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INTRODUCTION: This study investigated gender differences in the reading behaviors of Chinese middle school students, and whether gender stereotypes relating to choices of reading matter are supported. METHODS: A mixed-methods approach was adopted. Three thousand nine hundred and fifteen middle school (Grade 7) students completed a questionnaire designed to assess reading behaviors. Independent sample t-test and chi-square analyses were employed to examine gender differences in reading behaviors. The qualitative survey was supplemented with an open response survey (94 boys, 50 girls), which provided further insights into individuals' specific experiences and perspectives regarding reading behaviors and gender stereotypes in reading choices. RESULTS: This study revealed a number of gender-linked differences. Boys spent more time reading than girls but read the same number of books; boys were also more likely than girls to read digital texts, while girls were more likely to borrow their reading material. Choice of subject matter also differed: boys were more likely to read factual and action-based books, while girls' choices focused more on motives and emotions. Another significant difference was that boys paid more attention to the overall experience of reading, while girls paid more attention to the details of reading. Responses to the open response survey indicated that gender stereotypes in reading choices were prevalent among respondents, but some students' reading choices did not align with the stereotype associated with their gender. CONCLUSION: The mixed-methods approach proved valuable in both identifying gender differences in reading behaviors, and in highlighting the prevalence of gender stereotypes in reading choices among middle school students.
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Livros , Leitura , Estereotipagem , Estudantes , Humanos , Masculino , Feminino , Adolescente , China , Fatores Sexuais , Inquéritos e Questionários , Estudantes/psicologia , Estudantes/estatística & dados numéricos , Criança , População do Leste AsiáticoRESUMO
BACKGROUND: Extralevator abdominoperineal excision (ELAPE) has been recommended for treating low rectal cancer due to its potential advantages in improving surgical safety and oncologic outcomes as compared to conventional abdominoperineal excision (APE). In ELAPE, however, whether the benefits of intraoperative position change to a prone jackknife position outweighs the associated risks remains controversial. This study is to introduce a modified position change in laparoscopic ELAPE and evaluate its feasibility, safety and the long-term therapeutic outcomes. METHODS: Medical records of 56 consecutive patients with low rectal cancer underwent laparoscopic ELAPE from November 2013 to September 2016 were retrospectively studied. In the operation, a perineal dissection in prone jackknife position was firstly performed and the laparoscopic procedure was then conducted in supine position. Patient characteristics, intraoperative and postoperative outcomes, pathologic and 5-year oncologic outcomes were analyzed. RESULTS: The mean operation time was 213.5 ± 29.4 min and the mean intraoperative blood loss was 152.7 ± 125.2 ml. All the tumors were totally resected, without intraoperative perforation, conversion to open surgery, postoperative 30-day death, and perioperative complications. All the patients achieved pelvic peritoneum reconstruction without the usage of biological mesh. During the follow-up period, perineal hernia was observed in 1 patient, impaired sexual function in 1 patient, and parastomal hernias in 3 patients. The local recurrence rate was 1.9% and distant metastasis was noted in 12 patients. The 5-year overall survival rate was 76.4% and the 5-year disease-free survival rate was 70.9%. CONCLUSIONS: Laparoscopic ELAPE with modified position change is a simplified, safe and feasible procedure with favorable outcomes. The pelvic peritoneum can be directly closed by the laparoscopic approach without the application of biological mesh.
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Procedimentos Cirúrgicos do Sistema Digestório , Laparoscopia , Protectomia , Neoplasias Retais , Abdome/patologia , Abdome/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Períneo/cirurgia , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
ABSTRACT: Inositol 1, 4, 5-trisphosphate (IP3) signaling-mediated calcium release drives the contraction of vascular smooth muscles and hence regulates blood vessel volume and blood pressure. Melatonin supplementation has been suggested to be beneficial for hypertension. To determine whether the blood pressure-lowering effect of melatonin was accounted for by IP3 signaling, we evaluated the vasoconstriction response and IP3 signaling in isolated mouse thoracic aortic rings during melatonin incubation. C57BL/6 mice were given intraperitoneal injections daily with melatonin, and the systolic blood pressure and contractility of aortic rings from melatonin-treated mice were decreased, and the contraction suppression effect of melatonin was attributed to the impaired expression of contractile proteins in vascular smooth muscle cells rather than IP3 signaling. Our results further showed that melatonin increased the expression of γ-secretase, which could cleave and release the notch intracellular domain, and the notch intracellular domain prevented the transcription of contractile genes by interfering with the interaction between serum response factor and myocardin, the master regulator of contractile protein. In this article, we report a novel mechanism by which melatonin regulates smooth muscle contractility that does not depend on IP3 signaling.
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Melatonina , Vasoconstrição , Secretases da Proteína Precursora do Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/farmacologia , Animais , Cálcio/metabolismo , Proteínas Contráteis/metabolismo , Proteínas Contráteis/farmacologia , Inositol/metabolismo , Inositol/farmacologia , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteínas Nucleares , Fator de Resposta Sérica/metabolismo , Fator de Resposta Sérica/farmacologia , TransativadoresRESUMO
Real-time monitoring of drug metabolism in vivo is of great significance to drug development and toxicology research. The purpose of this study is to establish a rapid and visual in vivo detection method for the detection of an intermediate metabolite of the gold (I) drug. Gold (I) drugs such as sodium aurothiomalate (AuTM) have anti-inflammatory effects in the treatment of rheumatoid arthritis. Gold(III) ions (Au3+) are the intermediate metabolite of gold medicine, and they are also the leading factor of side effects in the treatment of patients. However, the rapid reduction of Au3+ to Au+ by thiol proteins in organisms limits the in-depth study of metabolism of gold drugs in vivo. Here we describe a luminescence Au3+ probe (RA) based on ruthenium (II) complex for detecting Au3+ in vitro and in vivo. RA with large Stokes shift, good water solubility and biocompatibility was successfully applied to detect Au3+ in living cells and vivo by luminescence imaging, and to trap the fluctuation of Au3+ level produced by gold (I) medicine. More importantly, the luminescent probe was used to the detection of the intermediate metabolites of gold (I) drugs for the first time. Overall, this work offers a new detection tool/method for a deeper study of gold (I) drugs metabolite.
Assuntos
Corantes Fluorescentes/química , Tiomalato Sódico de Ouro/química , Tiomalato Sódico de Ouro/metabolismo , Ouro/química , Compostos de Rutênio/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Lipopolissacarídeos/toxicidade , Camundongos , Estrutura Molecular , Células RAW 264.7 , Análise de Célula Única , Peixe-ZebraRESUMO
INTRODUCTION: Homeostasis of cholesterol is crucial for cellular function, and dysregulated cholesterol biosynthesis is a metabolic event that can lead to hepatic and cardiovascular abnormalities. OBJECTIVE: The aim of this study was to investigate the effects and mechanisms of domain-associated protein (Daxx) and androgen receptor (AR) on intracellular cholesterol synthesis. METHODS: HepG2 cells were transfected with pCDNA3.1(+)/Daxx plasmid or treated with testosterone propionate to observe the effects of Daxx and AR on intracellular cholesterol levels. Co-immunoprecipitation experiments were performed to identify the interaction between Daxx and AR and to explore the regulatory effects of this interaction on cholesterol synthesis. RESULTS: Our experiments showed that AR promoted cholesterol synthesis and accumulation by activating sterol-regulatory element-binding protein isoform 2. AR-induced cholesterol synthesis was inhibited by Daxx; however, the expression of AR was not affected. Further studies demonstrated the existence of direct binding between Daxx and AR and this interaction was required to suppress AR activity. CONCLUSIONS: The Daxx-mediated antagonism of AR depicts a more complete picture as to how Daxx regulates intracellular cholesterol level and provides a new target for treatment of atherosclerosis.
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Colesterol/biossíntese , Proteínas Correpressoras/metabolismo , Chaperonas Moleculares/metabolismo , Receptores Androgênicos/metabolismo , Compostos Azo , Colesterol/análise , Cromatografia Líquida de Alta Pressão , Colorimetria , Células Hep G2 , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Imunoprecipitação , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismoRESUMO
A three-dimensional (3-D) residual stress detection technique is proposed to detect and evaluate the residual stress occurring in optical components due to repairs carried out at laser induced damage sites. It is possible with a cross-orthogonal reflective photo-elastic setup to obtain complete 3-D information of the residual shearing stress around the damage site. The damaged volume of the optical component is numerically sliced into multilayers for this purpose and reflected light intensity is recorded from each layer. The shearing stress from the reflected light intensity is then calculated based on photo-elasticity theory. The validity of the approach is also verified in experiments where it could measure 3-D residual stress with an axial resolution of 10 µm along the light path.
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A variety of cardiovascular diseases is accompanied by the loss of vascular contractility. This study sought to investigate the effects of curcumin, a natural polyphenolic compound present in turmeric, on mouse vascular contractility and the underlying mechanisms. After mice were administered curcumin (100 mg·kg-1·d-1, ig) for 6 weeks, the contractile responses of the thoracic aorta to KCl and phenylephrine were significantly enhanced compared with the control group. Furthermore, the contractility of vascular smooth muscle (SM) was significantly enhanced after incubation in curcumin (25 µmol/L) for 4 days, which was accompanied by upregulated expression of SM marker contractile proteins SM22α and SM α-actin. In cultured vascular smooth muscle cells (VSMCs), curcumin (10, 25, 50 µmol/L) significantly increased the expression of myocardin, a "master regulator" of SM gene expression. Curcumin treatment also significantly increased the levels of caveolin-1 in VSMCs. We found that as a result of the upregulation of caveolin-1, curcumin blocked the activation of notch1 and thereby abolished Notch1-inhibited myocardin expression. Knockdown of caveolin-1 or activation of Notch1 signaling with Jagged1 (2 µg/mL) diminished these effects of curcumin in VSMCs. These findings suggest that curcumin induces the expression of myocardin in mouse smooth muscle cells via a variety of mechanisms, including caveolin-1-mediated inhibition of notch1 activation and Notch1-mediated repression of myocardin expression. This may represent a novel pathway, through which curcumin protects blood vessels via the beneficial regulation of SM contractility.
Assuntos
Curcumina/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Proteínas Nucleares/genética , Transativadores/genética , Actinas/metabolismo , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Caveolina 1/genética , Caveolina 1/metabolismo , Células Cultivadas , Curcumina/administração & dosagem , Relação Dose-Resposta a Droga , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
Daxx is a highly conserved nuclear transcriptional factor, which has been implicated in many nuclear processes including transcription and cell cycle regulation. Our previous study demonstrated Daxx also plays a role in regulation of intracellular cholesterol content. Daxx contains several domains that are essential for interaction with a growing number of proteins. To delineate the underlying mechanism of hypocholesterolemic activity of Daxx, we constructed a set of plasmids which can be used to overexpress different fragments of Daxx and transfected to HepG2 cells. We found that the C- terminal region Daxx626-740 clearly reduced intracellular cholesterol levels and inhibited the expression of SREBPs and SCAP. In GST pull-down experiments and Double immunofluorescence assays, Daxx626-740 was demonstrated to bind directly to androgen receptor (AR). Our findings suggest that the interaction of Daxx626-740 and AR abolishes the AR-mediated activation of SCAP/SREBPs pathway, which suppresses the de novo cholesterol synthesis. Thus, C-terminal domain of Daxx acts as a potential regulator of intracellular cholesterol content in HepG2 cells.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Colesterol/biossíntese , Proteínas Nucleares/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Correpressoras , Células Hep G2 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Chaperonas Moleculares , Proteínas Nucleares/química , Proteínas Nucleares/genética , Domínios Proteicos , Receptores Androgênicos/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismoRESUMO
Here we aimed to evaluate the effects of DAXX subcellular localization on ox-LDL induced macrophages apoptosis. Cytoplasmic localization vector DAXX-W621A and nuclear localization vector DAXX-S667A were constructed by point mutation in DAXX. Blank vector, full length DAXX, DAXX-W621A, DAXX-S667A was transfect into RAW264.7 cells, respectively. Then the cells were incubated with 100 mg/ml ox-LDL for 48 h. Immunofluorescent assay was used to assay the localization of DAXX. MTT and Flow cytometry was used to determine cellular viability and apoptosis. RT-PCR and Western blot were used to analyze the expression levels. A significantly increased expression of DAXX was found in transfected cells of DAXX. The content of DAXX in nucleus was significantly increased in DAXX(S667A), and DAXX was significantly increased in cytoplasm of DAXX(W621A). Besides, we found DAXX was mainly expressed in nucleus with a low-level expression in cytoplasm through immunofluorescence. However in DAXX(W621A) group, the DAXX began to transferred to cytoplasm, which exhibited significant florescence. After treated with ox-LDL, the cytoactive of DAXX-W621A exhibited significantly decreased level when compared DAXX group. However, after added inhibitor LMB, the inhibition was relieved. The cell viability was also significantly increased in DAXX-S667A group. The results of apoptosis rates were similar in each group. Furthermore, we found the expression of ASK1 and JNK was also consistent with the apoptosis rates. Cytoplasmic localization of DAXX can increase injury sensitivity of ox-LDL on cells, and nuclear localization can antagonise the effect of ox-LDL. Besides, it is certified ox-LDL induced apoptosis is mainly through ASK1-JNK pathway.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/fisiologia , Lipoproteínas LDL/fisiologia , Macrófagos/fisiologia , Proteínas Nucleares/metabolismo , Apoptose/genética , Western Blotting , Linhagem Celular , Núcleo Celular/metabolismo , Proteínas Correpressoras , Citoplasma/metabolismo , Primers do DNA/genética , Citometria de Fluxo , Imunofluorescência , Vetores Genéticos/genética , Humanos , Lipoproteínas LDL/metabolismo , Macrófagos/efeitos dos fármacos , Chaperonas Moleculares , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Ezetimibe is a potent inhibitor of Niemann-Pick type C1-Like 1 and has been approved for the treatment of hypercholesterolemia. Our preliminary study showed that ezetimibe promotes cholesterol efï¬ux from vascular smooth muscle cells (VSMCs). Our aim was to investigate the cellular mechanisms underlying the ezetimibe actions. METHODS AND RESULTS: Rat VSMCs were converted to foam cells by incubation with cholesterol:methyl-ß-cyclodextrin. The intracellular free cholesterol, total cholesterol, and the ratio of cholesteryl ester to total cholesterol were decreased after the incubation of VSMCs with different concentrations of ezetimibe (3, 10, 30, and 30 µmol/l) or treated with 30 µmol/l of ezetimibe for different time periods (6, 12, 24, and 48 h). Our results also showed that the expression of caveolin-1, liver X receptor α, and ATP-binding cassette transporter ABCA1 was enhanced, but the expression of nSREBP-1c was decreased in a concentration- and time-dependent manner. RNA interference was used to determine the roles of caveolin-1 and SREBP-1 in the lipid-lowering effect of ezetimibe. The results showed that caveolin-1 was involved in the regulation of intracellular cholesterol content, and the expression of caveolin-1 was repressed by SREBP-1. CONCLUSION: The present study indicates that ezetimibe protects VSMCs from cholesterol accumulation by regulating the expression of lipid metabolism-related genes.
Assuntos
Anticolesterolemiantes/farmacologia , Azetidinas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Caveolina 1/genética , Colesterol/farmacologia , Ezetimiba , Metabolismo dos Lipídeos/genética , Receptores X do Fígado , Masculino , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Receptores Nucleares Órfãos/genética , RNA Interferente Pequeno/genética , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , beta-Ciclodextrinas/farmacologiaRESUMO
A new acidophilic xylanase (XYN11A) from Penicillium oxalicum GZ-2 has been purified, identified and characterized. Synchronized fluorescence spectroscopy was used for the first time to evaluate the influence of metal ions on xylanase activity. The purified enzyme was identified by MALDI TOF/TOF mass spectrometry, and its gene (xyn11A) was identified as an open reading frame of 706 bp with a 68 bp intron. This gene encodes a mature protein of 196 residues with a predicted molecular weight of 21.3 kDa that has the 100 % identity with the putative xylanase from the P. oxalicum 114-2. The enzyme shows a structure comprising a catalytic module family 10 (GH10) and no carbohydrate-binding module family. The specific activities were 150.2, 60.2, and 72.6 U/mg for beechwood xylan, birchwood xylan, and oat spelt xylan, respectively. XYN11A exhibited optimal activity at pH 4.0 and remarkable pH stability under extremely acidic condition (pH 3). The specific activity, K m and V max values were 150.2 U/mg, 30.7 mg/mL, and 403.9 µmol/min/mg for beechwood xylan, respectively. XYN11A is a endo-ß-1,4-xylanase since it release xylobiose and xylotriose as the main products by hydrolyzing xylans. The activity of XYN11A was enhanced 155 % by 1 mM Fe(2+) ions, but was inhibited strongly by Fe(3+). The reason of enhancing the xylanase activity of XYN11A with 1 mM Fe(2+) treatment may be responsible for the change of microenvironment of tryptophan residues studied by synchronous fluorescence spectrophotometry. Inhibition of the xylanase activity by Fe(3+) was first time demonstrated to associate tryptophan fluorescence quenching.
Assuntos
Clonagem Molecular , Endo-1,4-beta-Xilanases/isolamento & purificação , Endo-1,4-beta-Xilanases/metabolismo , Metais/farmacologia , Penicillium/enzimologia , Sequência de Aminoácidos , Biotecnologia , Endo-1,4-beta-Xilanases/genética , Estabilidade Enzimática , Concentração de Íons de Hidrogênio , Hidrólise/efeitos dos fármacos , Cinética , Metais/metabolismo , Dados de Sequência Molecular , Peso Molecular , Penicillium/genética , Especificidade por Substrato , Temperatura , Triptofano/metabolismo , Xilanos/metabolismoRESUMO
Selenium, an essential trace element of the human body, is pivotal in human health and disease prevention. Nevertheless, the narrow therapeutic index of selenium, where the toxic and therapeutic doses are close, limits its clinical utility. Significantly, nanoscale selenium synthesized by different methods using polysaccharides as stabilizers has low toxicity properties and exhibits excellent bioactivity. Its biological activities, such as anti-tumor, anti-inflammatory, antioxidant, antibacterial, and immune function enhancement, are improved compared with traditional organic and inorganic selenium compounds, conferring greater potential for application in biomedicine. Therefore, this review evaluates the advancements in various synthesis methodologies for polysaccharide selenium nanoparticles (Se NPs) and their biological activities. It aims to provide a comprehensive theoretical basis and research directions for the future development of highly efficient, minimally toxic, and biocompatible polysaccharide-Se NPs and the application of polysaccharide-Se NPs in biomedicine.
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Antioxidantes , Nanopartículas , Polissacarídeos , Selênio , Selênio/química , Selênio/farmacologia , Polissacarídeos/química , Polissacarídeos/farmacologia , Polissacarídeos/síntese química , Humanos , Nanopartículas/química , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/síntese químicaRESUMO
Numerous studies have shown that a low level of high-density lipoprotein cholesterol (HDL-C) is an independent biomarker of cardiovascular disease. High-density lipoprotein (HDL) is considered to be a protective factor for atherosclerosis (AS). Therefore, raising HDL-C has been widely recognized as a promising strategy to treat atherosclerotic cardiovascular diseases (ASCVD). However, several studies have found that increasing HDL-C levels does not necessarily reduce the risk of ASCVD. HDL particles are highly heterogeneous in structure, composition, and biological function. Moreover, HDL particles from atherosclerotic patients exhibit impaired anti-atherogenic functions and these dysfunctional HDL particles might even promote ASCVD. This makes it uncertain that HDL-raising therapy will prevent and treat ASCVD. It is necessary to comprehensively analyze the structure and function of HDL subfractions. We review current advances related to HDL subfractions remodeling and highlight how current lipid-modifying drugs such as niacin, statins, fibrates, and cholesteryl ester transfer protein inhibitors regulate cholesterol concentration of HDL and specific HDL subfractions.
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Aterosclerose , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Doenças Cardiovasculares/prevenção & controle , Lipoproteínas HDL , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Colesterol , HDL-Colesterol , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controleRESUMO
In recent years, Flammulina velutipes (F. velutipes) has attracted consequential attention in various research fields due to its rich composition of proteins, vitamins, amino acids, polysaccharides, and polyphenols. F. velutipes polysaccharides (FVPs) are considered as key bioactive components of F. velutipes, demonstrating multiple physiological activities, including immunomodulatory, anti-inflammatory, and antibacterial properties. Moreover, they offer health benefits such as antioxidant and anti-aging properties, which have exceptionally valuable clinical applications. Polysaccharides derived from different sources exhibit a wide range of biomedical functions and distinct biological activities. The varied biological functions of polysaccharides, coupled with their extensive application in functional foods and clinical applications, have prompted a heightened focus on polysaccharide research. Additionally, the extraction, deproteinization, and purification of FVPs are fundamental to investigate the structure and biological activities of polysaccharides. Therefore, this review provides a comprehensive and systematic overview of the extraction, deproteinization, purification, characterization, and structural elucidation of FVPs. Furthermore, the biological activities and mechanisms of FVPs have been further explored through in vivo and in vitro experiments. This review aims to provide a theoretical foundation and guide future research and development of FVPs.
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Flammulina , Polissacarídeos Fúngicos , Animais , Humanos , Antibacterianos/farmacologia , Antibacterianos/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Antioxidantes/farmacologia , Antioxidantes/química , Flammulina/química , Polissacarídeos Fúngicos/química , Polissacarídeos Fúngicos/farmacologia , Fatores Imunológicos/farmacologia , Fatores Imunológicos/químicaRESUMO
The incidence and mortality of breast cancer, the most common malignant tumor among women in the world, are increasing year by year, which greatly threatens women's health. Ferroptosis is an iron and lipid reactive oxygen species (ROS)-dependent process, a novel form of cell death that is distinct from apoptosis and is closely related to the progression of breast cancer. Inducing the occurrence of ferroptosis in tumor cells can effectively block its malignant progress in vivo. Oridonin (ORI), the primary active ingredient extracted from the Chinese herbal medicine Rabdosia rubescens, has been shown to cause glutathione depletion and directly inhibit glutathione peroxidase 4 induced cell death by ferroptosis, but its mechanism of action in breast cancer remains inadequately elucidated. Therefore, we further investigated whether ORI could promote RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress pathway JNK/Nrf2/HO-1. In our study, we assessed cell survival of RSL3 and ORI treatment by MTT assay, and found that co-treatment with RSL3 and ORI inhibited cell proliferation, as evidenced by the cloning assay. To investigate the ability of ORI to promote RSL3-induced ferroptosis in breast cancer cells, we measured levels of ROS, malondialdehyde, glutathione, superoxide dismutase, and Fe2+ content. Lipid peroxidation, ROS, and mitochondrial membrane potential levels induced by co-treatment of ORI with RSL3 were reversed by ferrostatin-1, further confirming that the cell death induced by RSL3 and ORI was ferroptosis rather than other programmed cell death modes. Moreover, RSL3 and ORI co-treatment regulated the JNK/Nrf2/HO-1 axis, as demonstrated by western blotting and target activator validation. Our results showed that ORI could enhance the inhibitory effect of RSL3 on breast cancer cells viability via the induction of ferroptosis. Mechanistically, it potentiated RSL3-induced ferroptosis in breast cancer cells by activating the JNK/Nrf2/HO-1 axis. This study provides a theoretical basis for the application of ORI based on the mechanism of ferroptosis, and provides potential natural drug candidates for cancer prevention and treatment.
Assuntos
Neoplasias da Mama , Diterpenos do Tipo Caurano , Ferroptose , Heme Oxigenase-1 , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Ferroptose/efeitos dos fármacos , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Diterpenos do Tipo Caurano/farmacologia , Feminino , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Células MCF-7 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , CarbolinasRESUMO
In recent years, attention has increasingly focused on herbal medicines and their bioactive components attributed to their multi-target pharmacological activity and low side effects. Oridonin is a natural diterpenoid extracted from the traditional Chinese herb and is one of the main active components of Rabdosia rubescens. Modern pharmacological studies have shown that oridonin has anti-tumor, anti-bacterial, anti-inflammatory, anti-oxidant, cardiovascular protective, immunomodulatory, and other effects. Based on the published literature in recent years, we outline the pharmacological activities of oridonin, aiming to provide a theoretical basis for the design and development of new oridonin-based drugs, as well as to facilitate the process of oridonin for clinical use.
Assuntos
Antineoplásicos , Diterpenos do Tipo Caurano , Diterpenos , Neoplasias , Humanos , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/uso terapêutico , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Linhagem Celular TumoralRESUMO
The brain is the most cholesterol-rich organ in mammals. However, cholesterol metabolism in the brain is completely independent of other tissues due to the presence of the blood-brain barrier (BBB). Neurons, astrocytes and oligodendrocytes are the main cells responsible for cholesterol synthesis in the brain. The cholesterol content in the brain is maintained at a relatively constant level under strict regulation of synthesis, transport, and turnover, that is, brain cholesterol homeostasis. Once this balance is disrupted, neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) ensue. This review summarizes the processes controlling cholesterol homeostasis with respect to the synthesis, transport and turnover of cholesterol in the brain. We further focus on how cholesterol imbalance contributes to neurodegenerative diseases to explore the possibilities to modulate the key steps involved, which will provide clues for the development of therapies for the treatment of central nervous system (CNS) diseases.
Assuntos
Doenças Neurodegenerativas , Animais , Doenças Neurodegenerativas/metabolismo , Encéfalo/metabolismo , Barreira Hematoencefálica/metabolismo , Colesterol/metabolismo , Homeostase , Mamíferos/metabolismoRESUMO
Stormwater runoff is one of the most common non-point sources of water pollution to rivers, lakes, estuaries, and coastal beaches. While most pollutants and nutrients, including nitrate-nitrogen, in stormwater are discharged into receiving waters during the first-flush period, no existing best management practices (BMPs) are specifically designed to capture and treat the first-flush portion of urban stormwater runoff. This paper presents a novel BMP device for highway and urban stormwater treatment with emphasis on numerical modeling of the new BMP, called first-flush reactor (FFR). A new model, called VART-DN model, for simulation of denitrification process in the designed first-flush reactor was developed using the variable residence time (VART) model. The VART-DN model is capable of simulating various processes and mechanisms responsible for denitrification in the FFR. Based on sensitivity analysis results of model parameters, the denitrification process is sensitive to the temperature correction factor (b), maximum nitrate-nitrogen decay rate (K (max)), actual varying residence time (T (v)), the constant decay rate of denitrifiying bacteria (v (dec)), temperature (T), biomass inhibition constant (K (b)), maximum growth rate of denitrifiying bacteria (v (max)), denitrifying bacteria concentration (X), longitudinal dispersion coefficient (K (s)), and half-saturation constant of dissolved carbon for biomass (K (Car-X)); a 10% increase in the model parameter values causes a change in model root mean square error (RMSE) of -28.02, -16.16, -12.35, 11.44, -9.68, 10.61, -16.30, -9.27, 6.58 and 3.89%, respectively. The VART-DN model was tested using the data from laboratory experiments conducted using highway stormwater and secondary wastewater. Model results for the denitrification process of highway stormwater showed a good agreement with observed data and the simulation error was less than 9.0%. The RMSE and the coefficient of determination for simulating denitrification process of wastewater were 0.5167 and 0.6912, respectively, demonstrating the efficacy of the VART-DN model.
Assuntos
Bactérias/metabolismo , Reatores Biológicos , Desnitrificação/fisiologia , Modelos Biológicos , Nitratos/metabolismo , Nitrogênio/metabolismo , Poluentes Químicos da Água/metabolismo , Purificação da Água/métodos , Reatores Biológicos/microbiologia , ChuvaRESUMO
OBJECTIVE: To investigate the role of Runx3 gene CpG island methylation in the development of human gastric carcinoma. METHODS: A total of 150 tumor specimens from patients with gastric carcinoma and 50 normal tissue specimens were selected. Methylation specific PCR (MSP) and pyrosequencing (PS) were used to detect the methylation status of Runx3 gene promoter. RESULTS: Compared to normal tissue samples, a significant increase of CpG island methylation status of Runx3 gene was observed in gastric carcinomas (MSP: 67.3% vs. 40.0%, P = 0.002; PS: 76.0% vs. 30.0%, P < 0.01). Runx3 gene methylation was only related to tumor size (P < 0.05) based on MSP analysis. PS test however showed that the extent of methylation of Runx3 gene was related to the tumor size (P = 0.004), Lauren's classification (P = 0.043), depth of invasion (P < 0.01), lymph node metastasis (P = 0.021) and TNM staging (P = 0.045). CONCLUSIONS: Methylation status of Runx3 gene detectable by PS is closely correlated with clinicopathological parameters of gastric carcinoma, including tumor size, Lauren's classification, depth of invasion, lymph node metastasis and TNM staging. PS is more sensitive than MSP in the detection of Runx3 gene methylation, which may serve as an important marker for early diagnosis and treatment of gastric carcinoma.
Assuntos
Subunidade alfa 3 de Fator de Ligação ao Core/genética , Ilhas de CpG/genética , Metilação de DNA , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas/genética , Análise de Sequência de DNA , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Carga Tumoral , Adulto JovemRESUMO
AIM: To evaluate the effects of angiopoietin-1 (Ang-1) on myocardial endothelial cell function under high glucose (HG) condition. METHODS: Mouse heart myocardial endothelial cells (MHMECs) were cultured and incubated under HG (25 mmol/L) or normal glucose (NG, 5 mmol/L) conditions for 72 h. MTT was used to determine cellular viability, and TUNEL assay and caspase-3 enzyme linked immunosorbent assays were used to assay endothelial apoptosis induced by serum starvation. Immunoprecipitation and Western blot analysis were used to analyze protein phosphorylation and expression. Endothelial tube formation was used as an in vitro assay for angiogenesis. RESULTS: Exposure of MHMECs to HG resulted in dramatic decreases in phosphorylation of the Tie-2 receptor and its downstream signaling partners, Akt/eNOS, compared to that under NG conditions. Ang-1 (250 ng/mL) increased Tie-2 activation, inhibited cell apoptosis, and promoted angiogenesis. Ang-1-mediated protection of endothelial function was blunted by Ang-2 (25 ng/mL). CONCLUSION: Ang-1 activates the Tie-2 pathway and restores hyperglycemia-induced myocardial microvascular endothelial dysfunction. This suggests a protective role of Ang-1 in the ischemic myocardium, particularly in hearts affected by hyperglycemia or diabetes.