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BACKGROUND: Perineural invasion (PNI) is the invasion of nerves by cancer cells and is associated with poor survival in stage II colorectal cancer. However, PNI can be further subdivided according to the depth of invasion, and the depth of PNI has not been clearly linked to prognosis. METHOD: This study aimed to assess the prognostic value of different depths of PNI in stage II colorectal cancer. We defined PNI in the submucosal plexus and myenteric plexus as superficial perineural invasion (sup-PNI) and PNI in the subserous plexus as deep perineural invasion (deep-PNI). Patients were divided into three groups based on the depth of PNI: sup-PNI, deep-PNI and non-PNI. Then, univariate and multivariate Cox regression analyses were conducted to evaluate the role of PNI in the prognosis of stage II colorectal cancer. RESULTS: This study enrolled 3508 patients with stage II colorectal cancer who underwent resection for primary colorectal lesions between January 2013 and September 2019. Clinicopathological features, including elevated carcinoembryonic antigen (CEA) levels, T4 stage, poor differentiation, deficient DNA mismatch repair (dMMR), and vascular invasion, were correlated with deep-PNI. Multivariate analyses revealed that deep-PNI was associated with worse overall survival (OS; hazard ratio [HR], 3.546; 95% confidence interval [CI], 2.307-5.449; P < 0.001) and disease-free survival (DFS; HR, 2.921; 95% CI, 2.032-4.198; P < 0.001), compared with non-PNI. Conversely, no significant difference in OS or DFS was observed between the sup-PNI and non-PNI groups in multivariate analyses. CONCLUSIONS: The study demonstrated that the depth of PNI was an independent prognostic factor for patients with stage II colorectal cancer, and patients with deep PNI had a worse prognosis. Thus, patients with PNI require further subdivision according to the depth of invasion.
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Neoplasias Colorretais , Nervos Periféricos , Humanos , Prognóstico , Nervos Periféricos/patologia , Estudos Retrospectivos , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Invasividade Neoplásica/patologia , Estadiamento de NeoplasiasRESUMO
PURPOSE: Lymph node metastasis (LNM) is a crucial factor that determines the prognosis of T1 colorectal cancer (CRC) patients. We aimed to develop a practical prediction model for LNM in T1 CRC. METHODS: We conducted a retrospective analysis of data from 825 patients with T1 CRC who underwent radical resection at a single center in China. All enrolled patients were randomly divided into a training set and a validation set at a ratio of 7:3 using R software. Risk factors for LNM were identified through multivariate logistic regression analyses. Subsequently, a prediction model was developed using the selected variables. RESULTS: The lymph node metastasis (LNM) rate was 10.1% in the training cohort and 9.3% in the validation cohort. In the training set, risk factors for LNM in T1 CRC were identified, including depressed endoscopic gross appearance, sex, submucosal invasion combined with tumor grade (DSI-TG), lymphovascular invasion (LVI), and tumor budding. LVI emerged as the most potent predictor for LNM. The prediction model based on these factors exhibited good discrimination ability in the validation sets (AUC: 79.3%). Compared to current guidelines, the model could potentially reduce over-surgery by 48.9%. Interestingly, we observed that sex had a differential impact on LNM between early-onset and late-onset CRC patients. CONCLUSIONS: We developed a clinical prediction model for LNM in T1 CRC using five factors that are easily accessible in clinical practice. The model has better predictive performance and practicality than the current guidelines and can assist clinicians in making treatment decisions for T1 CRC patients.
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Neoplasias Colorretais , Modelos Estatísticos , Humanos , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologia , Linfonodos/cirurgia , Linfonodos/patologia , Metástase Linfática/patologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Distribuição Aleatória , ChinaRESUMO
BACKGROUND: Current guidelines only propose the importance of perineural invasion(PNI) on prognosis in stage II colon cancer. However, the prognostic value of PNI in other stages of colorectal cancer (CRC) is ambiguous. METHODS: This single-center retrospective cohort study included 3485 CRC patients who underwent primary colorectal resection between January 2013 and December 2016 at the Sixth Affiliated Hospital of Sun Yat-sen University. Associations of PNI with overall survival (OS) and disease-free survival (DFS) were evaluated using multivariable Cox proportional hazards regression models. In addition, interaction analyses were performed to explore the prognostic effects of PNI in different clinical subgroups. RESULTS: After median follow-up of 61.9 months, we found PNI was associated with poorer OS (adjusted hazard ratio [aHR], 1.290; 95% CI, 1.087-1.531) and DFS (aHR, 1.397; 95% CI, 1.207-1.617), irrespective of tumor stage. Interestingly, the weight of PNI was found second only to incomplete resection in the nomogram for risk factors of OS and DFS in stage II CRC patients. Moreover, OS and DFS were insignificantly different between stage II patients with PNI and stage III patients (both P > 0.05). PNI was found to be an independent prognostic factor of DFS in stage III CRC (aHR: 1.514; 95% CI, 1.211-1.892) as well. Finally, the adverse effect of PNI on OS was more significant in female, early-onset, and diabetes-negative patients than in their counterparts (interaction P = 0.0213, 0.0280, and 0.0186, respectively). CONCLUSION: PNI was an important prognostic factor in CRC, more than in stage II. The survival of patients with stage II combined with perineural invasion is similar with those with stage III. PNI in stage III CRC also suggests a worse survival.
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Neoplasias do Colo , Neoplasias Colorretais , Humanos , Feminino , Prognóstico , Estudos Retrospectivos , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Estadiamento de Neoplasias , Invasividade NeoplásicaRESUMO
BACKGROUND: A large proportion of the patients with cancer do not respond to immunotherapies. Recent studies suggested an important role for tumor-infiltrating cytotoxic T lymphocytes (CTL) in enhancing response to immunotherapy. Here, we aim to identify gene that induce proliferative and cytotoxic states of CD8+ T cells, and to investigate its effect on CAR-T cells against colorectal cancer. METHODS: Correlation between the expression of IFI35 with the activation and cytotoxicity of CD8+ T cells was assessed with TCGA and proteomic databases. Then we constructed murine colon cancer cells over-expressing IFI35 and tested their effect on anti-tumor immunity in both immunodeficient and immunocompetent mouse models. Flow cytometry and immunohistochemistry were performed to assess the immune microenvironment. Western blot analysis was used to identify the potential down-stream signaling pathway regulated by IFI35. We further investigated the efficacy of the rhIFI35 protein in combination with immunotherapeutic treatment. RESULTS: The transcriptional and proteomic analysis of the activation and cytotoxicity of CD8+ T cells in human cancer samples demonstrated that IFI35 expression is correlated with increased CD8+ T cell infiltration and predicted a better outcome in colorectal cancer. The number and cytotoxicity of CD8+ T cells were significantly increased in IFI35-overexpressing tumors. Mechanistically, we identified that the IFNγ-STAT1-IRF7 axis stimulated IFI35 expression, and that IFI35-mediated regulation of CD8+ T cell proliferation and cytotoxicity was dependent on PI3K/AKT/mTOR signaling pathway in vitro. Furthermore, IFI35 protein enhanced the efficacy of CAR-T cells against colorectal cancer cells. CONCLUSION: Our findings identify IFI35 as a new biomarker that can enhance the proliferation and function of CD8+ T cells, as well as increase the efficacy of CAR-T cells against colorectal cancer cells.
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Antineoplásicos , Neoplasias do Colo , Humanos , Animais , Camundongos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt/genética , Linfócitos T CD8-Positivos , Proteômica , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Microambiente TumoralRESUMO
Understanding the vibrational information encoded within the terahertz (THz) spectrum of biomolecules is critical for guiding the exploration of its functional responses to specific THz radiation wavelengths. This study investigated several important phospholipid components of biological membranes-distearoyl phosphatidylethanolamine (DSPE), dipalmitoyl phosphatidylcholine (DPPC), sphingosine phosphorylcholine (SPH), and lecithin bilayer-using THz time-domain spectroscopy. We observed similar spectral patterns for DPPC, SPH, and the lecithin bilayer, all of which contain the choline group as the hydrophilic head. Notably, the spectrum of DSPE, which has an ethanolamine head group, was different. Interestingly, density functional theory calculations confirmed that the absorption peak common to DSPE and DPPC at approximately 3.0 THz originated from a collective vibration of their similar hydrophobic tails. Accordingly, the cell membrane fluidity of RAW264.7 macrophages with irradiation at 3.1 THz was significantly enhanced, leading to improved phagocytosis. Our results highlight the importance of the spectral characteristics of the phospholipid bilayers when studying their functional responses in the THz band and suggest that irradiation at 3.1 THz is a potential non-invasive strategy to increase the fluidity of phospholipid bilayers for biomedical applications such as immune activation or drug administration.
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Fosfolipídeos , Espectroscopia Terahertz , Lecitinas , Espectroscopia Terahertz/métodosRESUMO
PURPOSE: The role of villous architecture in the prognosis of colon adenocarcinoma remains unclear. This study aimed to investigate the prognostic factors of colon adenocarcinoma with different types of villous architecture and to establish nomograms for predicting cancer-specific mortality. METHODS: This retrospective study included 10,427 patients with colon adenocarcinoma arising in adenomas with villous architectures. The patients were stratified into the tubulovillous adenocarcinoma cohort and villous adenocarcinoma cohort. The prognostic risk factors, which were incorporated into nomograms for survival prediction, were determined by the log-rank test and Cox hazard models. The Harrell's Concordance Index (C-index) and calibration curve were utilized to evaluate the prediction accuracy. RESULTS: The pathological type of villous architecture was independently associated with the mortality of the entire population. Age, race, tumor size, T/N/M stage, and chemotherapy were independent risk factors of mortality in both cohorts. Interestingly, tumor differentiation was a prognostic factor for tubulovillous adenocarcinoma rather than villous adenocarcinoma, while the retrieved lymph node number was a prognostic factor for villous adenocarcinoma rather than tubulovillous adenocarcinoma. Survival analysis showed that the mortality rate of villous adenocarcinoma was higher than that of tubulovillous adenocarcinoma (HR 1.361, P < 0.001). We then established nomograms to predict the mortality of both cohorts and found excellent discrimination and predictive accuracy (C-index 0.842 and 0.821). CONCLUSION: Villous architecture is a determinant of colon adenocarcinoma outcomes, which might prompt reports of villous architecture in colon adenocarcinoma specimens by pathologists. Our population-based nomograms could be useful for predicting the survival of patients with colon adenocarcinoma and guiding individualized treatments.
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Adenocarcinoma , Nomogramas , Adenocarcinoma/patologia , Colo/patologia , Humanos , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Programa de SEERRESUMO
BACKGROUND: Nanoscale tapioca starch (NTS) was successfully developed by high-speed jet in our previous study. In this study, the adsorption capacity of Cu2+ onto NTS was further discussed. The optimal adsorption conditions (pH, contact time, contact temperature, initial Cu2+ concentration, and adsorbent concentration), adsorption kinetics, isotherms, and thermodynamic were also evaluated. RESULTS: The results showed that NTS exhibited excellent performance in adsorption of Cu2+ , with adsorption capacities of 122.31 mg g-1 for Cu2+ (pH 7, 0.04 g L-1 , 0.2 g L-1 , 313.15 K and 10 min). The pseudo-second-order and Langmuir isotherms models could be used to explain the adsorption kinetics and adsorption equilibrium, respectively. The thermodynamic results showed that the adsorption process was spontaneous and endothermic with an increase in entropy. Cu2+ was adsorbed onto NTS, which was confirmed by energy dispersive spectrometry analysis. CONCLUSION: These findings indicated that NTS might be an effective, environment-friendly and renewable bio-resource adsorbent for removing heavy metals in industrial effluent. © 2021 Society of Chemical Industry.
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Cobre/química , Manihot/química , Extratos Vegetais/química , Amido/química , Poluentes Químicos da Água/química , Purificação da Água/métodos , Adsorção , Concentração de Íons de Hidrogênio , Resíduos Industriais/análise , Cinética , Temperatura , Termodinâmica , Purificação da Água/instrumentaçãoRESUMO
OBJECTIVES: To search for more effective radiation protectors with minimal toxicity, a water-soluble nitroxides Acetamido-Tempol (AA-Tempol) was evaluated for potential radioprotective properties in HUVEC cells (Human Umbilical Vein Endothelial cell line). METHODS: To study the anti-radiation effect of AA-Tempol in cell culture, the viability of irradiated HUVEC cells using a clonogenic survival assay was examined. The anti-apoptosis effects of AA-Tempol using Annexin V/propidium iodide staining in a flow cytometry assay was also evaluated. To elucidate the molecular mechanism of the anti-apoptosis effect of AA-Tempol against X-radiation induced HUVEC cell apoptosis, the expression of Bax, Bcl-2 and p53 and caspase-3 were examined. The changes in the level of malondialdehyde (MDA) and glutathione (GSH) in HUVEC cells after X-radiation were also investigated. RESULTS: Pretreatment of the HUVEC cells colony with AA-Tempol 1 h before X-radiation significantly increased the colony survival (p < 0.05) compared with the cells without pretreatment. This demonstrates that AA-Tempol provides an effective radiation protection in the irradiated HUVEC cells, thus reducing apoptosis from 20.1 ± 1.3% in 8 Gy X-radiated cells to 12.2 ± 0.9% (1.0 mmol/L-1 AA-Tempol) in AA-Tempo pretreated HUVEC cells. This implies that 1.0 mM AA-Tempol treatment significantly block the increase of caspase-3 activity in radiated HUVEC cells (P < 0.01), causing down-regulation in expressions of Bax and P53 and up-regulation in the expression of Bcl-2. Pretreatment with AA-Tempol also decreased the MDA activities (P < 0.01) and increase the GSH level (P < 0.05) in HUVEC cells compared to the 8Gy X-radiated cells without pretreatment. CONCLUSIONS: These observations indicate that AA-Tempol is a potential therapeutic agent against the radiation damage.
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Óxidos N-Cíclicos/farmacologia , Protetores contra Radiação/farmacologia , Apoptose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , HumanosRESUMO
The vibrating superfine mill (VSM) is a machine that belongs to the micronization technique. In this study, VSM was employed to produce micronized tapioca starch by varying micronization times (15, 30, 45, and 60 min). The structural and physicochemical properties of the micronized starch were then examined. Scanning electron microscopy studies revealed that micronized starch was partially gelatinized, and the granule size dramatically increased when micronization time increased. X-ray diffraction patterns showed that the relative crystallinity was decreased from 24.67% (native) to 4.13% after micronization treatment for 15 min and slightly decreased after that. The solubility of micronized starch significantly increased as the micronization time increased, which was associated with the destruction of the starch crystalline structure. Differential scanning calorimetry investigations confirmed that micronized starch was "partly gelatinized," and the degree of gelatinization increased to 81.27% when the micronization time was 60 min. The weight-average molar mass was reduced by 15.0% (15 min), 30.9% (30 min), 55.7% (45 min), and 70.5% (60 min), respectively, indicating that the molecular structure was seriously degraded. The results demonstrated that the physicochemical changes of micronized starch granules were related to the destruction of the starch structure. These observations would provide details on micronized starch and its potential applications. PRACTICAL APPLICATION: These observations would provide details on micronized starch and its potential applications. Moreover, we believe that when the structures of starches were known, it is probable that the effect of VSM on the structural and physicochemical properties change of other starches might be predicted by adjusting the processing time.
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Varredura Diferencial de Calorimetria , Manihot , Microscopia Eletrônica de Varredura , Solubilidade , Amido , Difração de Raios X , Amido/química , Manihot/química , Microscopia Eletrônica de Varredura/métodos , Gelatina/química , Tamanho da Partícula , Manipulação de Alimentos/métodos , Fenômenos QuímicosRESUMO
Background: Intestinal fibrosis is a common complication in inflammatory bowel disease (IBD), which still lacks of reliable markers and therapeutic options. Cellular senescence has been considered an important mechanism of intestinal fibrosis, but the underlying molecular link remains elusive. Methods: Tissues were stained using α-smooth muscle actin (α-SMA), fibronectin, and collagen I as markers of myofibroblastic differentiation. Cellular senescence was confirmed through Lamin B1 staining, senescence-associated ß-galactosidase staining, and the expression of senescence-associated secretory phenotype (SASP) factors. We explored the relationship between senescence of intestinal epithelial cells (IECs) and intestinal fibrosis, as well as the molecular mechanism underlying this interaction. The effects of irisin on cellular senescence and fibrosis were determined. Results: Here, we identify engulfment and cell motility protein 1 (ELMO1) as a novel biomarker for intestinal cellular senescence and fibrosis. In fibrostrictured tissues from patients and murine models with IBD, significantly high levels of cellular senescence score and factors were noted, which positively correlated with the fibrotic regulator fibronectin. Senescent IECs, not fibroblast itself, released SASP factors to regulate fibroblast activation. Prolonging exposure to severe and persistent injurious stimuli decreased ELMO1 expression, which dampened SIRT1 deacetylase activity, enhanced NF-κB (p65) acetylation, and thereby accelerated cellular senescence. Deletion of ELMO1 led to senescent IECs accumulation and triggered premature fibrosis in murine colitis. Furthermore, irisin, inhibiting the degradation of ELMO1, could downregulate p65 acetylation, reduce IECs senescence, and prevent incipient intestinal fibrosis in murine colitis models. Conclusions: This study reveals ELMO1 downregulation is an early symbol of intestinal senescence and fibrosis, and the altered ELMO1-SIRT1-p65 pathway plays an important role in intestinal cellular senescence and IBD-related fibrosis.
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The synthesis of constrained 12-membered rings is notably difficult. The main challenges result from constraints during the linear peptide cyclization. Attempts to overcome constraints through excessive activation frequently cause peptidyl epimerization, while insufficient activation of the C-terminus hampers cyclization and promotes intermolecular oligomer formation. We present a ß-thiolactone framework that enables the synthesis of cyclo-tetrapeptides via direct aminolysis. This tactic utilizes a mechanism that restricts C-terminal carbonyl rotation while maintaining high reactivity, thereby enabling efficient head-to-tail amidation, reducing oligomerization, and preventing epimerization. A broad range of challenging cyclo-tetrapeptides ( > 20 examples) are synthesized in buffer and exhibits excellent tolerance toward nearly all proteinogenic amino acids. Previously unattainable macrocycles, such as cyclo-L-(Pro-Tyr-Pro-Val), have been produced and identified as µ-opioid receptor (MOR) agonists, with an EC50 value of 2.5 nM. Non-epimerizable direct aminolysis offers a practical solution for constrained peptide cyclization, and the discovery of MOR agonist activity highlights the importance of overcoming synthetic challenges for therapeutic development.
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Peptídeos Cíclicos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/síntese química , Ciclização , Receptores Opioides mu/metabolismo , Oligopeptídeos/química , Humanos , Aminoácidos/químicaRESUMO
The abundant nervous system in intestine provides the basis for perineural invasion (PNI) of colorectal cancer (CRC). PNI is defined as the invasion of the nerves by cancer cells. Although PNI is already known to be an independent prognostic factor in CRC, the molecular mechanism underlying PNI remains obscure. In this study, we first demonstrated that CD51 could promote the neurotropism of tumor cells through cleavage with γ-secretase to generate an intracellular domain (ICD). Mechanistically, ICD of CD51 could bind to the transcription factor NR4A3, and act as a coactivator to promote the expression of downstream effectors, such as NTRK1, NTRK3, and SEMA3E. Pharmacological inhibition of γ-secretase impedes PNI mediated by CD51 in CRC both in vitro and in vivo and may become a potential therapeutic target for PNI in CRC.
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We aimed to prepare a new pH-sensing film based on the immobilization of purple cabbage anthocyanins (PCA) into Polyvinyl alcohol (PVA) reinforced by cellulose nanocrystals (CNC). FT-IR, XRD and TGA were used to assess the intermolecular interactions and thermo-stability of films. The addition of CNC and PCA resulted in an enhancement in UV-vis barrier, mechanical properties and moisture resistance. Inclusion of PCA imparted intelligent properties to the films. PCA-loaded films displayed strong visually detectable colorimetric responses to pH (2-13) and volatile ammonia. When applied to monitor shrimp freshness at 4 °C, PVA/CNC films containing 0.6 % PCA exhibited conspicuous color fluctuations from purple to gray blue upon deterioration. As a result, PVA/CNC-PCA colorimetric films were considered as intelligent packaging labels with significant mechanical, water vapor barrier properties and pH-sensing qualities for visual quality evaluation of fresh seafood products.
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Brassica , Nanopartículas , Antocianinas/química , Celulose/química , Embalagem de Alimentos/métodos , Concentração de Íons de Hidrogênio , Nanopartículas/química , Álcool de Polivinil/química , Alimentos Marinhos , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Background: Removal of colorectal polyps during screening could reduce the incidence of colorectal cancer (CRC). However, there is a lack of data on risk factors associated with recurrence of polyps, including conventional adenomas and serrated polyps (SPs). This study aimed to determine risk factors for recurrence of colorectal polyps and their subtypes based on the characteristics of the patients and polyps. Methods: A total of 1,165 patients diagnosed with conventional adenoma or SP in the Sixth Affiliated Hospital of Sun Yat-sen University between January 2013 and December 2019 were enrolled in this study, including 668 cases with conventional adenomas, 385 with SPs, and 112 with coexistence of adenomas and SPs. Univariate analysis and multivariate logistic regression were used to identify potential risk factors for polyp recurrence. A nomogram was established according to risk factors and the performance was evaluated using calibration plots. Results: During a median follow-up of 24 months, recurrent polyps were observed in 531 (45.6%) cases. Male, age ≥50 years, body mass index (BMI) ≥24 kg/m2, at least three polyps, smoking, alcohol consumption, family history of polyps, and family history of CRC were independent risk factors for polyp recurrence. The Harrell's C-index of the nomogram developed with these parameters was 0.69 and the calibration plots showed good agreement between actual polyp recurrence and nomogram-predicted recurrence probability. In the subtype analyses, conventional adenomas had the same risk factors for recurrence as all polyps, while smoking, alcohol consumption, family history of polyps, and family history of CRC were not risk factors for SP recurrence. Conclusions: We identified several risk factors for recurrence of colorectal polyps and found that some of them could increase the risk of adenoma recurrence but not SP recurrence, including smoking, alcohol consumption, and family history of polyps/CRC, which might help us to understand different etiology and biology between conventional adenomas and SPs.
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Nanoparticles are more promising than microcapsules as drug carriers because they can be absorbed directly by intestinal epithelial cells, significantly increasing the uptake and bioaccessibility of polyphenols. Our study aimed to use catechin (CC), epicatechin (EC) and proanthocyanidin (PAC) adsorption onto tapioca starch nanoparticles (TSNs), which were prepared by a physical method. These TSN loaded-polyphenols were subjected to adsorption kinetic, adsorption isotherm, adsorption capacity, antioxidant activity, and in vitro release analyses. The maximum adsorption capacities of TSNs for CC, EC and PACs were 179.39 mg g-1, 109.29 mg g-1 and 287.19 mg g-1, respectively. The adsorption dynamics and isotherms of polyphenols on TSNs conformed well to the pseudo-second-order kinetics and the Freundlich isotherms. Moreover, TSN loaded-polyphenols have low cytotoxicity and can continuously be released under stimulated gastric and intestinal conditions. Antioxidant activity tests showed that TSN loaded-polyphenols can remarkably scavenge DPPH free radicals; the IC50 of TSNs-CC, TSNs-EC and TSNs-PAC were 16.11, 16.59 and 16.93 µg mL-1, respectively.
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Catequina , Nanopartículas , Poluentes Químicos da Água , Adsorção , Antioxidantes , Catequina/química , Concentração de Íons de Hidrogênio , Cinética , Nanopartículas/química , Polifenóis/química , Amido/químicaRESUMO
Background: Prognosis varies among stage IV colorectal cancer (CRC). Our study aimed to build a robust prognostic nomogram for predicting overall survival (OS) of patients with stage IV CRC in order to provide evidence for individualized treatment. Method: We collected the information of 16,283 patients with stage IV CRC in the Surveillance, Epidemiology, and End Results (SEER) database and then randomized these patients in a ratio of 7:3 into a training cohort and an internal validation cohort. In addition, 501 patients in the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) database were selected and used as an external validation cohort. Univariate and multivariate Cox analyses were used to screen out significant variables for nomogram establishment. The nomogram model was assessed using time-dependent receiver-operating characteristic curve (time-dependent ROC), concordance index (C-index), calibration curve, and decision curve analysis. Survival curves were plotted using the Kaplan-Meier method. Result: The C-index of the nomogram for OS in the training, internal validation, and external validation cohorts were 0.737, 0.727, and 0.655, respectively. ROC analysis and calibration curves pronounced robust discriminative ability of the model. Further, we divided the patients into a high-risk group and a low-risk group according to the nomogram. Corresponding Kaplan-Meier curves showed that the prediction of the nomogram was consistent with the actual practice. Additionally, model comparisons and decision curve analysis proved that the nomogram for predicting prognosis was significantly superior to the tumor-node-metastasis (TNM) staging system. Conclusions: We constructed a nomogram to predict OS of the stage IV CRC and externally validate its generalization, which was superior to the TNM staging system.
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The delivery of bioactive macromolecular substances into cells provides an efficient approach to changing cellular conditions, and is thus of enormously potential therapeutic significance. It has also been an extremely difficult approach due the the impediment and protective nature of cell membrance until the protein transduction domain's (PTD's) capability to ferry macromolecule across cell membrance was discovered. PTD's efficient transductive function has rendered an exciting promise to the clinical treatment of diseases, therapeutic proteins drug development, and basic medical and applied research. The technology has been successfully applied to deliver a variety of substances into cells or tissue organs, and its superior application values have been explicitly demonstrated.
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Permeabilidade da Membrana Celular/fisiologia , Sistemas de Liberação de Medicamentos/métodos , Sinais Direcionadores de Proteínas , Transporte Proteico/fisiologia , Terapia Genética , HumanosRESUMO
Here, we examined the phytochemical profiles, antioxidant activity (AA), and antiproliferative activity (APA) of four Chinese bayberry (Myrica rubra Sieb. et Zucc.) pulp extracts. They were found to be rich in total phenolics content (TPC; 186.45 ± 5.42 to 498.94 ± 8.25 mg of gallic acid equiv./100 g FW) and total flavonoids content (TFC; 126.28 ± 4.18 to 194.35 ± 12.03 mg of catechin equiv./100 g FW). For all varieties, the free flavonoid/phenolic/anthocyanin contents were higher than that the bound fractions. Wild pink bayberry (WPB) displayed the highest values of TPC and TFC, and also showed the highest total antioxidant activity (TAA) as revealed by peroxyl radical scavenging capacity (PSC) (451.47 ± 8.01 µmol Vit. C equiv./100 g FW), and free cellular antioxidant activity (CAA) (184.99 ± 6.11 µmol quercetin equiv./100 g FW, no PBS wash; 117.78 ± 2.34 µmol quercetin equiv./100 g FW, PBS wash) assays. Bayberry extracts had a marked reduction in the APA of HepG2 cells, and WPB exhibited the lowest EC50 (8.50 ± 0.83 mg/ml) value, which was probably associated with cell cycle arrest and apoptosis induction. PRACTICAL APPLICATION: Chinese bayberry (Myrica rubra Sieb. et Zucc.) fruit is rich in natural phenolic compounds, which might be a functional ingredient in food and nutraceutical products. Our findings would provide a logical strategy to promote the comprehensive utilization of phenolics in bayberry fruit with both health and economy benefits.
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Frutas , Myrica , Compostos Fitoquímicos , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , China , Frutas/química , Myrica/química , Compostos Fitoquímicos/química , Extratos Vegetais/farmacologiaRESUMO
The regular consumption of polyphenol-rich foods is essential to prevent the onset of diseases. Wild fruits are known to possess higher levels of bioactive components than the domesticated fruits because of the severe environmental conditions they are grown in. The aim of this study was to evaluate the phytochemical profiles, and antioxidant and antiproliferative activities of a wild pink bayberry fruit after in vitro digestion and to compare them with results obtained with a chemical extraction method. A low release of total phenolics and anthocyanins was observed after digestion compared with chemical extraction, while more flavonol contents were found by HPLC analysis. The digesta samples demonstrated low levels of extracellular antioxidant activity (EAA) and cellular antioxidant activity (CAA). However, the cellular uptake rate was increased during the in vitro digestion, and the largest value of 75.35% was obtained in the colon step. Notably, the antiproliferative activity in the colon digesta (10.14 ± 0.13 mg mL-1) was close to that of extracts (7.6 ± 0.63 mg mL-1). Pearson correlation analysis revealed that EAA and CAA were significantly correlated with TPC, while the antiproliferative activity was significantly correlated with the total contents of three flavonol compounds (quercetin, kaempferol, and myricetin). Our observations provide new insights into the bioactivity variation of whole fruits as affected by simulated digestion.
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Antioxidantes/análise , Digestão/fisiologia , Frutas/química , Myrica/química , Compostos Fitoquímicos , Antocianinas/análise , Antocianinas/química , Antioxidantes/química , Proliferação de Células/efeitos dos fármacos , Fenóis/análise , Fenóis/química , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/químicaRESUMO
Currently, the impact of electromagnetic field (EMF) exposure on the nervous system is an increasingly arousing public concern. The present study was designed to explore the effects of continuous long-term exposure to L-band high-power microwave (L-HPM) on brain function and related mechanisms. Forty-eight male Institute of Cancer Research (ICR) mice were exposed to L-HPM at various power densities (0.5, 1.0, and 1.5 W/m2) and the brain function was examined at different time periods after exposure. The morphology of the brain was examined by hematoxylin-eosin (HE) and deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. Furthermore, cholinergic markers, oxidative stress markers, and the expression of c-fos were evaluated to identify a "potential" mechanism. The results showed that exposure to L-HPM at 1.5 W/m2 can cause generalized injuries in the hippocampus (CA1 and CA3) and cerebral cortex (the first somatosensory cortex) of mice, including cell apoptosis, cholinergic dysfunction, and oxidative damage. Moreover, the deleterious effects were closely related to the power density and exposure time, indicating that long-term and high-power density exposure may be detrimental to the nervous system.