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1.
Food Chem Toxicol ; 134: 110867, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31586655

RESUMO

Ellagic acid (EA), a natural plant polyphenol, is usually used as a functional additive in variety of health foods. However, the potential toxicity of EA to human health should be paid enough attention. To clarify its biological toxicity in vivo, this study explored the binding mechanism of EA with bovine serum albumin (BSA) by means of spectroscopic approaches and molecular docking insimulative physiological conditions. The results showed that the mixture of BSA with EA could spontaneously cause the formation of BSA-EA complex through electrostatic interaction under simulative physiological conditions (0.01 mol·L-1Tris-HCl, 0.015 mol L-1 NaCl, pH = 7.4). Molecular docking experiments revealed that EA was primarily bound to the hydrophobic pocket of the site I (subdomain IIA) of BSA. It has been reported that the binding of small functional molecules to serum albumins remarkably impacts their absorption, distribution, metabolism, and excretion features. Therefore, this study might be helpful for human to have an in-depth understanding of the biological effect of EA in vivo and guide human to take it safely and reasonably.

2.
J Sep Sci ; 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31642160

RESUMO

Ginkgolide B is in great demand worldwide on account of its extensive and excellent pharmacological effects, however, it is difficult to separate and purify ginkgolide B. In this study, ginkgolide B molecularly imprinted polymers were prepared by combining software simulation and molecular imprinting technique, and its characterization and adsorption performed evaluation were performed to understand the adsorption behavior of the polymers. The adsorption equilibrium concentration of molecularly imprinted polymers was 0.70 mg/mL, and the adsorption equilibrium time was 4 h. Meanwhile, the adsorption isotherm of the polymers for ginkgolide B fitted well with the Langmuir model, and the adsorption kinetics was in line with the pseudo-second-order kinetics. In contrast, the adsorption capacity of molecularly imprinted polymers on ginkgolide B was higher than that of non-molecular imprinted polymers, with better selectivity and better adsorption after repeated use for 6 times. The application experiments showed that molecular imprinted polymers have a good adsorption effect in low purity samples. Therefore, the polymers reported herein can be expected to apply in the adsorption and separation of ginkgolide B samples. This article is protected by copyright. All rights reserved.

3.
Colloids Surf B Biointerfaces ; 184: 110510, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31561046

RESUMO

Rapid endothelialization on small diameter artificial blood vessels is an effective strategy to facilitate long-term patency and inhibit thrombosis. The gene delivery can enhance the proliferation and migration of endothelial cells (ECs), which is beneficial for rapid endothelialization. REDV-G-TAT-G-NLS-Cys (abbreviated as TP-G) peptide could weakly condense pEGFP-ZNF580 (pZNF580) and transfect ECs, but its transfection efficiency was still very low because of its low positive charge, low stability and weak endosome escape ability. In order to develop more stable and efficient gene carriers with low cytotoxicity, in the present study, we conjugated different amounts of TP-G peptide onto poly(lactide-co-glycolide)-g-polyethylenimine (PLGA-g-PEI) amphiphilic copolymers via a hetero-poly(ethylene glycol) spacer (OPSS-PEG-NHS). The TP-G peptide and PEI could cooperatively and strongly condense pZNF580. The carrier's cytotoxicity was reduced by the introduction of poly(ethylene glycol) spacer. They condensed pZNF580 to form gene complexes (PPP-TP-G/pZNF580) with suitable size and positive zeta potential for gene delivery. The transfected ECs promoted their migration ability as demonstrated by cell migration assay. The results of cellular uptake and confocal laser scanning microscopy showed significantly high internalization efficiency, endosomal/lysosomal escape and nucleus location of pZNF580 by this multifunctional TP-G peptide sequence conjugated gene delivery system. Furthermore, several inhibitors were used to study the cellular uptake pathways of PPP-TP-G/pZNF580 complexes. The results showed that PPP-TP-G2/Cy5-oligonucleotide complexes exhibited the optimized endocytosis pathways which facilitated for cellular uptake. In conclusion, the multifunctional TP-G peptide conjugated gene carriers could promote the transfection efficiency due to the multifunction of REDV, cell-penetrating peptide and nuclear localization signal in the peptide sequence, which could be a suitable gene carrier for endothelialization.

4.
Acta Biomater ; 97: 344-359, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31377424

RESUMO

Surface modification by conjugating biomolecules has been widely proved to enhance biocompatibility of small-caliber artificial vascular grafts. In this study, we aimed at developing a multifunctional vascular graft that provides not only good hemocompatibility but also in situ rapid endothelialization. Herein, a vascular graft (inner diameter ∼2 mm) was fabricated by electrospinning with poly(lactic acid-co-caprolactone) and gelatin, and then biofunctionalized with antithrombotic peptide with sequence LTFPRIVFVLG (ACH11) and cell adhesion peptide with sequence CAG through adhesive poly(dopamine) coating. We developed this graft with the synergistic properties of low thrombogenicity and rapid endothelialization. The successful grafting of both CAG and ACH11 peptides was confirmed by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The surface micromorphology of the modified surfaces was observed by field emission scanning electron microscopy. Our results demonstrated that the multifunctional surface suppressed the denaturation of absorbed fibrinogen, hindered coagulation factor Xa activation, and inhibited platelet adhesion and aggregation. Importantly, this modified surface could selectively enhance endothelial cells adhesion, proliferation and release of nitric oxide. Upon in vivo implantation of 6 weeks, the multifunctional vascular graft showed improved patency and superior vascular endothelialization. Overall, the results effectively demonstrated that the co-immobilization of ACH11 and CAG provided a promising method for the improvement of hemocompatibility and endothelialization of vascular grafts. STATEMENT OF SIGNIFICANCE: Electrospun small-caliber vascular grafts are increasingly used to treat cardiovascular diseases. Despite their success related to their good biodegradation and mechanical strength, they have some drawbacks, such as low hemocompatibility and endothelialization. The single-function ligands are insufficient to modify surface with both good hemocompatibility and rapid endothelialization simultaneously. Therefore, we functionalized electrospun vascular graft by novel antithrombotic peptide and cell-adhesive peptide to construct superior anticoagulation and ECs-selective adhesion surface in present study. The multifunctional vascular grafts benefit for high long-term patency and rapid endothelialization.

5.
Radiother Oncol ; 140: 159-166, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31302346

RESUMO

BACKGROUND: Surveillance was recommended for patients after R0 esophagectomy by National Comprehensive Cancer Network (NCCN) guidelines. However, local failure was high in locally advanced patients (48-78%). The present study aimed to determine whether adjuvant treatment improved survival for stage IIb-III thoracic esophageal squamous cell carcinoma (TESCC). METHODS: A retrospective review of patients diagnosed as esophageal carcinoma at the Chinese Academy of Medical Sciences Cancer hospital, between January 2004 and December 2011, was performed. A database compiling 975 patents with node positive or stage III thoracic esophageal carcinoma after R0 surgery with or without postoperative radiation/chemoradiation was created. A 1:1 matched study group was generated by the Greedy method after propensity score matching (PSM) analysis. Survival curves were calculated by the Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate analyses were using the Cox proportional hazards regression model. RESULTS: 975 patients were enrolled in the study, 510 patients (52.3%) did not receive any postoperative treatment after R0 surgery and 465 patients had either postoperative chemoradiation or radiotherapy. Median follow-up was 69.2 months. After PSM, 222 well-balanced patients in each group demonstrated the same results. The 3-year, 5-year survival rates and median survival in surgery group (33.0%, 26.4%, 24.3 months) were inferior to those in postoperative treatment group (48.3%, 37.1% and 34.3 months), (P = 0.002). Compared with radiotherapy, postoperative chemoradiation did not improve DFS and OS (P = 0.692; P = 0.368). N stage and adjuvant treatment are independent prognostic factors. CONCLUSIONS: Adjuvant treatment could improve survival for patients with stage IIb-III TESCC.

6.
Sci Rep ; 9(1): 10497, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324827

RESUMO

We aimed to establish a risk model using computed tomography-based compactness to predict overall survival (OS) and progression-free survival (PFS) after multimodal treatment for esophageal squamous cell carcinoma (ESCC). We extracted pre-treatment computed tomography-based tumor data (volume, surface area, and compactness) for 512 cases of ESCC that were treated at 3 centers. A risk model based on compactness was trained using Cox regression analyses of data from 83 cases, and then the model was validated using two independent cohorts (98 patients and 283 patients). The largest cohort (283 patients) was then evaluated using the risk model to predict response to radiotherapy with or without chemotherapy. In the three datasets, the pre-treatment compactness risk model provided good accuracy for predicting OS (P = 0.012, P = 0.022, and P = 0.003) and PFS (P < 0.001, P = 0.003, and P = 0.005). Patients in the low-risk group did not experience a significant OS benefit from concurrent chemoradiotherapy (P = 0.099). Furthermore, after preoperative concurrent chemoradiotherapy, the OS outcomes were similar among patients in the low-risk group who did and did not achieve a pathological complete response (P = 0.127). Tumor compactness was correlated with clinical T stage but was more accurate for predicting prognosis after treatment for ESCC, based on higher C-index values in all three datasets. The compactness-based risk model was effective for predicting OS and PFS after multimodal treatment for ESCC. Therefore, it may be useful for guiding personalized treatment.

8.
Nat Commun ; 10(1): 2375, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147543

RESUMO

Human antigen R (HuR) is a member of the Hu family of RNA-binding proteins and is involved in many physiological processes. Obesity, as a worldwide healthcare problem, has attracted more and more attention. To investigate the role of adipose HuR, we generate adipose-specific HuR knockout (HuRAKO) mice. As compared with control mice, HuRAKO mice show obesity when induced with a high-fat diet, along with insulin resistance, glucose intolerance, hypercholesterolemia and increased inflammation in adipose tissue. The obesity of HuRAKO mice is attributed to adipocyte hypertrophy in white adipose tissue due to decreased expression of adipose triglyceride lipase (ATGL). HuR positively regulates ATGL expression by promoting the mRNA stability and translation of ATGL. Consistently, the expression of HuR in adipose tissue is reduced in obese humans. This study suggests that adipose HuR may be a critical regulator of ATGL expression and lipolysis and thereby controls obesity and metabolic syndrome.


Assuntos
Tecido Adiposo Branco/metabolismo , Proteína Semelhante a ELAV 1/genética , Intolerância à Glucose/genética , Hipercolesterolemia/genética , Resistência à Insulina/genética , Lipase/genética , Obesidade/genética , Adipócitos/patologia , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/imunologia , Animais , Crescimento Celular , Dieta Hiperlipídica , Proteína Semelhante a ELAV 1/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Intolerância à Glucose/metabolismo , Humanos , Hipercolesterolemia/metabolismo , Hipertrofia , Inflamação/imunologia , Lipase/metabolismo , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Biossíntese de Proteínas , Estabilidade de RNA/genética , Gordura Subcutânea/metabolismo
9.
Int J Radiat Oncol Biol Phys ; 105(2): 319-328, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31228553

RESUMO

PURPOSE: Clinical tools are unavailable for accurate prediction of pathologic responses to chemoradiation therapy (CRT) among patients with esophageal squamous cell carcinoma (ESCC) before surgery. We evaluated tumor remission and tumor-infiltrating lymphocytes (TILs) during CRT as predictors of pathologic response and prognostic markers for patients with locally advanced ESCC treated with neoadjuvant CRT (neo-CRT) or definitive CRT. METHODS AND MATERIALS: We analyzed patients with locally advanced ESCC (N = 164) who underwent neo-CRT (N = 48) or definitive CRT (N = 116). Patients underwent endoscopic ultrasonography and biopsies when induction CRT finished. Tumor remission characteristics were designated minor (-/+) to excellent remission (ER) (+++). TILs were determined in 10% increments. Tumor remission, TILs, or both were associated with pathologic complete response (pCR) and survival in the neo-CRT group and then analyzed in the definitive CRT group. RESULTS: ER and lymphocyte-predominant ESCC (LPE; ≥60% TILs) were identified according to the pCR rate and disease-free survival. We built a prediction model for pCR incorporating ER and LPE. The area under the receiver operating characteristic curve was 0.877, and sensitivity and specificity were 86.7% and 90.9%, respectively. Furthermore, this model identified pathologic response with an excellent calibration. Disease-free survival of patients with ER and LPE tumors was significantly longer than that of other patients. CONCLUSIONS: When we included tumor remission and TILs during CRT, our model predicted pCR with high probability and helped stratify prognostic subgroups, thereby guiding future therapy decisions for patients with locally advanced ESCC. Validation of this model in larger, prospective, multicenter studies is essential.

10.
Biomater Sci ; 7(8): 3307-3319, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31204746

RESUMO

Small interfering RNA (siRNA)-based therapy is an emerging treatment to address serious cardiovascular disease. It is essential to construct highly efficient vehicles for therapeutic siRNA intracellular delivery. Extracellular signal-regulated kinase-2 (ERK2) siRNA (abbreviated as ERK2-siRNA) is known as a type of siRNA to selectively silence the expression of ERK2. Herein, a type of ternary delivery system characterized by an endosome-selective-self-accelerating-escape ability was designed and prepared for the purpose of inhibiting the migration of vascular smooth muscle cells (VSMCs) in vitro. This system was called ternary ERK2-siRNA complexes (abbreviated as TRCs-Aco), which were fabricated via sequential electrostatic self-assembly of a star-shaped cell-penetrating peptide based on polyhedral oligomeric silsesquioxane (POSS-(C-G-R8-G-W)16), ERK2-siRNA and a pH-sensitive anionic polymer of cis-aconitic anhydride grafted ε-poly(l-lysine). Importantly, TRCs-Aco could break down the obstacle of biocompatibility-silencing efficiency. In comparison with the parent binary siRNA complexes (abbreviated as BRCs), which are composed of POSS-(C-G-R8-G-W)16 and ERK2-siRNA, our designed TRCs-Aco revealed more excellent biocompatibility including hemocompatibility and cytocompatibility. Unexpectedly, TRCs-Aco exhibited stronger ERK2 silencing efficiency at the level of mRNA and protein, which was mainly due to its remarkable self-accelerating endosomal escape. Definitive evidence demonstrated that this ternary ERK2-siRNA delivery system significantly prevented the migration of VSMCs and decreased the dermal thickness in bleomycin-treated mice. In brief, this unique structured system could provide a valuable nanoplatform for highly efficient siRNA delivery in VSMCs, and it might hold great potential in guiding ERK2-siRNA-based proliferative disease therapy.

11.
Ann Surg Oncol ; 26(9): 2890-2898, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31183641

RESUMO

BACKGROUND: Effective tools evaluating the prognosis for patients with esophageal cancer undergoing surgery is lacking. The current study aimed to develop a nomogram to predict overall survival (OS) and provide evidence for adjuvant therapy for patients with esophageal carcinoma after esophagectomy. METHODS: The study retrospectively reviewed patients with pathologic T1N +/T2-4aN0-3, M0 thoracic esophageal squamous cell carcinoma after radical esophagectomy, with or without adjuvant therapy, in one institution as the training cohort (n = 2281). A nomogram was established using Cox proportional hazard regression to identify prognostic factors for OS, which were validated in an independent validation cohort (n = 1437). Area under curve (AUC) values of receiver operating characteristic curves were calculated to evaluate prognostic efficacy. RESULTS: In the training cohort, the median OS was 50.46 months, and the 5-year OS rate was 47.08%. Adjuvant therapy, sex, tumor location, grade, lymphovascular invasion, removed lymph nodes, and T and N categories were identified as predictive factors for OS. The nomogram showed favorable prognostic efficacy in the training and validation cohorts (5-year OS AUC: 0.685 and 0.744, respectively), which was significantly higher than that of the American Joint Committee on Cancer (AJCC) staging system. The nomogram distinguished OS rates among six risk groups, whereas AJCC could not separate the OS of 2A and 1B, 3C and 3B, or 3A and 2B. Patients with a nomogram score of 72 to 227 were predicted to achieve a 5-year OS increase of 10% or more from adjuvant therapy. CONCLUSION: The nomogram could effectively predict OS and aided decision making in adjuvant therapy for patients with thoracic esophageal squamous cell carcinoma after esophagectomy.

13.
J Mol Cell Cardiol ; 132: 49-59, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31071332

RESUMO

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without an effective pharmaceutical treatment. Genetic studies have proved the involvement of smooth muscle phenotype switch in the development of AAA. The alpha subunit of the heterotrimeric G stimulatory protein (Gsα) mediates receptor-stimulated production of cyclic adenosine monophosphate (cAMP). However, the role of smooth muscle Gsα in AAA formation remains unknown. APPROACH AND RESULTS: In this study, mice with knockout of smooth muscle-specific Gsα (GsαSMKO) were generated by cross-breeding Gsαflox/flox mice with SM22-CreERT2 transgenic mice, induced in adult mice by tamoxifen treatment. Gsα deficiency induced a smooth muscle phenotype switch from a contractile to a synthetic state. Mechanically, Gsα deletion reduced cAMP level and increased the level of human antigen R (HuR), which binds with the adenylate uridylate-rich elements of the 3' untranslated region of Krüppel-like factor 4 (KLF4) mRNA, thereby increasing the stability of KLF4. Moreover, genetic knockdown of HuR or KLF4 rescued the phenotype switch in Gsα-deficient smooth muscle cells. Furthermore, with acute infusion of angiotensin II, the incidence of AAA was markedly higher in ApoE-/-/GsαSMKO than ApoE-/-/Gsαflox/flox mice and induced increased elastic lamina degradation and aortic expansion. Finally, the levels of Gsα and SM α-actin were significantly lower while those of HuR and KLF4 were higher in human AAA samples than adjacent nonaneurysmal aortic sections. CONCLUSIONS: Gsα may play a protective role in AAA formation by regulating the smooth muscle phenotype switch and could be a potential therapeutic target for AAA disease.

14.
Thorac Cancer ; 10(6): 1431-1440, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31102336

RESUMO

BACKGROUND: Whether postoperative radiotherapy is beneficial in the treatment of esophageal squamous cell carcinoma with one or two regional lymph node (LN) metastases (pN1) after esophagectomy is uncertain. This study aimed to explore the effect of postoperative radiotherapy (PORT) on survival. METHODS: Propensity score-matching (PSM) analysis was conducted to balance the two arms (surgery only [S] or surgery plus postoperative radiotherapy [PORT]). The survival rate was calculated by the Kaplan-Meier method and analyzed using the log-rank test. RESULTS: A total of 992 cases confirmed positive for one or two regional LN metastases were eligible. After PSM, 622 patients were reviewed. Each group consisted of 311 cases. The median follow-up was 80.7 months. For the overall cohort, the one-, three- and five-year overall survival (OS) were 90.6%, 51.9% and 38.2%, respectively. Disease-free survival (DFS) was 76.0%, 41.4% and 32.1%, respectively. The five-year OS and DFS were 45.0% and 39.8% for PORT, which was significantly higher than the S group (31.3% and 24.2%, both P < 0.001). On subgroup analysis, PORT was associated with improved OS and DFS for patients with pathological stage pT3-4N1M0, compared with S group (five-year OS 41.3% vs. 23.5%, P < 0.001; five-year DFS 35.8% vs. 18.8%, P < 0.001). However, for pT1-2N1M0 patients, PORT did not benefit OS and DFS compared with S (P = 0.063). CONCLUSIONS: In summary, the addition of PORT after esophagectomy was associated with a statistically significant improvement in OS and DFS for patients with pathological one or two lymph-node positive pathology, in particular for stage pT3-4N1M0 patients.

15.
Clin Sci (Lond) ; 133(11): 1215-1228, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31101724

RESUMO

Background: Although junctional adhesion molecule-like protein (JAML) has recently been implicated in leukocyte recruitment during inflammation and wound repair, its role in atherosclerosis remains to be elucidated. Methods and results: First, we showed that JAML was strongly expressed in atherosclerotic plaques of cardiovascular patients. Similar results were obtained with atherosclerotic plaques of ApoE-/- mice. Co-immunofluorescence staining showed that JAML was mainly expressed in macrophages. Enhanced expression of JAML in cultured macrophages was observed following exposure of the cells to oxLDL. The functional role of JAML in atherosclerosis and macrophages function was assessed by interference of JAML with shRNA in vivo and siRNA in vitro Silencing of JAML in mice significantly attenuated atherosclerotic lesion formation, reduced necrotic core area, increased plaque fibrous cap thickness, decreased macrophages content and inflammation. In addition, histological staining showed that JAML deficiency promoted plaques to stable phenotype. In vitro, JAML siRNA treatment lowered the expression of inflammatory cytokines in macrophages treated with oxLDL. The mechanism by which JAML mediated the inflammatory responses may be related to the ERK/NF-κB activation. Conclusions: Our results demonstrated that therapeutic drugs which antagonize the function of JAML may be a potentially effective approach to attenuate atherogenesis and enhance plaque stability.

16.
BMC Cancer ; 19(1): 397, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036088

RESUMO

BACKGROUND: The importance of definitive radiotherapy for elderly patients with esophageal and esophagogastric-junction cancer is pronounced. However, little is known in terms of the best way to combine radiotherapy with other treatment options. This study aims to compare the efficiency of SIB radiotherapy alone with SIB radiotherapy concurrent and consolidated with S-1 for elderly patients. Comprehensive geriatric assessment is also incorporated in the procedure of treatment. METHODS/DESIGN: The study is a two arm, open, randomized multicenter Phase III trial with patients over 70 years old with stage IIA-IVB (UICC 2002, IVB only with metastasis to supraclavicular or celiac lymph nodes) squamous cell carcinoma or adenocarcinoma of esophagus or gastroesophageal junction. A total of 300 patients will be randomized using a 1:1 allocation ratio stratified by disease stage and study site. Patients allocated to the SIB arm will receive definitive SIB radiotherapy (95%PTV/PGTV 50.4Gy/59.92Gy/28f) while those randomized to SIB + S-1 arm will receive definitive SIB radiotherapy concurrent and consolidated with S-1. The primary endpoint of the trial is 1-year overall survival. Secondary objectives include progression-free survival, recurrence-free survival (local-regional and distant), disease failure pattern, toxicity profile as well as quality of life. Besides, detailed radiotherapy protocol and quality assurance procedure have been incorporated into this trial. DISCUSSION: The proportion of elderly patients in esophageal cancer is now growing, but there is a lack of evidence in term of treatment standard for this group of patients, which is what we aim to obtain through this prospective phase III study. TRIAL REGISTRATION: clinicaltrials.gov NCT02979691 . Registered November 22, 2016.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/terapia , Radioterapia de Intensidade Modulada/métodos , Neoplasias Gástricas/terapia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Combinação de Medicamentos , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/efeitos dos fármacos , Junção Esofagogástrica/patologia , Junção Esofagogástrica/efeitos da radiação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Masculino , Estadiamento de Neoplasias , Avaliação de Resultados (Cuidados de Saúde)/métodos , Avaliação de Resultados (Cuidados de Saúde)/estatística & dados numéricos , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Estudos Prospectivos , Radioterapia de Intensidade Modulada/efeitos adversos , Neoplasias Gástricas/patologia , Tegafur/administração & dosagem , Tegafur/efeitos adversos
17.
J Mol Cell Cardiol ; 130: 131-139, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30935996

RESUMO

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without an effective pharmaceutical treatment. Liver kinase B1 (LKB1), a tumor suppressor, is a central regulator of cell polarity and energy homeostasis. However, the role of LKB1 in the development of AAA has not been explored. In this study, mice with knockout of smooth muscle-specific LKB1 (LKB1SMKO) were generated by cross-breeding LKB1flox/flox mice with SM22-CreERT2 transgenic mice and induced in adult mice by tamoxifen treatment. LKB1 deficiency increased the expression of matrix metalloproteinase 2 (MMP-2), which was inhibited by LKB1 overexpression. Mechanistically, LKB1 could bind to the MMP-2 transcription factor, specificity protein 1 (Sp1), thereby reducing the binding of Sp1 to the MMP-2 promoter to inhibit MMP-2 expression. LKB1 expression was significantly reduced in abdominal aortas of the mouse AAA model. Moreover, smooth muscle-specific LKB1 deletion exaggerated angiotensin II-induced AAA formation accompanied by increased AAA incidence and aortic expansion. Finally, LKB1 level was significantly lower and MMP-2 level higher in human AAA samples than adjacent nonaneurysmal aortic sections. Thus, these results suggest that LKB1 may play a protective role in AAA formation by inhibiting MMP-2 expression and could be a potential therapeutic target for AAA disease.

18.
Macromol Rapid Commun ; 40(12): e1800916, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30990950

RESUMO

Multifunctional carriers with both gene transfection property and fluorescent tracking function have attracted significant attention in recent years. Herein, a kind of perylene diimide derivative (PDI-C10C8) is conjugated onto the polyethylenimine-g-poly(lactide-co-glycolide)-g-polyethylenimine (PLGA-PEI) polymer to obtain fluorescent multifunctional polymer and micelles (abbreviated as MP). Then, the REDV-G-TAT-G-NLS (TP-G) peptide sequence is grafted onto this MP to obtain multifunctional micelles labeled by perylene diimide derivative (MP-TP-G). These micelles exhibit enhanced photobleaching stability compared with the reference Cy5-labeled micelles, and the fluorescent images of cellular uptake show bright red emission without any background noise. Confocal laser scanning microscope (CLSM) experiments show that gene complexes can deliver gene into nucleus. MP-TP-G carriers do not enter into the cell nucleus, which proves that the nuclear localization signal sequence may not exert its nucleus accumulation ability via conjugating to the amphiphilic polymers. The high transfection efficiency and the enhanced photobleaching stability, combined with the ability to monitor the detailed process of cellular uptake and gene delivery, make these multifunctional micelles have great potential application for endothelialization of artificial blood vessels and gene delivery process study.

19.
Biomater Sci ; 7(5): 2061-2075, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30855618

RESUMO

For clinical application of therapeutic gene delivery, it is urgent to develop safe and in vivo efficient delivery systems. Nowadays, gene delivery carriers based on functional peptides have attracted much attention due to their excellent biocompatibility, biodegradability and biological multifunctionality. In the present study, a star-shaped integrated functional peptide, polyhedral oligomeric silsesquioxane (POSS-(C-G-NLS-G-TAT)16, abbreviated as PP1), was synthesized through "thiol-ene" click chemistry between the TAT-G-NLS-G-C multifunctional peptide sequence and inorganic octa-diallyl POSS. Cationic PP1 was mixed with the pZNF580 plasmid to obtain stable binary gene complexes (BCPs) with membrane penetrating and nucleus targeting functions. In order to improve BCPs' biocompatibility, cellular uptake, and endosome escape, they were further modified using an anionic polymer of PLL-g-CAGW21%-g-Acon (n = 47%, 57% and 64%) having an EC targeting ligand (CAGW peptide) and a charge reversal moiety (cis-aconitic amide) through electrostatic absorption to obtain ternary gene complexes (TCPs). By adjusting the weight ratio of PP1/pZNF580 plasmid/PLL-g-CAGW21%-g-Acon to 5/1/1.25, TCPs-1 with n = 47%, TCPs-2 with n = 57% and TCPs-3 with n = 64% exhibited a neutral zeta potential and suitable particle size; thus they were used for further biological evaluation. Compared with BCPs (5/1 weight ratio of PP1/pZNF580 plasmid), TCPs exhibited high hemocompatibility and cytocompatibility; more interestingly, they also showed significantly enhanced gene delivery efficiency. The TCP groups achieved perfect transfection effects in the proliferation and migration of human umbilical vein endothelial cells (HUVECs), and especially high neovascularization in vitro and in vivo. Our results demonstrated that the high graft ratio of cis-aconitic amide provided benefits of high biocompatibility and gene delivery efficiency, and the TCPs-3 group showed the optimized transfection efficiency among the three groups. Importantly, HUVECs transfected with TCPs-3 exhibited an outstanding ability to enhance angiogenesis in vivo. In brief, this multifunctional ternary gene system with the EC targeting ligand and membrane penetrating, charge reversal and nucleus targeting functions is a promising platform for the transfection of HUVECs, and may be useful for the treatment of cardiovascular diseases in clinical applications.


Assuntos
Portadores de Fármacos/química , Neovascularização Fisiológica/genética , Peptídeos/química , Transfecção , Amidas/química , Movimento Celular/genética , Proliferação de Células/genética , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Concentração de Íons de Hidrogênio , Compostos de Organotecnécio/química , Propriedades de Superfície
20.
Stem Cell Res Ther ; 10(1): 17, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635025

RESUMO

BACKGROUND: Cell therapy remains the most promising approach against ischemic heart injury. However, poor survival of engrafted cells in ischemic sites diminishes its therapeutic efficacy. Follistatin-like 1 (Fstl1) is documented as a novel pro-survival cardiokine for cardiomyocytes, and it is protective during ischemic heart injury. In the present study, we characterize the potential of Fstl1 as an effective strategy to enhance hypoxia resistance of donor cells and optimize stem cell-based therapy. METHODS: Murine bone marrow-derived mesenchymal stem cells (MSCs) were expanded in monolayer culture and characterized by flow cytometry. MSCs were subjected to hypoxia to mimic cardiac ischemic environment. Expression of Fstl1 was monitored 0, 24, and 48 h following hypoxia. Constitutive expression of Fstl1 in MSCs was achieved by lentivirus-mediated Fstl1 overexpression. Genetically modified MSCs were further collected for cell death and proliferation assay following 48 h of hypoxic treatment. Acute myocardial infarction (MI) model was created by ligating the left anterior descending coronary artery, while control MSCs (MSCs-mCherry) or Fstl1-overexpressing MSCs (MSCs-Fstl1) were injected into the peri-infarct zone simultaneously. Subsequently, retention of the donor cells was evaluated on post-therapy 1, 3, & 7 days. Finally, myocardial function, infarct size, inflammation, and neovascularization of the infarcted hearts were calculated thereafter. RESULTS: Expression of Fstl1 in hypoxic MSCs declines dramatically in a time-dependent manner. In vitro study further demonstrated that Fstl1 promotes survival and proliferation of hypoxic MSCs. Moreover, Fstl1 significantly prolongs MSC survival/retention after implantation. Finally, transplantation with Fstl1-overexpressing MSCs significantly improves post-MI cardiac function by limiting scar formation, reducing inflammatory response, and enhancing neovascularization. CONCLUSIONS: Our results suggest Fstl1 is an intrinsic cardiokine promoting survival and proliferation of MSCs, thereby optimizing their engraftment and therapeutic efficacy during cell therapy.

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