RESUMO
PURPOSE: Transferrin receptors (TfRs) are overexpressed in tumor cells but are scarce in normal tissues, which makes TfR an attractive target for drug treatment of cancer. The objective of this study was to evaluate the potential of BP9a (CAHLHNRS) as a peptide vector for constructing TfR targeted peptide-drug conjugates and selective drug delivery. METHODS: Doxorubicin (DOX) was connected to BP9a via a disulfide-intercalating linker to afford a reduction-responsive BP9a-SS-DOX conjugate. By using HepG2 human liver cancer cells and L-O2 normal hepatic cells as TfR over-expressing and low-expressing in vitro models, respectively, TfR mediated cellular uptake of this conjugate was studied by using flow cytometry and confocal laser scanning microscopy. The in vitro cytotoxicities of the conjugate against HepG2 and L-O2 cells were examined by cell counting kit-8 (CCK-8) assay to evaluate its tumorous specificity. RESULTS: Cellular uptake and TfR blockage test results showed that the BP9a-SS-DOX conjugate gained entry into HepG2 cells via endocytosis mediated by TfR and mainly accumulated in cytoplasm. The in vitro antiproliferative activity of this conjugate against HepG2 cells (IC50 6.21 ± 1.12 µM) was approximately one-sixth of that of free DOX (IC50 1.03 ± 0.13 µM). However, its cytotoxic effect on L-O2 cells was obviously reduced compared with that of free DOX. CONCLUSIONS: The BP9a-SS-DOX conjugate showed specific antiproliferative activity against HepG2 liver cancer cells. Our study suggests that BP9a has the potential to target chemotherapeutic agents to tumor cells over-expressing TfR and facilitate selective drug delivery.
Assuntos
Antibióticos Antineoplásicos/química , Doxorrubicina/química , Portadores de Fármacos/química , Peptídeos/química , Receptores da Transferrina/metabolismo , Linhagem Celular , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Endocitose , Humanos , Terapia de Alvo Molecular/métodos , Oxirredução , Transdução de SinaisRESUMO
Currently, there are no standardized, objective, and clinically applicable methods to predict the outcome of pulsed dye laser (PDL) therapy on capillary vascular malformation (CVM) patients. The introduction of a method that can predict the outcome prior to treatment will be valuable for both the patients and the doctors. In this study, the authors treated CVM with 595-nm wavelength PDL in Chinese patients (n = 686) and analyzed the efficacy of treatment and complications retrospectively in a 5-year period. Nearly 18 % of patients (n = 122) had 76 % or more clearing of lesions; over 52 % of patients (n = 360) had more than 50 % of clearing. The lesions in head and neck region had the best effective rate (58.3 %), followed by trunk (42.9 %) and extremities (35.6 %). The efficacy of PDL therapy is related to age, type, and location of lesions. Fifty-seven patients (8.3 %) had complications, including 2.0 % blistering (n = 14), 4.5 % hyperpigmentation (n = 31), 1.3 % hypopigmentation (n = 9), and 0.4 % hypertrophic scarring (n = 3). Based on these preliminary data, the authors established a standardized, objective, and clinically applicable equation that may be applied to predict the efficacy of 595 nm PDL therapy on a newly diagnosed Chinese CVM patients based on the age, type, and location of lesions.
Assuntos
Lasers de Corante , Malformações Vasculares/cirurgia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Curva ROC , Estudos Retrospectivos , Resultado do Tratamento , Malformações Vasculares/patologia , Adulto JovemRESUMO
Glucuronidation and sulfation are the two major phase II metabolic pathways for flavones, natural compounds that hold great potential for improving human health. We investigated the positional preference for sulfation and glucuronidation of seven structurally similar flavones in vitro and in situ. An FVB mouse intestinal perfusion model was used in addition to three small intestine S9 fractions catalyzing sulfation only (Sult enzymes), glucuronidation only (Ugt enzymes) or both (Sult and Ugt enzymes). In both the single and co-reaction S9 systems, flavones containing 7-OH groups were conjugated only at 7-OH despite the presence of other hydroxyl groups, and 7-OH glucuronidation was faster than sulfation (P <0.05). The sulfation rate was enhanced in the Sult-Ugt co-reaction system, while glucuronidation was usually unchanged by the presence of Sult. In the intestinal perfusate, sulfation patterns were the same in the small intestine and colon, and the excretion rate of 7-O-sulfate was the fastest or second fastest. The excretion of 7-O-glucuronidates was faster in small intestine (P < 0.05) than in colon. The S9-mediated sulfation rates of the different flavones were significantly correlated with the excretion rates of the same flavones from perfused intestine. In conclusion, flavone glucuronidation and sulfation rates were sensitive to minor changes in molecular structure. In intestinal S9 fractions, both Ugts and Sults preferentially catalyzed reactions at 7-OH. The sulfation rate was significantly enhanced by simultaneous glucuronidation, but glucuronidation was unaltered by sulfation. Sulfation rates in mouse S9 fractions correlated with sulfation rates in perfused intestine.
Assuntos
Flavonas/metabolismo , Glucuronídeos/metabolismo , Mucosa Intestinal/metabolismo , Sulfatos/metabolismo , Animais , Flavonas/química , Glucuronosiltransferase , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos , Perfusão , Proteína S9 Ribossômica , Proteínas Ribossômicas/metabolismo , Relação Estrutura-Atividade , SulfotransferasesRESUMO
BACKGROUND: The aging of the population has made the health problems of the elderly increasingly prominent, and their health needs are increasing. Existing studies on health resource integration approaches are mostly incomplete in assessing the health service capacity from the perspective of the health service provider. OBJECTIVE: The unmet health needs of the elderly were sampled and analyzed from the perspective of health service demanders. To explore how to build an integrated medical organization structure to better meet the health needs of the elderly. METHODS: A whole-group sampling method was used to conduct a questionnaire survey of 1527 older adults in N district of H city, Zhejiang province, China, to cross-sectionally analyze their current status of unmet health needs. RESULTS: The survey and analysis found that the needs of the elderly in this community to obtain disease-related knowledge, rational exercise, a healthy diet, and access to health information were not met. There were more patients with chronic diseases, and the top three chronic disease prevalence rates were hypertension (40.2%), dyslipidemia (8.4), and diabetes (7%). Chronic disease co-morbidities accounted for 13.3%. CONCLUSION: The relatively independently set up health service system at the present stage in China can no longer fully meet the health needs of the elderly, and the health service providers should provide integrated and continuous health services to meet the needs of whole-cycle health management. Therefore, we believe that effectively integrating various health service providers in the region and building an integrated health service organization with general practitioners as the core may be a solution to the current situation of unmet health needs of the elderly.
Assuntos
Recursos em Saúde , Serviços de Saúde , Humanos , Idoso , Estudos Transversais , China/epidemiologia , Doença CrônicaRESUMO
High-performance membranes exceeding the conventional permeability-selectivity upper bound are attractive for advanced gas separations. In the context microporous polymers have gained increasing attention owing to their exceptional permeability, which, however, demonstrate a moderate selectivity unfavorable for separating similarly sized gas mixtures. Here we report an approach to designing polymeric molecular sieve membranes via multi-covalent-crosslinking of blended bromomethyl polymer of intrinsic microporosity and Tröger's base, enabling simultaneously high permeability and selectivity. Ultra-selective gas separation is achieved via adjusting reaction temperature, reaction time and the oxygen concentration with occurrences of polymer chain scission, rearrangement and thermal oxidative crosslinking reaction. Upon a thermal treatment at 300 °C for 5 h, membranes exhibit an O2/N2, CO2/CH4 and H2/CH4 selectivity as high as 11.1, 154.5 and 813.6, respectively, transcending the state-of-art upper bounds. The design strategy represents a generalizable approach to creating molecular-sieving polymer membranes with enormous potentials for high-performance separation processes.
RESUMO
In this study, a peptide-drug conjugate was designed and synthesized by connecting a transferrin receptor (TfR)-targeted binding peptide analog BP9a (CAHLHNRS) with doxorubicin (DOX) through N-succinimidyl-3-maleimidopropionate (SMP) as the cross-linker. Confocal laser scanning microscopy results indicated that free DOX mainly accumulated in the nuclei of both TfR overexpressed HepG2 hepatoma cells and L-O2 normal liver cells expressing low level of TfR; most of the BP9a-DOX conjugate displayed cytoplasmic location, and its cellular uptake by HepG2 cells was obviously reduced by TfR blockage test. Nevertheless, the cellular uptake of this conjugate by L-O2 cells was much less than that of free DOX. Meanwhile, the BP9a-DOX conjugate exhibited lower in vitro antiproliferative activity against HepG2 cells than free DOX, but its cytotoxic effect on L-O2 cells was decreased compared with that of free DOX. These results suggest that BP9a could be applied as a potential TfR-targeted peptide vector for selective drug delivery.
Assuntos
Antineoplásicos/química , Peptídeos Penetradores de Células/química , Doxorrubicina/química , Portadores de Fármacos/química , Peptídeos/química , Receptores da Transferrina/metabolismo , Antineoplásicos/farmacologia , Permeabilidade da Membrana Celular , Reagentes de Ligações Cruzadas/química , Doxorrubicina/farmacologia , Desenvolvimento de Medicamentos , Liberação Controlada de Fármacos , Humanos , Maleimidas/química , Terapia de Alvo Molecular , Succinimidas/químicaRESUMO
The objective of this work was to investigate the effect of boletus polysaccharide (BPS) on diabetic hepatopathy in streptozotocin (STZ)-induced type 2 diabetes mellitus (T2DM) rats for the first time. The rats were fed with high-fat diet (HFD) for 4 weeks and induced with STZ by a single intraperitoneal injection to develop T2DM model. The HFD was given continually for another 4 weeks after diabetes induction, following the drugs of BPS (400â¯mg/kgâ¯bw/day) infused to stomach of rats once a day. After the administration, blood was drawn from the posterior orbital venous plexus of the inner canthus and the rats were then sacrificed. The blood glucose and lipid, alanine transaminase (ALT) and aspartate transaminase (AST) were detected immediately. Besides, their livers were dissected for biochemical and histopathological assays. And the levels of malonaldehyde, glutathione and antioxidant enzymes in liver were detected. In addition, histopathological examinations of liver were performed to verify the liver injury. The expressions of NF-κB, TNF-α, SREBP1c, and CYP7A1 were test to trace out the mechanistic pathways. Compared with T2DM model group, the blood glucose, TC, TG, ALT, AST, and MDA and so on were significantly reduced, and CAT, SOD, GSH, GPx were significantly increased in the rats treated with BPS. The histopathological examination showed the liver injury in BPS treated rats was alleviated. The expressions of SREBP1c, NF-κB and TNF-α were significantly decreased, and the expressions of CYP7A1 was significantly increased. All these experimental findings demonstrate that BPS exhibited antidiabetic effects rats possibly through its inhibition of oxidative stress and inflammation, supporting that BPS has a promising therapeutic effect in the treatment of diabetic hepatopathy in rats.
Assuntos
Hipoglicemiantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/farmacologia , Alanina Transaminase/sangue , Animais , Antioxidantes/metabolismo , Aspartato Aminotransferases/sangue , Basidiomycota/metabolismo , Glicemia/análise , Colesterol 7-alfa-Hidroxilase/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica , Hipoglicemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , NF-kappa B/metabolismo , Polissacarídeos/uso terapêutico , Ratos , Ratos Wistar , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
PURPOSE: The purpose of this study is to identify a prospective association between CA125 and tumorigenic ovarian cancer cells, using the new method of orthotopic transplantation (1). METHOD: After making the surgical ovarian cancer specimen into cell suspension, we separated the tumorigenic cells from the nontumorigenic cancer cells based on cell surface marker (cancer antigen CA125 and lineage markers) expression. We developed a SCID mice model in which the CA125+/ lineage- and CA125-/ lineage- cells were injected into ovarian parenchyma by use of a microinjector. As a measure of effectiveness of tumor-forming, tumor weight, abdominal distension, ascites volume and activity, subcutaneous fat were determined or observed. Immunohistochemistry was done to determine tumor cell markers. RESULTS: We found that the cells of CA125+/ lineage- were able to form new tumors; whereas, an equal quantity of CA125-/lineage- cells failed to form any tumors. The new generated tumor contained additional CA125-/lineage- tumorigenic cells as well as the phenotypically diverse population of nontumorigenic cells. Quantities were judged to be significantly different P < 0.0001. CONCLUSION: CA125+/ lineage- cells, which may be ovarian cancer stem cells, were the source for tumor recurrence. The strategies designed to target this cell population may lead to more effective therapies.
Assuntos
Biomarcadores Tumorais/análise , Antígeno Ca-125/biossíntese , Proteínas de Membrana/biossíntese , Neoplasias Epiteliais e Glandulares/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/patologia , Animais , Antígeno Ca-125/análise , Carcinoma Epitelial do Ovário , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Xenoenxertos , Humanos , Proteínas de Membrana/análise , Camundongos , Camundongos SCID , Microscopia ConfocalRESUMO
Amine-loaded poly(amide-imide) (PAI)/silica hollow fiber sorbents are created and used in a rapid temperature swing adsorption (RTSA) system for CO2 capture under simulated postcombustion flue gas conditions. Poly(ethylenimine) (PEI) is infused into the PAI/mesoporous silica hollow fiber sorbents during fiber solvent exchange steps after fiber spinning. A lumen-side barrier layer is also successfully formed on the bore side of PAI/silica hollow fiber sorbents by using a mixture of Neoprene with cross-linking agents in a post-treatment process. The amine loaded fibers are tested in shell-and-tube modules by exposure on the shell side at 1 atm and 35 °C to simulated flue gas with an inert tracer (14 mol % CO2, 72 mol % N2, and 14 mol % He, at 100% relative humidity (RH)). The fibers show a breakthrough CO2 capacity of 0.85 mmol/g-fiber and a pseudoequilibrium CO2 uptake of 1.19 mmol/g-fiber. When tested in the temperature range of 35-75 °C, the PAI/silica/PEI fiber sorbents show a maximum CO2 capacity at 65 °C, owing to a trade-off between thermodynamic and kinetic factors. To overcome mass transfer limitations in rigidified PEI infused in the silica, an alternate PEI infusion method using a glycerol/PEI/methanol mixture is developed, and the CO2 sorption performance is improved significantly, effectively doubling the functional sorption capacity. Specifically, the glycerol-plasticized sorbents are found to have a breakthrough and equilibrium CO2 capacity of 1.3 and 2.0 mmol/g of dry fiber sorbent at 35 °C, respectively. Thus, this work demonstrates two PAI-based sorbents that are optimized for different sorption conditions with the PAI/silica/PEI sorbents operating effectively at 65 °C and the PAI/silica/PEI-glycerol sorbents operating well at 35 °C with significantly improved sorption capacity.
RESUMO
Amine/silica/polymer composite hollow fiber adsorbents are produced using a novel reactive post-spinning infusion technique, and the obtained fibers are shown to capture CO2 from simulated flue gas. The post-spinning infusion technique allows for functionalization of polymer/silica hollow fibers with different types of amines during the solvent exchange step after fiber spinning. The post-spinning infusion of 3-aminopropyltrimethoxysilane (APS) into mesoporous silica/cellulose acetate hollow fibers is demonstrated here, and the materials are compared with hollow fibers infused with poly(ethyleneimine) (PEI). This approach results in silica/polymer composite fibers with good amine distribution and accessibility, as well as adequate porosity retained within the fibers to facilitate rapid mass transfer and adsorption kinetics. The CO2 adsorption capacities for the APS-infused hollow fibers are shown to be comparable to those of amine powders with similar amine loadings. In contrast, fibers that are spun with presynthesized, amine-loaded mesoporous silica powders show negligible CO2 uptake and low amine loadings because of loss of amines from the silica materials during the fiber spinning process. Aminosilica powders are shown to be more hydrophilic than the corresponding amine containing composite hollow fibers, the bare polymer as well as silica support. Both the PEI-infused and APS-infused fibers demonstrate reduced CO2 adsorption upon elevating the temperature from 35 to 80 °C, in accordance with thermodynamics, whereas PEI-infused powders show increased CO2 uptake over that temperature range because of competing diffusional and thermodynamic effects. The CO2 adsorption kinetics as probed via TGA show that the APS-infused hollow fiber adsorbents have more rapid uptake kinetics than their aminosilica powder analogues. The adsorption performance of the functionalized hollow fibers is also assessed in CO2 breakthrough experiments. The breakthrough results show a sharp CO2 front for APS-grafted fibers, indicating fast kinetics with comparable pseudo-equilibrium capacities to the CO2 equilibrium capacities measured via thermogravimetric analysis (TGA). The results indicate the post-spinning infusion method provides a new platform for synthesizing composite polymer/silica/amine fibers that may facilitate the ultimate scale-up of practical fiber adsorbents for flue gas CO2 capture applications.