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1.
Biochem Biophys Res Commun ; 583: 114-120, 2021 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-34735872

RESUMEN

Energy metabolism is essential for almost all organisms. At the molecular level, adenosine monophosphate activated protein kinase (AMPK) plays a vital role in cellular energy homeostasis. Its molecular characterization in invertebrates, including Daphnia pulex, and the understanding of its role in response to environmental contaminants is limited. In this study, three subunits of AMPK (AMPKα, ß, and γ) were cloned in D. pulex, and assigned the GenBank accession numbers MT536758, MT536759, and MT536760, respectively. Their full lengths were 2,000, 1,384, and 2594 bp, respectively, and contained open reading frames of 526, 274, and 580 amino acids, respectively. Bioinformatic analysis revealed that the three AMPK subunits all have features representative of the AMPK superfamily, and were correspondingly clustered with each orthologue branch. The three AMPK subunit genes, AMPKα, ß, and γ, had the highest similarity to those of other organisms at 82%, 94%, and 71%, respectively. Nanoplastics significantly increased AMPKα expression, but decreased that of AMPKß and γ. These results identified AMPKα, ß, and γ in D. pulex, and showed that they all encode proteins with conserved functional domains. This study provides basic information on how three types of AMPK in aquatic organisms respond to environmental contaminants.

2.
Exp Dermatol ; 26(11): 1118-1124, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28605165

RESUMEN

It has been reported that the proteasome activator REGγ is associated with multiple oncogenic pathways in human cancers. However, the role of REGγ in the development of melanoma and the underlying mechanisms remain unclear. In this study, we attempted to investigate the effects of REGγ on human melanoma cell proliferation in vitro and in vivo. We demonstrated that knockdown of REGγ inhibited melanoma cell growth and arrested melanoma cell at G1 phase. Furthermore, depletion of REGγ also inhibited the xenograft growth of human melanoma. Mechanistically, REGγ activates Wnt/ß-catenin signal pathway by degrading GSK-3ß in melanoma cell lines and mouse models. Transient knockdown of ß-catenin effectively blocked cell proliferation in REGγ wild-type melanoma cells. In human melanoma samples, REGγ was overexpressed and positively correlated with ß-catenin levels. This study demonstrates that REGγ is a central molecule in the development of melanoma by regulating Wnt/ß-catenin pathway. This suggests that targeting REGγ could be an alternative therapeutic approach for melanoma.


Asunto(s)
Autoantígenos/genética , Proliferación Celular/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Melanoma/genética , Complejo de la Endopetidasa Proteasomal/genética , Vía de Señalización Wnt/genética , beta Catenina/metabolismo , Animales , Autoantígenos/metabolismo , Línea Celular Tumoral , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular , Técnicas de Silenciamiento del Gen , Glucógeno Sintasa Quinasa 3 beta/genética , Humanos , Melanoma/metabolismo , Ratones , Trasplante de Neoplasias , Complejo de la Endopetidasa Proteasomal/metabolismo , ARN Mensajero/metabolismo , ARN Interferente Pequeño , beta Catenina/genética
3.
Anal Bioanal Chem ; 409(19): 4637-4646, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28573318

RESUMEN

A new fluorescent probe, 6-amino-1,3-naphthalenedisulfonic acid (ANDSA), has been developed for the determination of trace nitrite in different waters. This probe is based on the selective reaction of nitrite with ANDSA in hydrochloric acid solution to form the corresponding diazonium acid in sodium hydroxide solution at room temperature. The diazonium acid produced has high fluorescence intensity at 488 nm (excitation at 367 nm), whereas ANDSA has high fluorescence intensity at 465 nm (excitation at 354 nm). The synchronous fluorescence (Δλ = 121 nm) spectrum and the first-derivative synchronous fluorescence spectrum of diazonium acid greatly overlapped with those of ANDSA. The zero-crossing method was used to measure the first-derivative value (dF/dλ) of the first-derivative spectra, in which physical separation of excess ANDSA was unnecessary. The zero-crossing point was located at 351.2 nm for ANDSA, at which dF/dλ of diazonium acid was proportional to the nitrite concentration. Therefore, dF/dλ at 351.2 nm was selected as the analytical signal. Under the optimized experimental conditions, the signal intensity was linear over a nitrite concentration range of 0.006-0.075 mg L-1, with a correlation coefficient better than 0.9994. The limit of detection was 2.1 µg L-1 for the determination of nitrite by the proposed method. The relative standard deviation of the method for the determination of nitrite in real water samples was below 2.45%, and the corresponding recoveries were between 95.7% and 104.1%. The validity of the proposed method was further confirmed by comparison with the reference method with use of the t test. Graphical abstract ANDSA reacts with nitrite to form diazonium acid with higher fluorescence intensity. For ANDSA, dF/dλ was zero at 351.2 nm, whereas dF/dλ of diazonium acid at 351.2 nm was close to the maximum value.

4.
Proc Natl Acad Sci U S A ; 110(27): 11005-10, 2013 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-23766372

RESUMEN

Our recent studies suggest a role for the proteasome activator REG (11S regulatory particles, 28-kDa proteasome activator)γ in the regulation of tumor protein 53 (p53). However, the molecular details and in vivo biological significance of REGγ-p53 interplay remain elusive. Here, we demonstrate that REGγ-deficient mice develop premature aging phenotypes that are associated with abnormal accumulation of casein kinase (CK) 1δ and p53. Antibody array analysis led us to identify CK1δ as a direct target of REGγ. Silencing CK1δ or inhibition of CK1δ activity prevented decay of murine double minute (Mdm)2. Interestingly, a massive increase of p53 in REGγ(-/-) tissues is associated with reduced Mdm2 protein levels despite that Mdm2 transcription is enhanced. Allelic p53 haplodeficiency in REGγ-deficient mice attenuated premature aging features. Furthermore, introducing exogenous Mdm2 to REGγ(-/-) MEFs significantly rescues the phenotype of cellular senescence, thereby establishing a REGγ-CK1-Mdm2-p53 regulatory pathway. Given the conflicting evidence regarding the "antiaging" and "proaging" effects of p53, our results indicate a key role for CK1δ-Mdm2-p53 regulation in the cellular aging process. These findings reveal a unique model that mimics acquired aging in mammals and indicates that modulating the activity of the REGγ-proteasome may be an approach for intervention in aging-associated disorders.


Asunto(s)
Envejecimiento Prematuro/etiología , Envejecimiento Prematuro/metabolismo , Quinasa Idelta de la Caseína/metabolismo , Complejo de la Endopetidasa Proteasomal/deficiencia , Envejecimiento Prematuro/patología , Animales , Autoantígenos/genética , Femenino , Genes p53 , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Complejo de la Endopetidasa Proteasomal/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Piel/metabolismo , Piel/patología , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
5.
Artículo en Inglés | MEDLINE | ID: mdl-38268436

RESUMEN

Considering the differences between individuals, in this paper, an uncertainty analysis model for predicting rupture risk of atherosclerotic arteries is established based on a back-propagation artificial neural network. The influence of isotropy and anisotropy on the rupture risk of atherosclerotic arteries is analyzed, and the results demonstrate the effectiveness of the artificial neural network in predicting the rupture risk. Moreover, the rupture risk of atherosclerotic arteries at different inflation sizes are simulated. This study contributes to a better understanding of the underlying mechanisms of atherosclerotic arteries rupture and promotes the advancement of artificial neural networks in atherosclerosis research.

6.
Artículo en Inglés | MEDLINE | ID: mdl-38733532

RESUMEN

Soft biological tissues, such as arterial tissue, have the ability to grow and remodel in response to damage. Computational method plays a critical role in understanding the underlying mechanisms of tissue damage and healing. However, the existing healing model often requires huge computation time and it is inconvenient to implement finite element simulation. In this paper, we propose a computationally efficient gradient-enhanced healing model that combines the advantages of the gradient-enhanced damage model, the homeostatic-driven turnover remodeling model, and the damage-induced growth model. In the proposed model, the evolution of healing-related parameters can be solved explicitly. Additionally, an adaptive time increment method is used to further reduce computation time. The proposed model can be easily implemented in Abaqus, requiring only a user subroutine UMAT. The effectiveness of proposed model is verified through a semi-analytical example, and the influence of the variables in the proposed model is investigated using uniaxial tension and open-hole plate tests. Finally, the long-term development of aneurysms is simulated to demonstrate the potential applications of the proposed model in real biomechanical problems.

7.
Biomed Pharmacother ; 171: 116176, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38242038

RESUMEN

Depression is a prevalent and debilitating psychiatric illness. However, the antidepressant drugs currently prescribed are only effective in a limited group of patients. Histone modifications mediated by histone acetylation are considered to play an important role in the pathogenesis and treatment of depression. Recent studies have revealed that histone deacetylase inhibitors may be involved in the pathogenesis of depression and the underlying mechanism of the antidepressant therapeutic action. Here, we first conducted virtual screening of histone deacetylase-5 (HDAC5) inhibitors against HDAC5, a target closely related to depression, and identified compound T2943, further verifying its inhibitory effect on enzyme activities in vitro. After stereotaxic injection of T2943 into the hippocampus of mice, the antidepressant effect of T2943 was evaluated using behavioral experiments. We also used different proteomic and molecular biology analyses to determine and confirm that T2943 promoted histone 3 lysine 14 acetylation (H3K14ac) by inhibiting HDAC5 activity. Following the overexpression of adenoviral HDAC5 in the hippocampus of mice and subsequent behavioral analyses, we confirmed that T2943 exerts antidepressant effects by inhibiting HDAC5 activity. Our findings highlight the efficacy of targeting HDAC5 to treat depression and demonstrate the potential of using T2943 as an antidepressant.


Asunto(s)
Histonas , Proteómica , Humanos , Antidepresivos/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo
8.
J Transl Med ; 11: 179, 2013 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-23890086

RESUMEN

BACKGROUND: Adipose-derived stromal cells (ADSCs) are a good alternative to multipotent stem cells for regenerative medicine. Low tidal volume (LVT) has proved to be an effective ventilation strategy. However, it is not known if ADSCs and LVT can protect against ventilator-induced lung injury (VILI). This study was aimed to determine the potential of ADSCs and LVT to repair following VILI and to elucidate the mechanisms responsible for this section. METHODS: A total of 72 rats were randomly assigned into group I (sham group, n=18), group II (1 h of high tidal volume-ventilated (HVT) 40 mL/kg to peak airway pressures of approximately 35 cm H2O and 100% oxygen, n=18), group III (1 h of HVT followed by 6 h LVT 6 mL/kg to peak airway pressures of approximately 6 cm H2O and 100% oxygen, n=18) and group IV (1 h of HVT followed by intravenous injection of 5 × 106 ADSCs, n=18). All animals were sacrificed 7 after the experiments lasted for 7 hours. Bronchoalveolar lavage fluid (BALF) was collected and lungs were harvested for analysis. RESULTS: High tidal volume-ventilated (HVT) rats exhibited typical VILI features compared with sham rats. Lung edema, histological lung injury index, concentrations of total protein, total cell counts, number of neutrophils in bronchoalveolar lavage fluid (BALF), tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, IL-10 and transforming growth factor-ß1 in BALF were significantly increased in HVT rats. Additionally, gene and protein levels of Na+ channel subunits, Na-K-ATPase pump activity and alveolar fluid clearance were significantly decreased in HVT rats. All these indices of VILI were significantly improved in rats treated with ADSCs. However, compared with ADSCs treatment, LVT strategy had little therapeutic effect in the present study. CONCLUSION: These results may provide valuable insights into the effects of ADSCs in acute lung injury.


Asunto(s)
Tejido Adiposo/citología , Lesión Pulmonar Inducida por Ventilación Mecánica/terapia , Animales , Biomarcadores/metabolismo , Líquido del Lavado Bronquioalveolar , Diferenciación Celular , Membrana Celular/metabolismo , Forma de la Célula , Quimiocinas/metabolismo , Canales Epiteliales de Sodio/genética , Canales Epiteliales de Sodio/metabolismo , Regulación de la Expresión Génica , Pulmón/enzimología , Pulmón/patología , Pulmón/fisiopatología , Masculino , Infiltración Neutrófila , Ratas Sprague-Dawley , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Células del Estroma/trasplante , Volumen de Ventilación Pulmonar , Trasplante Autólogo , Lesión Pulmonar Inducida por Ventilación Mecánica/fisiopatología
9.
Fish Shellfish Immunol ; 32(5): 645-50, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22281607

RESUMEN

In this study, we explored the pathogenic mechanism of white spot syndrome virus (WSSV) in crayfish, Cherax quadricarinatus, by investigating activities of enzymes related to innate immune function during infection. After 6-12 h of exposure to WSSV, the activities of four enzymes, phenoloxidase (PO), peroxidase (POD), superoxide dismutase (SOD) and lysozyme (LSZ), increased in the gills of C. quadricarinatus but then sharply decreased during longer infection times. Except for PO, the activities of other enzymes in the WSSV-infected crayfish (Group II) were significantly lower than those of the controls at 72 h post-exposure (P < 0.01). Interestingly, the enzyme activities in the group treated with polysaccharides before challenge with WSSV (Group III) were higher than those in Group II. This phenomenon demonstrated that the polysaccharides could improve the immuno-enzyme activities and enhance the organism's antiviral defenses. Morphological examination by transmission electron microscopy revealed abundant WSSV particles and significant damage in the gills of infected crayfish. WSSV infection caused parts of the gill epithelium and microvilli to be reduced in number and size or damaged; meanwhile, the mitochondria morphology changed, with parts of the cristae diminished leaving large vacuoles. Moreover, electron dense deposits appeared and heterochromatinized nuclei could be seen in blood cells with ruptured nuclear membranes and outflow of nucleoplasm. The findings of this study furthers our understanding of the biochemical alterations induced by viral infections, including changes in the antioxidant status, oxidative stress and lysozyme activity, which could help to advance strategies for control of WSSV in crayfish.


Asunto(s)
Astacoidea/inmunología , Astacoidea/virología , Virus del Síndrome de la Mancha Blanca 1/fisiología , Amilosa/farmacología , Animales , Astacoidea/enzimología , Astacoidea/ultraestructura , Branquias/enzimología , Branquias/metabolismo , Branquias/patología , Branquias/ultraestructura , Microscopía Electrónica de Transmisión , Muramidasa/metabolismo , Oxidorreductasas/metabolismo , Reacción en Cadena de la Polimerasa
10.
Int J Numer Method Biomed Eng ; 37(3): e3427, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33301233

RESUMEN

Computational modeling can provide insight into understanding the damage mechanisms of soft biological tissues. Our gradient-enhanced damage model presented in a previous publication has shown advantages in considering the internal length scales and in satisfying mesh independence for simulating damage, growth and remodeling processes. Performing sensitivity analyses for this model is an essential step towards applications involving uncertain patient-specific data. In this paper, a numerical analysis approach is developed. For that we integrate two existing methods, that is, the gradient-enhanced damage model and the surrogate model-based probability analysis. To increase the computational efficiency of the Monte Carlo method in uncertainty propagation for the nonlinear hyperelastic damage analysis, the surrogate model based on Legendre polynomial series is employed to replace the direct FEM solutions, and the sparse grid collocation method (SGCM) is adopted for setting the collocation points to further reduce the computational cost in training the surrogate model. The effectiveness of the proposed approach is illustrated by two numerical examples, including an application of artery dilatation mimicking to the clinical problem of balloon angioplasty.


Asunto(s)
Algoritmos , Humanos , Método de Montecarlo , Incertidumbre
11.
Cell Death Dis ; 12(1): 31, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33414427

RESUMEN

Long noncoding RNAs (lncRNAs) have drawn growing attention owing to their important effects in various tumors, including hepatocellular carcinoma (HCC). Recently, a newly identified lncRNA, ZFPM2 antisense RNA 1 (ZFPM2-AS1), was reported to serve as an oncogene in gastric cancer. However, its function in tumors remains largely unknown. In this study, we identified ZFPM2-AS1 as a novel HCC-related lncRNA, which was observed to be distinctly upregulated in HCC tissues and associated with shorter overall survival. Luciferase reporter and chromatin immunoprecipitation assays suggested that overexpression of ZFPM2-AS1 was induced by STAT1. Functional investigations suggested that the inhibition of ZFPM2-AS1 suppressed cell proliferation, metastasis, cell cycle progression while accelerated cell apoptosis. Mechanistic studies showed that there were two binding sites of miR-653 within the sequence of ZFPM2-AS1 and the levels of ZFPM2-AS1 were negatively correlated with miR-653. In addition, ZFPM2-AS1 could reverse the suppressor effects of miR-653 on the proliferation and metastasis of HCC cells by the modulation of GOLM1, a target gene of miR-653. To conclude, we provided a better understanding of the interaction mechanism between ZFPM2-AS-miR-653-GOLM1 axis, which may help develop prognostic biomarkers and therapeutic target for HCC.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Proteínas de Unión al ADN/metabolismo , Neoplasias Hepáticas/metabolismo , ARN Largo no Codificante/fisiología , Factor de Transcripción STAT1/metabolismo , Factores de Transcripción/metabolismo , Anciano , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/metabolismo , Persona de Mediana Edad
12.
World J Diabetes ; 12(1): 84-97, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33520110

RESUMEN

BACKGROUND: The efficacy of novel glucose-lowering drugs in treating non-alcoholic fatty liver disease (NAFLD) is unknown. AIM: To evaluate the efficacy of glucose-lowering drugs dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors in treating NAFLD and to perform a comparison between these treatments. METHODS: Electronic databases were systematically searched. The inclusion criteria were: Randomized controlled trials comparing DPP-4 inhibitors, GLP-1 RAs, or SGLT2 inhibitors against placebo or other active glucose-lowering drugs in NAFLD patients, with outcomes of changes in liver enzyme [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] from baseline. RESULTS: Nineteen studies were finally included in this meta-analysis. Compared with placebo or other active glucose-lowering drug treatment, treatment with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors all led to a significant decrease in ALT change and AST change from baseline. The difference between the DPP-4 inhibitor and SGLT2 inhibitor groups in ALT change was significant in favor of DPP-4 inhibitor treatment (P < 0.05). The trends of reduction in magnetic resonance imaging proton density fat fraction and visceral fat area changes were also observed in all the novel glucose-lowering agent treatment groups. CONCLUSION: Treatment with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors resulted in improvements in serum ALT and AST levels and body fat composition, indicating a beneficial effect in improving liver injury and reducing liver fat in NAFLD patients.

13.
Zhonghua Nei Ke Za Zhi ; 49(1): 14-8, 2010 Jan.
Artículo en Zh | MEDLINE | ID: mdl-20356474

RESUMEN

OBJECTIVE: To investigate the possibility and utility of metformin alone or in combination with fosinopril to reduce blood pressure in patients with essential hypertension. METHODS: A total of 140 cases of non-diabetic essential hypertension with hyperinsulinemia were recruited and randomly assigned to two groups: a group of 68 treated with metformin 500 mg tid and a group of 72 treated with fosinopril 10 mg qd. The duration of the treatment was 8 weeks. Combination therapy with the two drugs was used after 4 weeks of treatment if needed. If the target goals of systolic blood pressure (SBP) < 140 mm Hg (1 mm Hg = 0.133 kPa) and/or diastolic blood pressure (DBP) < 90 mm Hg were not attained 4 weeks, combination therapy with two drugs was used in either group in the next 4 weeks. The changes of blood pressure and insulin sensitivity of the two groups were observed before and after treatment. RESULTS: (1) After 4 weeks of treatment, SBP in metformin group and fosinopril group decreased by (13.0 +/- 1.2) mm Hg and (15.4 +/- 1.4) mm Hg, and DBP decreased by (9.0 +/- 1.0) mm Hg and (10.4 +/- 1.1) mm Hg respectively. After 8 weeks of treatment, SBP in metformin group and fosinopril group decreased by (17.8 +/- 1.5) mm Hg and (20.9 +/- 1.5) mm Hg, and DBP decreased by (13.2 +/- 0.9) mm Hg and (15.3 +/- 1.1) mm Hg respectively. There was no significant difference in the decline of blood pressure between the two groups (P > 0.05). The rates of combination therapy were both 54% in the two groups. (2) Fasting insulin as well as 30 min and 120 min insulin levels after oral glucose tolerance test and insulin area under the curve in the metformin group were significantly reduced after 4 and 8 weeks of treatment as compared with those of baseline (P < 0.05 and P < 0.01). In the fosinopril group, however, they decreased only after 8 weeks treatment (P < 0.05). The insulin action index in the metformin group was higher than that in the fosinopril group after 4 weeks of treatment (P < 0.05), but there was no significant difference between the two groups after 8 weeks of treatment (P > 0.05). CONCLUSION: Metformin and fosinopril have similar antihypertensive effect and a good synergy in essential hypertension with hyperinsulinemia.


Asunto(s)
Antihipertensivos , Metformina , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Fosinopril , Humanos , Hiperinsulinismo , Metformina/uso terapéutico
14.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(1): 14-19, 2020 Jan.
Artículo en Zh | MEDLINE | ID: mdl-32314719

RESUMEN

Objective To investigate the block effect of amentoflavone (AF) on the inflammation of mouse BV-2 microglial cells induced by lipopolysaccharide (LPS). Methods BV-2 microglial cells were treated with AF at different concentrations, and cell viability was determined by CCK-8 assay to get the AF concentration that had no effect on the cell viability. BV-2 microglia cells were pretreated with 10 mol/L AF, and 1 hour later, 1.0 g/mL LPS was used to induce inflammatory response in the BV-2 microglial cells. Real-time quantitative PCR was performed to detect the gene expression of interleukin 1ß (IL-1ß), tumor necrosis factor α (TNF-α), cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS). The protein expression of COX2 and iNOS were measured by Western blot analysis. Immunofluorescence staining was used to observe the location and expression of COX2 and iNOS. Results CCK-8 showed that 10 mol/L AF did not affect the viability in BV-2 microglial cells. The treatment of 1.0 g/mL LPS could significantly up-regulate the mRNA expression of IL-1ß, TNF-α, COX2, iNOS, and the protein expression of COX2 and iNOS. Compared with the only LPS treatment, 10 mol/L AF pretreatment markedly decreased the elevated gene and protein expression induced by LPS. In addition, AF significantly inhibited the expression of COX2 and iNOS, and less microglial cells were activated. Conclusion AF can inhibit the inflammation of BV-2 microglial cells induced by LPS.


Asunto(s)
Biflavonoides/farmacología , Inflamación , Microglía/efectos de los fármacos , Animales , Línea Celular , Ciclooxigenasa 2/metabolismo , Interleucina-1beta/metabolismo , Lipopolisacáridos , Ratones , Óxido Nítrico Sintasa de Tipo II/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
15.
Oncol Rep ; 44(2): 577-588, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32627006

RESUMEN

Cancer stem cells are responsible for tumorigenesis, progression, recurrence and metastasis. Intestinal stem cells (ISCs) are regarded as the origin of intestinal neoplasia. Inflammation also serves an important role in intestinal neoplasia. To explore the molecular mechanisms underlying the inflammation­mediated induction of intestinal tumorigenesis, the present study investigated the function of tumor necrosis factor (TNF)­α in the malignant transformation of ISCs. NCM460 spheroid (NCM460s) cells with higher expression of stem cell genes, such as Oct4, Nanog, Sox2 and Lgr5, and with a higher ratio of CD133+, were obtained from NCM460 cells in serum­free medium. TNF­α accelerated cell proliferation, migration and invasion, induced chemotherapy resistance and the epithelial­mesenchymal transition. NF­κB and Wnt/ß­catenin pathways were activated in TNF­α­induced inflammatory responses, leading to the nuclear translocation of p65 and ß­catenin, as well as promoter activity of NF­κB and TCF/LEF transcription factors. It was further demonstrated that TNF­α­induced activation of the NF­κB and Wnt/ß­catenin signaling pathways, as well as the upregulation of proinflammatory cytokines, were significantly suppressed by p65­knockdown. Notably, PDTC, an inhibitor of NF­κB signaling, reversed TNF­α­induced activation of the NF­κB and Wnt/ß­catenin pathways. A similar role was observed for IWP­2, an inhibitor of Wnt/ß­catenin signaling. Collectively, these results demonstrated that the NF­κB and Wnt/ß­catenin pathways were activated to promote TNF­α­induced malignant transformation of ISCs, in which these two pathways cross­regulated each other.


Asunto(s)
Células Madre Adultas/patología , Antineoplásicos/farmacología , Transformación Celular Neoplásica/patología , Neoplasias Intestinales/patología , Factor de Necrosis Tumoral alfa/metabolismo , Antineoplásicos/uso terapéutico , Benzotiazoles/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal/inmunología , Técnicas de Silenciamiento del Gen , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/patología , Neoplasias Intestinales/tratamiento farmacológico , Neoplasias Intestinales/inmunología , Prolina/análogos & derivados , Prolina/farmacología , Esferoides Celulares , Tiocarbamatos/farmacología , Factor de Transcripción ReIA/antagonistas & inhibidores , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Regulación hacia Arriba , Vía de Señalización Wnt/efectos de los fármacos , Vía de Señalización Wnt/inmunología
16.
J R Soc Interface ; 17(162): 20190708, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31964269

RESUMEN

Healing of soft biological tissues is the process of self-recovery or self-repair after injury or damage to the extracellular matrix (ECM). In this work, we assume that healing is a stress-driven process, which works at recovering a homeostatic stress metric in the tissue by replacing the damaged ECM with a new undamaged one. For that, a gradient-enhanced continuum healing model is developed for three-dimensional anisotropic tissues using the modified anisotropic Holzapfel-Gasser-Ogden constitutive model. An adaptive stress-driven approach is proposed for the deposition of new collagen fibres during healing with orientations assigned depending on the principal stress direction. The intrinsic length scales of soft tissues are considered through the gradient-enhanced term, and growth and remodelling are simulated by a constrained-mixture model with temporal homogenization. The proposed model is implemented in the finite-element package Abaqus by means of a user subroutine UEL. Three numerical examples have been achieved to illustrate the performance of the proposed model in simulating the healing process with various damage situations, converging towards stress homeostasis. The orientations of newly deposited collagen fibres and the sensitivity to intrinsic length scales are studied through these examples, showing that both have a significant impact on temporal evolutions of the stress distribution and on the size of the damage region. Applications of the approach to carry out in silico experiments of wound healing are promising and show good agreement with existing experiment results.


Asunto(s)
Modelos Biológicos , Cicatrización de Heridas , Simulación por Computador , Análisis de Elementos Finitos , Estrés Mecánico
17.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(1): 33-41, 2020 Jan.
Artículo en Zh | MEDLINE | ID: mdl-32314722

RESUMEN

Objective To investigate the role of PI3K/AKT pathway in the proliferation of SW620Lgr5+ colon cancer stem cells (CSCs) in inflammatory environment. Methods The expression level of Lgr5 in SW620, SW480, HT29 and HCT116 human colon cancer cells were analyzed by Western blot analysis. SW620 cells were selected to analyze the proportion of Lgr5+ cells by fluorescence activated cell sorting (FACS). The cells were cultured in serum-free medium (SFM) to form spheroid cells. Furthermore, Lgr5+ CSCs were isolated from the spheroid cells by FACS system. The biological characteristics of Lgr5+ CSCs were assessed by the colony formation assay and 5-FU chemotherapy sensitivity assay. The inflammatory microenvironment of Lgr5+ CSCs was established with TNF-α and the optimum conditions of TNF-α were analyzed using CCK-8 assay. CSCs were treated with PI3K/AKT pathway inhibitor MK2206. The experimental cells were divided into a blank control group, MK2206 group, TNF-α group and TNF-α combined with MK2206 group. The cell proliferation and apoptosis of each group were detected by colony formation assay and annexin V-FITC/PI double labeling assay. Finally, Western blot analysis was used to analyze the protein expression of AKT, phospho-AKT(p-AKT), GSK-3ß and p-GSK-3ß. Results The expression of Lgr5 in the SW620 cells was significantly higher than that in the other colon cancer cells. FACS showed 6.9% of SW620 cells were Lgr5+. After cultured in SFM, the proportion of Lgr5+ in SW620 spheroid cells increased to 34.5%. The proliferation ability and drug resistance were significantly enhanced in SW620Lgr5+ CSCs compared with SW620 cells. The treatment of 1 ng/mL TNF-α for 24 hours promoted the most remarkably increase of the viability of SW620Lgr5+ CSCs. Compared with the control group, TNF-α significantly increased the colony forming ability of SW620Lgr5+ CSCs. MK2206 statistically decreased the colony forming ability of SW620Lgr5+ CSCs, and increased its apoptosis rate. In addition, MK2206 significantly decreased the colony forming ability of SW620Lgr5+ CSCs compared with the TNF-α treatment group. TNF-α treatment increased the phosphorylation of AKT and GSK-3ß in SW620Lgr5+ CSCs, but the phosphorylation was inhibited by MK2206. Conclusion TNF-α activates PI3K/AKT pathway to promote the proliferation of SW620Lgr5+ CSCs.


Asunto(s)
Neoplasias del Colon/patología , Células Madre Neoplásicas/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/farmacología , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Receptores Acoplados a Proteínas G , Esferoides Celulares , Microambiente Tumoral
18.
Life Sci ; 254: 117655, 2020 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-32277980

RESUMEN

AIMS: There have been recent reports that reconsolidation-based interventions attenuate drug reward memories in rodents. The insular cortex (IC) is an essential part of neural circuits that underlie cue-drug memory reconsolidation. GABAergic interneurons in the IC are a potent control on network excitability and play an important role in the inhibitory mediation of reward circuits. However, the function of GABAergic neurons in the IC for memory reconsolidation remains unclear; therefore, we conducted this study to clarify this. MAIN METHODS: We applied morphine-induced conditioned place preference (mCPP) paradigm and pharmacogenetic techniques to study the mediation effect of GABAergic neurons in the IC on mCPP reconsolidation. Moreover, we preliminarily explored the possible mechanisms of mediating GABAergic neurons in the IC involved in mCPP reconsolidation by assessing Arc and Erg-1 protein levels in the IC. KEY FINDINGS: We found that post-retrieval immediate activation of GABAergic neurons in the IC impaired mCPP reconsolidation. In addition, this effect was not reversed by a priming morphine injection. Further, post-retrieval inhibition and non-retrieval excitation of GABAergic neurons in the IC had no effect on mCPP. SIGNIFICANCE: Taken together, our findings suggest that GABAergic neurons in the IC are closely involved in mCPP reconsolidation. Specifically, their excitation could eliminate established mCPP and prevent the relapse risk by disruption of the reconsolidation. The underlying molecular biological mechanisms could involve reduced Arc and Erg-1 levels.


Asunto(s)
Corteza Cerebral/citología , Señales (Psicología) , Memoria , Morfina/administración & dosificación , Neuronas/metabolismo , Recompensa , Ácido gamma-Aminobutírico/metabolismo , Animales , Masculino , Ratas , Ratas Sprague-Dawley
19.
RSC Adv ; 10(6): 3092-3104, 2020 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-35497733

RESUMEN

Metabolomics is the study of the investigation of small molecules derived from cellular and organism metabolism, which reflects the outcomes of the complex network of biochemical reactions in living systems. As the most recent member of the omics family, there has been notable progress in metabolomics in the last decade, mainly driven by the improvement in mass spectrometry (MS). MS-based metabolomic strategies in modern health and medical science studies provide innovative tools for novel diagnostic and prognostic approaches, as well as an augmented role in drug development, nutrition science, toxicology, and forensic science. In the present review, we not only introduce the application of MS-based metabolomics in the above fields, but also discuss the MS analysis technologies commonly used in metabolomics and the application of metabolomics in precision medicine, and further explore the challenges and perspectives of metabolomics in the field of health and medical science, which are expected to make a little contribution to the better development of metabolomics.

20.
Neurosci Lett ; 728: 134978, 2020 05 29.
Artículo en Inglés | MEDLINE | ID: mdl-32302699

RESUMEN

The steroid hormone 17ß-estradiol (estrogen) exerts neuroprotective effects in several types of neurological disorders including epilepsy. The novel G protein-coupled estrogen receptor 1 (GPER1), also called GPR30, mediates the non-genomic effects of 17ß-estradiol. However, the specific role of GPER1 in status epilepticus (SE) remains unclear. In this report, we evaluated the effects of GPER1 on the hippocampus during SE and the underlying mechanism was studied. Our results revealed that pilocarpine-induced GPER1-KD epileptic rats exhibited a shorter latency to generalized convulsions and strikingly elevated seizure severity. Additionally, the electroencephalographic seizure activity also corresponded to these results. Fast-Fourier analysis indicated an enhancement of power in the theta and alpha bands during SE in GPER1-KD rats. In addition, epilepsy-induced pathological changes were dramatically exacerbated in GPER1-KD rats, including neuron damage and neuroinflammation in hippocampus. GPER1 might be associated with the susceptibility to and severity of epileptic seizures. In summary, our results suggested that GPER1 plays a neuroprotective role in SE, and might be a candidate target for epilepsy therapy.


Asunto(s)
Hipocampo/metabolismo , Receptores de Estrógenos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Estado Epiléptico/metabolismo , Animales , Electroencefalografía , Estradiol/farmacología , Estrógenos/metabolismo , Estrógenos/farmacología , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/efectos de los fármacos , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológico
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