RESUMEN
Lung carcinoma is the leading cause of cancer-related death worldwide. Chemotherapy remains the cornerstone of lung cancer treatment. Unfortunately, most types of cancer will develop resistance to chemotherapies over the time. One of the efforts to prevent the chemotherapy resistance is to find alternative chemotherapy drugs. Mogrol has been found to have antitumor activity. However, little is known about the pharmacological mechanisms underlying the suppression of mogrol on lung cancers. In this study, we observed that mogrol exposure significantly reduced the tumor volume and weight in tumor-bearing nude mice without obvious effect on body weight and cardiac function. Mogrol also significantly inhibited the proliferation and migration of lung cancer cells, including non-small-cell lung carcinoma cells, A549, H1299, H1975 and SK-MES-1 cells, with no obvious effect on control human bronchial epithelial cells (HBE). Further studies revealed that mogrol stirred excessive autophagy and autophagic flux, and finally, autophagic cell death, in lung cancer cells, which could be attenuated by autophagy inhibitors, 3-MA and chloroquine. Furthermore, mogrol significantly activated AMPK to induce autophagy and autophagic cell death, which could be abrogated by Compound C, an AMPK inhibitor. In addition, mogrol induced a significant increase in p53 activity in lung cancer cells, accompanied with cell cycle arrest and apoptosis, which could be weakened by p53 silence. Our results indicated that mogrol effectively suppressed lung cancer cells in vivo and in vitro by inducing the excessive autophagy and autophagic cell death via activating AMPK signaling pathway, as well as cell cycle arrest and apoptosis via activating p53 pathway.
Asunto(s)
Muerte Celular Autofágica , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Apoptosis , Autofagia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Pulmón/patología , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Desnudos , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
In hypertrophic hearts, autophagic flux insufficiency is recognized as a key pathology leading to maladaptive cardiac remodeling and heart failure. This study aimed to illuminate the cardioprotective role and mechanisms of a new myokine and adipokine, irisin, in cardiac hypertrophy and remodeling. Adult male wild-type, mouse-FNDC5 (irisin-precursor)-knockout and FNDC5 transgenic mice received 4â¯weeks of transverse aortic constriction (TAC) alone or combined with intraperitoneal injection of chloroquine diphosphate (CQ). Endogenous FNDC5 ablation aggravated and exogenous FNDC5 overexpression attenuated the TAC-induced hypertrophic damage in the heart, which was comparable to the protection of irisin against cardiomyocyte hypertrophy induced by angiotensin II (Ang II) or phenylephrine (PE). Accumulated autophagosome and impaired autophagy flux occurred in the TAC-treated myocardium and Ang II- or PE-insulted cardiomyocytes. Irisin deficiency caused reduced autophagy and aggravated autophagy flux failure, whereas irisin overexpression or supplementation induced protective autophagy and improved autophagy flux, which were reversed by autophagy inhibitors Atg5 siRNA, 3-MA and CQ. Irisin boosted the activity of only AMPK but not Akt and MAPK family members in hypertrophic hearts and cultured cardiomyocytes and further activated ULK1 at Ser555 but not Ser757 and did not affect the mTOR-S6K axis. Blockage of AMPK and ULK1 with compund C and SBI-0206965, respectively, both abrogated irisin's protection against cardiomyocyte hypertrophic injury and reversed its induction of both autophagy and autophagy flux. Our results suggest that irisin protects against pressure overload-induced cardiac hypertrophy by inducing protective autophagy and autophagy flux via activating AMPK-ULK1 signaling.
Asunto(s)
Proteínas Quinasas Activadas por AMP/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Cardiomegalia/genética , Fibronectinas/genética , Insuficiencia Cardíaca/genética , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Angiotensina II/administración & dosificación , Animales , Autofagia/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/antagonistas & inhibidores , Benzamidas/administración & dosificación , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/patología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/patología , Humanos , Ratones , Ratones Transgénicos , Miocitos Cardíacos/efectos de los fármacos , Fenilefrina/administración & dosificación , Presión , Pirimidinas/administración & dosificación , Transducción de Señal , Serina-Treonina Quinasas TOR/genéticaRESUMEN
The paper presents an NP-video rendering system based on natural phenomena. It provides a simple nonphotorealistic video synthesis system in which user can obtain a flow-like stylization painting and infinite video scene. Firstly, based on anisotropic Kuwahara filtering in conjunction with line integral convolution, the phenomena video scene can be rendered to flow-like stylization painting. Secondly, the methods of frame division, patches synthesis, will be used to synthesize infinite playing video. According to selection examples from different natural video texture, our system can generate stylized of flow-like and infinite video scenes. The visual discontinuities between neighbor frames are decreased, and we also preserve feature and details of frames. This rendering system is easy and simple to implement.
Asunto(s)
Grabación en Video/métodos , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
The role of medical image technology in the medical field is becoming more and more obvious. Doctors can use medical image technology to more accurately understand the patient's condition and make accurate judgments and diagnosis and treatment in order to make a large number of medical blurred images clear and easy to identify. Inspired by the human vision system (HVS), we propose a simple and effective method of low-light image enhancement. In the proposed method, first a sampler is used to get the optimal exposure ratio for the camera response model. Then, a generator is used to synthesize dual-exposure images that are well exposed in the regions where the original image is underexposed. Next, the enhanced image is processed by using a part of low-light image enhancement via the illumination map estimation (LIME) algorithm, and the weight matrix of the two images will be determined when fusing. After that, the combiner is used to get the synthesized image with all pixels well exposed, and finally, a postprocessing part is added to make the output image perform better. In the postprocessing part, the best gray range of the image is adjusted, and the image is denoised and recomposed by using the block machine 3-dimensional (BM3D) model. Experiment results show that the proposed method can enhance low-light images with less visual information distortions when compared with those of several recent effective methods. When it is applied in the field of medical images, it is convenient for medical workers to accurately grasp the details and characteristics of medical images and help medical workers analyze and judge the images more conveniently.
Asunto(s)
Aumento de la Imagen , Procesamiento de Imagen Asistido por Computador , Algoritmos , Compuestos de Calcio , Humanos , Aumento de la Imagen/métodos , Procesamiento de Imagen Asistido por Computador/métodos , ÓxidosRESUMEN
BACKGROUND: Liver dysfunction and liver failure are serious complications of sepsis, directly leading to septic progression and death. Now, there is no specific therapeutics available for sepsis-related liver dysfunction. Prim-O-glucosylcimifugin (POG), a chromone richest in the roots of Saposhnikovia divaricata (Turcz.) Schischk, is usually used to treat headache, rheumatoid arthritis and tetanus. While, the underlying mechanisms of POG against sepsis-induced liver damage and dysfunction are still not clear. PURPOSE: To study the anti-sepsis effect of POG, and its pharmacological mechanism to protect liver injury by weakening the function of macrophages in septic livers through inhibiting NOD-like receptor protein 3 (NLRP3) inflammasome pathway. METHOD: In vivo experiments, septic mouse model was induced by cecal ligation and puncture (CLP), and then the mortality was detected, liver inflammatory damages and plasma biomarkers of liver injury were evaluated by histopathological staining and biochemical assays, respectively. In vitro experiments, mouse primary peritoneal macrophages were treated with lipopolysaccharide (LPS) and ATP, and then the activated-inflammasomes, macrophage migration and polarization were detected by ASC immunofluorescence staining, transwell and flow cytometry assays, respectively. NLRP3 inflammasome components NLRP3, caspase-1, IL-1ß and IL-18 protein expressions were detected using western blot assays, and the contents of IL-1ß and IL-18 were measured by ELISA assays. RESULTS: POG treatment significantly decreased the mortality, liver inflammatory damages, hepatocyte apoptosis and plasma biomarkers of liver injury in CLP-challenged male WT mice, which were comparable to those in ibuprofen (a putative anti-inflammatory drug)-supplemented septic male WT mice and septic NLRP3 deficient-male mice. POG supplementation significantly suppressed NLRP3 inflammasome activation in septic liver tissues and cultured macrophages, by significantly reducing NLRP3, cleaved-caspase-1, IL-1ß and IL-18 levels, the activated-inflammasome ASC specks, and macrophage infiltration and migration, as well as M1-like polarization, but significantly increasing M2-like polarization. These findings were similar to the pharmacological effects of ibuprofen, NLRP3 deficiency, and a special NLRP3 inhibitor, MCC950. CONCLUSION: POG protected against sepsis by inhibiting NLRP3 inflammasome-mediated macrophage activation in septic liver and attenuating liver inflammatory injury, indicating that it may be a potential anti-sepsis drug candidate.
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Inflamasomas , Sepsis , Adenosina Trifosfato , Animales , Caspasa 1/metabolismo , Cromonas , Ibuprofeno , Interleucina-18 , Lipopolisacáridos , Hígado/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas NLR , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Sepsis/metabolismoRESUMEN
BACKGROUND: Abnormalities of the L-arginine-nitric oxide pathway induce hypertension. 5-Lipoxygenase (5-LO) is the key enzyme involved in synthesis of leukotrienes (LTs). However, whether nitricoxide synthase dysfunction induces hypertensive vascular remodeling by regulating 5-LO activity and its downstream inflammatory metabolites remains unknown. METHODS AND RESULTS: Six-week L-NAME treatment significantly induced hypertension and vascular remodeling in both wild-type (WT) and 5-LO-knockout (5-LO-KO) mice, and blood pressure in caudal and carotid arteries was lower in 5-LO-KO than WT mice with L-NAME exposure. On histology, L-NAME induced less media thickness, media-to-lumen ratio, and collagen deposition and fewer Ki-67-positive vascular smooth muscle cells (VSMCs) but more elastin expression in thoracic and mesenteric aortas of 5-LO-KO than L-NAME-treated WT mice. L-NAME significantly increased LT content, including LTB4 and cysteinyl LT (CysLTs), in plasma and neutrophil culture supernatants from WT mice. On immunohistochemistry, L-NAME promoted the colocalization of 5-LO and 5-LO-activating protein on the nuclear envelope of cultured neutrophils, which was accompanied by elevated LT content in culture supernatants. In addition, LTs significantly promoted BrdU incorporation, migration and phenotypic modulation in VSMCs. CONCLUSION: L-NAME may activate the 5-LO/LT pathway in immune cells, such as neutrophils, and promote the products of 5-LO metabolites, including LTB4 and CysLTs, which aggravate vascular remodeling in hypertension. 5-LO deficiency may protect against hypertension and vascular remodeling by reducing levels of 5-LO downstream inflammatory metabolites.