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Serum hepatitis B core-related antigen (HBcrAg) is considered a surrogate marker of the amount and activity of intrahepatic covalently closed circular DNA. This study aimed to explore the prognostic value of HBcrAg on patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative hepatectomy undergoing antiviral therapy (AVT). Data of 949 consecutive patients with HBV-related HCC undergoing curative resection between 2010 and 2013 were reviewed. Serum HBcrAg levels were measured at surgery (baseline) for all patients and at the time of 2 years postoperatively (on-treatment) for those without recurrence. Primary endpoint was tumor recurrence. High HBcrAg levels are associated with malignant phenotypes. HBcrAg independently affected both recurrence and overall survival (OS) in patients with negative hepatitis B e antigen (HBeAg-, p = .007 and p = .042, respectively) but not in their positive HBeAg (HBeAg+) counterparts (p = .100 and p = .075, respectively). Patients with high baseline HBcrAg had higher late, but not early recurrence rates than those with low baseline HBcrAg levels, regardless of HBeAg status (HBeAg+: p = .307 for early, p = .001 for late; HBeAg-: p = .937 for early, p < .001 for late). On-treatment HBcrAg independently affected late recurrence in patients stratified by both cirrhosis and HBeAg (p < .001 for all). The predictive power of HBcrAg kinetics for late recurrence was better than that of the baseline and on-treatment HBcrAg. High HBcrAg levels during long-term AVT are associated with late recurrence of HCC after hepatectomy. Combining baseline and on-treatment HBcrAg might be valuable in identifying patients at a high risk of relapse and stratifying surveillance strategies postoperatively.
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Quinone imines are important derivatives of quinones with a wide range of applications in organic synthesis and the pharmaceutical industry. The attack of nucleophilic reagents on quinone imines tends to lead to aromatization of the quinone skeleton, resulting in both the high reactivity and the unique reactivity of quinone imines. The extreme value of quinone imines in the construction of nitrogen- or oxygen-containing heterocycles has attracted widespread attention, and remarkable advances have been reported recently. This review provides an overview of the application of quinone imines in the synthesis of cyclic compounds via the domino annulation reaction.
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Hierarchical nanomaterials have received increasing interest for many applications. Here, we report a facile programmable strategy based on an embedded segmental crystallinity design to prepare unprecedented supramolecular planar nanobrush-like structures composed of two distinct molecular packing motifs, by the self-assembly of one particular diblock copolymer poly(ethylene glycol)-block-poly(N-octylglycine) in a one-pot preparation. We demonstrate that the superstructures result from the temperature-controlled hierarchical self-assembly of preformed spherical micelles by optimizing the crystallization-solvophobicity balance. Particularly remarkable is that these micelles first assemble into linear arrays at elevated temperatures, which, upon cooling, subsequently template further lateral, crystallization-driven assembly in a living manner. Addition of the diblock copolymer chains to the growing nanostructure occurs via a loosely organized micellar intermediate state, which undergoes an unfolding transition to the final crystalline state in the nanobrush. This assembly mechanism is distinct from previous crystallization-driven approaches which occur via unimer addition, and is more akin to protein crystallization. Interestingly, nanobrush formation is conserved over a variety of preparation pathways. The precise control ability over the superstructure, combined with the excellent biocompatibility of polypeptoids, offers great potential for nanomaterials inaccessible previously for a broad range of advanced applications.
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Cadmium (Cd) is an environmental heavy metal, and its accumulation is harmful to animal and human health. The cytotoxicity of Cd includes oxidative stress, apoptosis, and mitochondrial histopathological changes. Furthermore, polystyrene (PS) is a kind of microplastic piece derived from biotic and abiotic weathering courses, and has toxicity in various aspects. However, the potential mechanism of action of Cd co-treated with PS is still poorly unclear. The objective of this study was to investigate the effects of PS on Cd-induced histopathological injury of mitochondria in the lung of mice. In this study, the results have showed that Cd could induce the activity of oxidative enzymes of the lung cells in mice, increasing the content of partial microelement and the phosphorylation of inflammatory factor NF-κB p65. Cd further destroys the integrity of mitochondria by increasing the expression of apoptotic protein and blocking the autophagy. In addition, PS solely group aggravated the lung damage in mice, especially mitochondrial toxicity, and played a synergistic effect with Cd in lung injury. However, how PS can augment mitochondrial damage and synergism with Cd in lung of mice requiring further exploration. Therefore, PS was able to exacerbate Cd-induced mitochondrial damage to the lung in mice by blocking autophagy, and was associated with the apoptosis.
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Cádmio , Poliestirenos , Humanos , Camundongos , Animais , Cádmio/toxicidade , Poliestirenos/toxicidade , Plásticos/farmacologia , Autofagia , Estresse Oxidativo , Apoptose , PulmãoRESUMO
Nature-made hydrogels typically combine a wide range of multiscale fibers into biological composite networks, which offer an adaptive property. Inspired by nature, we report a facile approach to construct hybrid hydrogels from a range of natural or commercially available synthetic nongelling polymers (e.g., poly(ethylene glycol), poly(acrylic acid), carboxylated cellulose nanocrystal, and sodium alginate) at a concentration as low as 0.53 wt % using a nonionic fibrous peptide hydrogelator. Through simply mixing the peptide hydrogelator with a polymer aqueous solution, stable hybrid hydrogels can be formed with the concentration of hydrogelator at â¼0.05 wt %. The gel strength of the resulting hydrogels can be effectively modulated by the concentration, molecular weight, and terminal group of the polymer. We further demonstrate that the molecular interactions between the peptide hydrogelator and the polymer are very crucial for the formation of hybrid hydrogel, which synergically induce the gelation at considerably low concentrations. A peptide hydrogelator can be easily obtained by aminolysis of alkyl-oilgo(γ-benzyl-l-glutamate) samples. Live/Dead assays indicate low cytotoxicity of the hybrid hydrogel toward HeLa cells. Combining the low-cost, scalable synthesis, and biocompatibility, the prepared peptide hydrogelator presents a potential candidate to expand the scope of polymer hydrogels for biomedical applications and also shows considerable commercial significance.
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Hidrogéis , Polímeros , Células HeLa , Humanos , Hidrogéis/química , Hidrogéis/toxicidade , Peptídeos/toxicidade , Polietilenoglicóis/química , Polímeros/químicaRESUMO
Aggregation-induced emission (AIE) luminogens with highly tunable properties show great potential for many applications. In this study, we synthesized a new family of AIE-type poly(ethylene glycol)-block-poly(9-anthrylmethyl lysine) (PEG-b-PLys-An) diblock copolymers by taking advantage of amphiphilic self-assembly and rigid helical backbones. These copolymers can self-assemble into various assemblies through nanoprecipitation methods. The micelles using N,N-dimethylformamide (DMF) as a cosolvent present brighter fluorescence than the vesicles prepared from tetrahydrofuran (THF). We demonstrate that the decreased solubility of copolymers in DMF results in the formation of more compact micelles with more excimer formation during the self-assembly process, while better solvent THF favors the formation of vesicles with stretched core chains. In addition, the secondary conformation of the polypeptide block shows pronounced effects on the fluorescence property. We further show the internalization of the assemblies using two types of cells by cellular uptake experiments. By the delicate design of the block copolymer, we successfully prepare the morphology- and conformation-dependent AIE materials for potential biomedical applications.
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Micelas , Polímeros , Conformação Molecular , Polietilenoglicóis/química , Polímeros/química , SolubilidadeRESUMO
Osteoclastogenesis is an ongoing rigorous course that includes osteoclast precursors fusion and bone resorption executed by degradative enzymes. Osteoclastogenesis is controlled by endogenous signaling and/or regulators or affected by exogenous conditions and can also be controlled both internally and externally. More evidence indicates that autophagy, inflammation, and immunity are closely related to osteoclastogenesis and involve multiple intracellular organelles (e.g., lysosomes and autophagosomes) and certain inflammatory or immunological factors. Based on the literature on osteoclastogenesis induced by different regulatory aspects, emerging basic cross-studies have reported the emerging disquisitive orientation for osteoclast differentiation and function. In this review, we summarize the partial potential therapeutic targets for osteoclast differentiation and function, including the signaling pathways and various cellular processes.
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Reabsorção Óssea , Osteogênese , Autofagia , Reabsorção Óssea/metabolismo , Diferenciação Celular , Humanos , Inflamação/metabolismo , Osteoclastos/metabolismo , Ligante RANK/metabolismoRESUMO
Laboratory simulation is the only feasible way to achieve Martian environmental conditions on Earth, establishing a key link between the laboratory and Mars exploration. The mineral phases of some Martian surface materials (especially hydrated minerals), as well as their spectral features, are closely related to environmental conditions. Therefore, Martian environment simulation is necessary for Martian mineral detection and analysis. A Mars environment chamber (MEC) coupled with multiple in situ spectral sensors (VIS (visible)-NIR (near-infrared) reflectance spectroscopy, Raman spectroscopy, laser-induced breakdown spectroscopy (LIBS), and UV-VIS emission spectroscopy) was developed at Shandong University at Weihai, China. This MEC is a comprehensive research platform for Martian environmental parameter simulation, regulation, and spectral data collection. Here, the structure, function and performance of the MEC and the coupled spectral sensors were systematically investigated. The spectral characteristics of some geological samples were recorded and the effect of environmental parameter variations (such as gas pressure and temperature) on the spectral features were also acquired by using the in situ spectral sensors under various simulated Martian conditions. CO2 glow discharge plasma was generated and its emission spectra were assigned. The MEC and its tested functional units worked well with good accuracy and repeatability. China is implementing its first Mars mission (Tianwen-1), which was launched on 23 July 2020 and successfully entered into a Mars orbit on 10 February 2021. Many preparatory works such as spectral databases and prediction model building are currently underway using MECs, which will help us build a solid foundation for real Martian spectral data analysis and interpretation.
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OBJECTIVE: The aim of the study was to systematically review and meta-analyze the available evidence regarding the association between timing of repair or referral and clinical outcomes in bile duct injury (BDI). BACKGROUND: Surgical repair is recommended for patients with complex BDI following laparoscopic cholecystectomy. However, consensus on the timing of surgery or referral to a specialist is lacking. METHODS: We searched PubMed, Embase, Cochrane Library, and Scopus for eligible studies. The coprimary outcomes were repair failure in follow-up and postoperative complications. We pooled odds ratios (ORs) using random-effects models. RESULTS: We included 32 studies. The rate of repair failure was significantly higher for early versus delayed repair [OR 1.65, 95% confidence interval (CI) 1.14-2.37, P= 0.007], lower for early versus delayed referral (OR 0.28, 95% CI 0.17-0.45, P < 0.001), but did not differ substantially for on-table versus postcholecystectomy repair (OR 2.06, 95% CI 0.89-4.73, P = 0.09). Regarding postoperative complications, early referral outperformed delayed referral (OR 0.24, 95% CI 0.09-0.68, P= 0.007); however, we found no significant differences between early and delayed repair (OR 1.34, 95% CI 0.96-1.87, P= 0.08), or between on-table and postcholecystectomy repair (OR 1.13, 95% CI 0.42-3.07, P= 0.81). At the cutoff time point of 6 weeks, early repair was associated with increased rates of repair failure (OR 4.03; P < 0.001), postoperative complications (OR 2.18; P < 0.001), and biliary stricture (OR 6.23; P < 0.001). CONCLUSIONS: Among patients with BDI, early referral and delayed repair appear to confer favorable outcomes.
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Ductos Biliares/lesões , Ductos Biliares/cirurgia , Procedimentos Cirúrgicos do Sistema Biliar , Colecistectomia Laparoscópica , Complicações Pós-Operatórias/cirurgia , Tempo para o Tratamento , Humanos , Doença Iatrogênica , Encaminhamento e Consulta , Falha de TratamentoRESUMO
Bioinspired thermoresponsive polymeric materials with tunable phase-transition behaviors are highly desirable for biomedical applications. Here, we reported a facile approach for the synthesis of both lower critical solution temperature (LCST) and upper critical solution temperature (UCST) types of thermoresponsive polypeptoids with tunable phase-transition temperature in the range of 29--55 °C. The introduction of alkyl groups and ethylene glycol (EG) units results in a controlled phase-transition behavior under fairly mild conditions. A very sharp transition (ΔT ≤ 1.5 °C) is observed by simply adjusting pH and the alkyl chain length. In particular, the carboxyl-containing polypeptoids display designable UCST behavior, which can be finely tuned in both water and methanol. All these features make the obtained polymers beneficial for practical applications. More interestingly, we demonstrate that the hydrophilic EG group behaves as an excellent regulator to tune the UCST behavior, while the hydrophobic alkyl residues show remarkable capability to regulate the LCST behavior of the system. We hope that such systematic structure-property studies will enable the design of smart polymer materials to meet the specific needs of future applications.
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Transição de Fase , Polímeros , Interações Hidrofóbicas e Hidrofílicas , Polimerização , TemperaturaRESUMO
BACKGROUND: Increasing evidence suggests that dysregulated long non-coding RNAs (lncRNAs) are involved in tumorigenesis and progression. RP11-284F21.9, one of the temporally expressed S-phase lncRNAs in cancer cells, was recently identified by nascent RNA capture sequencing. METHODS: Cal-27, Tca8113, SCC-9, HB56, and oral squamous cell carcinoma (OSCC) tissues were used in the experiment. RNA extraction, qRT-PCR, plasmid construction, cell proliferation, EdU labeling, Transwell migration, luciferase reporter, and western blotting were used to investigate the exact role and function of RP11-284F21.9 in cancer. RESULTS: RP11-284F21.9 was upregulated in human OSCC samples and cell lines. RP11-284F21.9 depletion suppressed the proliferation, migration, and invasion of OSCC cell lines. There was interaction between RP11-284F21.9, miR-383-5p, and MAL2. Increased MAL2 and decreased miR-383-5p expression were also detected in OSCC tissues and cell lines. In addition, RP11-284F21.9 knockdown could reduce MAL2 expression, while miR-383-5p inhibitors abolished this repressive effect. RP11-284F21.9 acted as a competing endogenous RNA (ceRNA) of miR-383-5p, leading to MAL2 upregulation, and subsequently promoted OSCC progression. CONCLUSION: RP11-284F21.9/miR-383-5p represents a novel and potential therapeutic target for the treatment of OSCC.
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Carcinoma de Células Escamosas , MicroRNAs/genética , Neoplasias Bucais , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Bucais/genéticaRESUMO
OBJECTIVE: To describe a method to fabricate donor tooth replica to assist surgeons in preparation of recipient socket during tooth autotransplantation. MATERIALS AND METHODS: A total of 28 compromised molars in 27 patients were transplanted with third molars using computer-aided rapid prototyping (CARP) technique. Surgery time and extra-alveolar time were documented. Postoperatively, the distance between cervix of transplanted tooth and the alveolar wall was measured. The degree of postoperative pain experienced was assessed with visual analog scale at day 1, 3, and 7. RESULTS: From 28 clinical cases, the average extra-alveolar time and surgery time were 2.5 minutes (±1.3) and 44 minutes (±6.8), respectively. Postoperatively, the average distance between cervix of transplanted tooth and the alveolar wall was 0.87 mm (±0.15) at the mesial-cervix, 0.95 mm (±0.17) at the distal-cervix, 0.88 mm (±0.18) at the buccal-cervix, and 0.95 mm (±0.13) at the lingual-cervix. The value of visual analog scale score significantly decreased from day 1 to day 3. CONCLUSIONS: CARP is a reliable technique for fabrication of tooth like surgical replicas in conventional autotransplantation. CLINICAL SIGNIFICANCE: CARP technique minimized extra-oral time, reduced iatrogenic damage, and consequently increased the survival rate of tooth autotransplantation.
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Cirurgia Assistida por Computador , Dente , Tomografia Computadorizada de Feixe Cônico , Feminino , Humanos , Dente Molar , Dente Serotino , Transplante AutólogoRESUMO
OBJECTIVE: To investigate the incidence rate of infectious diseases during hospitalization in late preterm infants in Beijing, China, as well as the risk factors for infectious diseases and the effect of breastfeeding on the development of infectious diseases. METHODS: Related data were collected from the late preterm infants who were hospitalized in the neonatal wards of 25 hospitals in Beijing, China, from October 23, 2015 to October 30, 2017. According to the feeding pattern, they were divided into a breastfeeding group and a formula feeding group. The two groups were compared in terms of general status and incidence rate of infectious diseases. A multivariate logistic regression analysis was used to investigate the risk factors for infectious diseases. RESULTS: A total of 1 576 late preterm infants were enrolled, with 153 infants in the breastfeeding group and 1 423 in the formula feeding group. Of all infants, 484 (30.71%) experienced infectious diseases. The breastfeeding group had a significantly lower incidence rate of infectious diseases than the formula feeding group (22.88% vs 31.55%, P=0.033). The multivariate logistic regression analysis showed that breastfeeding was an independent protective factor against infectious diseases (OR=0.534, P=0.004), while male sex, premature rupture of membranes, gestational diabetes mellitus, and asphyxia were risk factors for infectious diseases (OR=1.328, 5.386, 1.535, and 2.353 respectively, P < 0.05). CONCLUSIONS: Breastfeeding can significantly reduce the incidence of infectious diseases and is a protective factor against infectious diseases in late preterm infants. Breastfeeding should therefore be actively promoted for late preterm infants during hospitalization.
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Aleitamento Materno , Doenças Transmissíveis , Hospitalização , Recém-Nascido Prematuro , Pequim/epidemiologia , China/epidemiologia , Doenças Transmissíveis/epidemiologia , Feminino , Hospitais , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , GravidezRESUMO
A series of pegylated polypeptoids have been readily synthesized by a strategy combining ring-opening polymerization (ROP) and thiol-yne photoaddition. The polypeptoids simultaneously incorporated branched oligo(ethylene glycol) (OEG) units and thioether bonds in the side-chains. All the polypeptoids are readily soluble in aqueous solution and show reversible thermo-responsive properties. The cloud points (CPs) were demonstrated to be readily tunable in the range of ~25°C-60°C by varying the chemical composition, OEG chain length and the degree of polymerization. Attractively, the chemical compositions of the side chains are readily tunable via adjusting the molar ratios of a mixture of thiol terminated OEG molecules, which avoid synthesizing new monomers or copolymerization of different monomers. Further, the oxidation/reduction of thioether groups shows significant influence on the CPs, providing a second stimulus to tune the phase transition behaviors. Considering the biocompatibility and degradability, the dual-responsive polypeptoids are potential candidates for various biomedical or biotechnological applications.
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Peptídeos/química , Polietilenoglicóis/química , Oxirredução , Polimerização , Espectroscopia de Infravermelho com Transformada de Fourier , Compostos de Sulfidrila/química , Temperatura , Raios Ultravioleta , Água/químicaRESUMO
OBJECTIVES: the aim of this study was to evaluate the prognostic significance of preoperative serum lipid in patients with gallbladder cancer (GBC). METHODS: ninety-nine patients with GBC between October 2009 and December 2013 were reviewed in this retrospective study. Total serum cholesterol (TC), total triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein A (Apo-A), apolipoprotein B (Apo-B) and free fatty acids (FFA) were measured before surgery. The correlation of serum lipid levels with clinical data, including gender, age, tumor size, lymph nodes metastasis, tumor differentiation, distant metastasis and TNM stage were analyzed by univariate and multivariate survival analysis to evaluate independent prognostic factors. RESULTS: compared with the normal HDL-C group (n = 57), the overall survival rate among GBC patients with low HDL-C levels (n = 42) was reduced (p < 0.05). However, there were no significant differences in overall survival for patients with different levels of TC, TG, Apo-A, Apo-B, LDL-C or FFA. The serum level of HDL-C was associated with TNM stage (p < 0.05) and distant metastasis (p < 0.001). The multivariate prognosis analysis showed that HDL-C and lymph nodes metastasis were independent prognostic factors (p < 0.05). A prognostic evaluation model based on HDL-C and lymph nodes metastasis was established. CONCLUSION: preoperative serum HDL-C level was closely associated with distant metastasis of patients with GBC. HDL-C level may be a valuable prognostic factor for GBC patients. The combination of HDLC and lymph nodes metastasis can better predict the prognosis of GBC.
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HDL-Colesterol/sangue , Neoplasias da Vesícula Biliar/sangue , Neoplasias da Vesícula Biliar/mortalidade , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Post-hepatectomy Liver Failure (PHLF) remains the primary cause of perioperative death. The kinetics of transaminase levels are usually measured as markers of hepatocellular injury following partial hepatectomy, but their correlation with PHLF and post-operative mortality is unclear. The aim of study was to compare the post-operative transaminase kinetics with short term survival in those patients that developed PHLF. METHODS: A retrospective review of patients with HBV-related HCC and who developed PHLF was performed. Logistic regression analysis was conducted to analyze risk factors for postoperative delayed elevation of ALT (PDE-ALT) PHLF and lethal PHLF. RESULT: Of the 69 patients who developed PHLF 36 (52%) died. In those patients who died the mean ± SD ALT and AST rose from day (POD) 1-3 and continued to fluctuate with highly abnormal levels beyond day 3 with a mean ± SD peak ALT level beyond POD 3 of 1851 ± 1644 U/L (p < 0.001). CONCLUSIONS: The kinetics of the post-operative transaminases were significantly correlated with perioperative mortality in those patients who developed PHLF. PDE-ALT indicates an increased risk of death in HBV-related HCC patients with PHLF.
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Alanina Transaminase/sangue , Carcinoma Hepatocelular/cirurgia , Hepatectomia/mortalidade , Hepatite B , Falência Hepática/sangue , Falência Hepática/mortalidade , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Biomarcadores/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/virologia , Feminino , Hepatectomia/efeitos adversos , Hepatite B/sangue , Hepatite B/mortalidade , Hepatite B/virologia , Humanos , Cinética , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Regulação para CimaRESUMO
Amphiphilic block copolymers containing polypeptides can self-assemble into a variety of nonspherical structures arising from strong interactions between peptide units. Here, we report the synthesis of a pH-responsive poly(ethyl glycol)-block-poly(l-glutamic acid)-block-poly(N-octylglycine) (PEG-b-PGA-b-PNOG) triblock copolymers by sequential ring-opening polymerization using amine-terminated poly(ethyl glycol) as the macroinitiator followed by selective deprotection of the benzyl protecting group. The obtained triblock copolymer can be directly dispersed in aqueous solution with hydrophilic PEG, pH-responsive PGA block, and hydrophobic PNOG. We present a systematic study of the influence of pH, molar fraction, and molecular weight on the self-assemblies. It was found that the PEG-b-PGA-b-PNOG triblock tends to form two-dimensional nanodisks and nanosheet-like assemblies. The nanodisk-to-nanosheet transition is highly dependent on the pH and molar fraction despite the different molecular weights. We demonstrate that the dominant driving force of the nanodisks and nanosheets is the hydrophobicity of the PNOG blocks. The obtained bioinspired 2D nanostructures are potential candidates for applications in nanoscience and biomedicine.
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Nanoestruturas/química , Peptídeos/química , Polietilenoglicóis/química , Ácido Poliglutâmico/química , Concentração de Íons de Hidrogênio , PolimerizaçãoRESUMO
The stimuli-responsive polypeptides have drawn extensive attention because of their promising applications in biotechnology considering their biocompatibility, biodegradability, and bioactivity. In this tutorial review, we summarize the most recent progress in this area, including thermo-, redox-, photo-, and biomolecule responsive polypeptides over the past decade. The design and synthesis of stimuli-responsive polypeptides will be briefly introduced. The correlation between the structure and properties, particularly the effects of polypeptide conformation, will be emphasized here. In addition, the applications of stimuli-responsive polypeptides in controlled drug release and tissue engineering are briefly discussed.
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Biotecnologia , Peptídeos , Polímeros , Modelos Moleculares , TemperaturaRESUMO
Our previous experiment confirmed that high-mobility group box chromosomal protein 1 (HMGB1) was involved in the pathogenesis of Lupus nephritis (LN) by upregulating the proliferation of the mouse mesangial cell line (MMC) through the cyclin D1/CDK4/p16 system, but the precise mechanism is still unknown. Therefore, in the present study, we demonstrated that HMGB1 induced the proliferation of MMC cells in a time- and concentration-dependent manner, downregulated phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression, increased the level of Akt serine 473 phosphorylation, and induced p65 subunit nuclear translocation. The overexpression of PTEN prevented the upregulation of HMGB1-induced proliferation by blocking the activation of Akt. The knockdown of Akt by siRNA technology and blocking the nuclear factor-κB (NF-κB) pathway using pyrrolidine dithiocarbamate (PDTC) and SN50, inhibitors of NF-κB, both attenuated the HMGB1-induced proliferation by counteracting the activation of the cyclin D1. In addition, while sh-Akt partly blocked the nuclear translocation of the p65 subunit, PDTC did not affect the activation of the Akt induced by HMGB1 in MMC cells. These findings indicate that HMGB1 induced the proliferation of MMC cells by activating the PTEN/phosphoinositide-3-kinase (PI3K)/Akt/NF-κB signaling pathway.
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Ciclina D1/genética , Proteína HMGB1/genética , Nefrite Lúpica/genética , Células Mesangiais/metabolismo , PTEN Fosfo-Hidrolase/genética , Animais , Proliferação de Células , Ciclina D1/metabolismo , Técnicas de Silenciamento de Genes , Proteína HMGB1/metabolismo , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Proteína Oncogênica v-akt/genética , Proteína Oncogênica v-akt/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosforilação , Transdução de Sinais/genéticaRESUMO
The oxidation-responsive behaviors of OEGylated poly-L-cysteine homopolypeptides, that is, poly(L-EG(x)MA-C)n, were investigated. These poly-L-cysteine derivatives adopted mixed conformation in water, in which the ß-sheet accounted for a significant proportion. Upon oxidation, the thioethers in polypeptide side chains were converted to polar sulfone groups, which triggered the secondary structure transition from ß-sheet preferred conformation to random coil. Accordingly, the increase of side-chain polarity together with conformation changes increased samples' water solubility and cloud point temperature. Using mPEG45-NH2 as macroinitiator, we synthesized PEG45-b-poly(L-EG2MA-C)22 diblock copolymer via ring-opening polymerization (ROP) of L-EG2MA-C N-carboxyanhydride (NCA). The PEG45-b-poly(L-EG2MA-C)22 was able to self-assemble into spherical micelles in aqueous solution, and the micelles could undergo an oxidation-triggered disassembly due to the oxidation-responsive thioethers. Such a new class of oxidation-responsive polypeptides might provide a promising platform to construct inflammation targeting drug delivery systems.