglycemic effect of Gln accompanied with insulin. The hypoglycemic effect of Gln was reversed by GPNA. CONCLUSIONS These findings suggest that Gln enhances the hypoglycemic role of insulin through the PI3K/AKT/GLUT4 signaling pathway and glycogen synthesis pathway.


Assuntos
Transportador de Glucose Tipo 4/metabolismo , Glutamina/farmacologia , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Glicogênio/biossíntese , Proteína Quinase C/metabolismo , Ratos , Regulação para Cima/efeitos dos fármacos
17.
Exp Ther Med ; 14(5): 5219-5227, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29201240

RESUMO

The transient receptor potential melastatin 2 (TRPM2) channel, a Ca2+ permeable channel activated by cAMP, is expressed on pancreatic ß-cells and is responsible for the regulation of insulin secretion. It is known that glucose-stimulated insulin secretion (GSIS) can be potentiated by glucagon like peptide-1 (GLP-1), and that the changes in the extracellular glucose concentration alter the levels of intracellular adenosine ATP and cAMP. The present study hypothesized that TRPM2 mediates the modulatory effect of GLP-1 on insulin secretion. The results demonstrated that silencing of TRPM2 eliminated GLP-1-enhanced insulin secretion, indicating the involvement of TRPM2 in this process. In addition, the results of current recordings of TRPM2 and measurement of the resulting insulin secretion in ß-cells in the presence of GLP-1 and various concentrations of glucose suggest that GLP-1 regulates GSIS via the TRPM2 channel. Furthermore, inhibiting the activity or expression of TRPM2 attenuated GLP-1-induced GSIS. By using specific activators or inhibitors, the present study demonstrated that the two primary downstream effectors of the GLP-1 receptor, exchange protein directly activated by cAMP and protein kinase A, differentially influence GSIS and GLP-1-potentiated GSIS. In conclusion, the present study revealed the role of TRPM2 in GLP-1-regulated insulin secretion. The results of the present study provide a novel avenue for the prevention and treatment of diabetes and its complications.

18.
Biomed Pharmacother ; 92: 285-292, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28551549

RESUMO

Photodynamic therapy (PDT) is emerging as a promising method for the treatment of various cancer diseases. However, the clinical application of PDT is limited due to the lack of effective photosensitizers. In this study, a novel chlorophyll derivative, N,N-bis(2-carboxyethyl)pyropheophorbide a (BPPA), had been synthesized and characterized. BPPA had a characteristic long wavelength absorption peak at 669nm and a singlet oxygen quantum yield of 0.54. To investigate the photodynamic ability of BPPA against cholangiocarcinoma (CCA), cellular uptake, subcellular location and bio-distribution, in vitro and in vivo PDT efficacy of BPPA were studied. The results showed that BPPA could rapidly accumulate in QBC-939 cells and localize in the cytoplasm. BPPA- PDT was effective in reducing the cell viability in a drug dose- and light dose-dependent manner in vitro. In CCA xenograft nude mouse model, the concentration of BPPA in the plasma lowered rapidly, and the fluorescence signal peaked at 0.5h and 2h after injection in the skin and tumor, respectively. Significant quantities could be observed in the tumor. BPPA followed by irradiation could significantly inhibit growth of tumors, and histological examination revealed necrotic damage in PDT-treated tumors. These results suggested that BPPA could be a promising drug candidate for photodynamic therapy in cholangiocarcinoma.


Assuntos
Neoplasias dos Ductos Biliares/tratamento farmacológico , Clorofila/uso terapêutico , Colangiocarcinoma/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Clorofila/química , Clorofila/farmacologia , Colangiocarcinoma/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Distribuição Aleatória , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
19.
Patient Prefer Adherence ; 11: 787-793, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28458523

RESUMO

OBJECTIVES: The purpose of this study was to assess the efficacy and practicability of patient-to-patient (PTP) education strategy on glycemic control among patients with type 2 diabetes mellitus. METHODS: Eligible subjects from outpatient clinic were recruited and randomized to either intervention group or control group. Inpatients with poor outcomes and complications acted as mentors to share their experience with the intervention group in three tailored classes. Besides, the intervention group received general advice from specialists. The control group received general advice only. The glucose metabolic status and behavior modification indicators were evaluated before and after intervention. In addition, both groups finished a questionnaire survey regarding awareness to diabetic complications after intervention. RESULTS: Eighty-four subjects were recruited (42 subjects for each group), and 51 subjects finished the study. Both the intervention group (n=29) and the control group (n=22) showed a tendency toward a decrease in glycosylated hemoglobin level (A1c, -0.8% vs -0.4%, P<0.05) and improvement in behavior modification (+5.0 vs +2.8, P<0.05) after 6 months. The intervention group (13.8%) obtained a higher percentage than the control group (9.1%) whose A1c reached ≤7%. The body mass index did not change significantly in any group. The questionnaire score about complication awareness was higher in the intervention group than in the control group. CONCLUSION: This preliminary evidence suggests that PTP education strategy is acceptable for facilitating the outcome of glycemic control. Patient sense of complications may work on A1c reduction.

20.
Carbohydr Res ; 445: 32-39, 2017 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-28395252

RESUMO

Hydrogels are good candidates to satisfy many needs for functional and tunable biomaterials. How to precisely control the gel structure and functions is crucial for the construction of sophisticated soft biomaterials comprising the hydrogels, which facilitates the impact of the surrounding environment on a unique biological function occurring. Here, glucose-responsive hydrogels comprised of 3-acrylamidophenyl boronic acid copolymerized with 2-lactobionamidoethyl methacrylate (p(APBA-b-LAMA)) were synthesized, and further evaluated as carriers for insulin delivery. The formation of (p(APBA-b-LAMA)) hydrogel was based on dynamic covalent bond using the association of boronic acid with diols. P(APBA-b-LAMA) hydrogel with the typical porous structure showed a rapid increase in equilibrium of swelling, which was up to 1856% after incubation with aqueous solution. Using insulin as a model protein therapeutic, p(APBA-b-LAMA) hydrogel exhibited high drug loading capability up to 15.6%, and also displayed glucose-dependent insulin release under physiological conditions. Additionally, the viability of NIH3T3 cells was more than 90% after treated with p(APBA-b-LAMA) hydrogel, indicating that the hydrogel had no cytotoxicity. Consequently, the novel p(APBA-b-LAMA) hydrogel has a practical application for diabetes treatment.


Assuntos
Ácidos Borônicos/química , Portadores de Fármacos/química , Ésteres/química , Glucose/metabolismo , Hidrogéis/química , Insulina/química , Ácidos Polimetacrílicos/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Hidrogéis/toxicidade , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Células NIH 3T3 , Polimerização
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