RESUMEN
Centenarians (CENs) are excellent subjects to study the mechanisms of human longevity and healthy aging. Here, we analyzed the transcriptomes of 76 centenarians, 54 centenarian-children, and 41 spouses of centenarian-children by RNA sequencing and found that, among the significantly differentially expressed genes (SDEGs) exhibited by CENs, the autophagy-lysosomal pathway is significantly up-regulated. Overexpression of several genes from this pathway, CTSB, ATP6V0C, ATG4D, and WIPI1, could promote autophagy and delay senescence in cultured IMR-90 cells, while overexpression of the Drosophila homolog of WIPI1, Atg18a, extended the life span in transgenic flies. Interestingly, the enhanced autophagy-lysosomal activity could be partially passed on to their offspring, as manifested by their higher levels of both autophagy-encoding genes and serum beclin 1 (BECN1). In light of the normal age-related decline of autophagy-lysosomal functions, these findings provide a compelling explanation for achieving longevity in, at least, female CENs, given the gender bias in our collected samples, and suggest that the enhanced waste-cleaning activity via autophagy may serve as a conserved mechanism to prolong the life span from Drosophila to humans.
Asunto(s)
Autofagia/genética , Longevidad/genética , Transcriptoma , Anciano , Anciano de 80 o más Años , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Beclina-1/genética , Beclina-1/metabolismo , Catepsina B/genética , Catepsina B/metabolismo , Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/metabolismo , Femenino , Humanos , Lisosomas/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , ATPasas de Translocación de Protón Vacuolares/genética , ATPasas de Translocación de Protón Vacuolares/metabolismoRESUMEN
In order to evaluate effects of extraction techniques on the physicochemical characteristics and antioxidant activities of kiwifruit polysaccharides (KPS), and further explore KPS as functional food ingredients, both microwave-assisted extraction (MAE) and ultrasonic-assisted extraction (UAE) were optimized for the extraction of KPS. Furthermore, the physicochemical structures and antioxidant activities of KPS extracted by different techniques were investigated. The optimal extraction conditions of UAE and MAE for the extraction of KPS were obtained by response surface methodology. Different extraction techniques significantly affected the contents of uronic acids, molecular weights, molar ratios of constituent monosaccharides, and the degree of esterification of KPS. Results showed that KPS exhibited remarkable DPPH and ABTS radical scavenging activities, and reducing power. The high antioxidant activities observed in KPS extracted by the MAE method (KPS-M) might be partially attributed to its low molecular weight and high content of unmethylated galacturonic acid. Results suggested that the MAE method could be a good potential technique for the extraction of KPS with high antioxidant activity, and KPS could be further explored as functional food ingredients.
Asunto(s)
Actinidia/química , Antioxidantes/química , Antioxidantes/farmacología , Frutas/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Polisacáridos/química , Polisacáridos/farmacología , Fraccionamiento Químico/métodos , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Microondas , Peso Molecular , Monosacáridos/química , Fitoquímicos/química , Espectroscopía Infrarroja por Transformada de Fourier , Ondas UltrasónicasRESUMEN
Background: Some observational studies and clinical experiments suggest a close association between gut microbiota and metabolic diseases. However, the causal effects of gut microbiota on adrenal diseases, including Adrenocortical insufficiency, Cushing syndrome, and Hyperaldosteronism, remain unclear. Methods: This study conducted a two-sample Mendelian randomization analysis using summary statistics data of gut microbiota from a large-scale genome-wide association study conducted by the MiBioGen Consortium. Summary statistics data for the three adrenal diseases were obtained from the FinnGen study. The study employed Inverse variance weighting, MR-Egger, and MR-PRESSO methods to assess the causal relationship between gut microbiota and these three adrenal diseases. Additionally, a reverse Mendelian randomization analysis was performed for bacteria found to have a causal relationship with these three adrenal diseases in the forward Mendelian randomization analysis. Cochran's Q statistic was used to test for heterogeneity of instrumental variables. Results: The IVW test results demonstrate that class Deltaproteobacteria, Family Desulfovibrionaceae, and Order Desulfovibrionales exhibit protective effects against adrenocortical insufficiency. Conversely, Family Porphyromonadaceae, Genus Lachnoclostridium, and Order MollicutesRF9 are associated with an increased risk of adrenocortical insufficiency. Additionally, Family Acidaminococcaceae confers a certain level of protection against Cushing syndrome. In contrast, Class Methanobacteria, Family Lactobacillaceae, Family Methanobacteriaceae, Genus. Lactobacillus and Order Methanobacteriales are protective against Hyperaldosteronism. Conversely, Genus Parasutterella, Genus Peptococcus, and Genus Veillonella are identified as risk factors for Hyperaldosteronism. Conclusions: This two-sample Mendelian randomization analysis revealed a causal relationship between microbial taxa such as Deltaproteobacteria and Desulfovibrionaceae and Adrenocortical insufficiency, Cushing syndrome, and Hyperaldosteronism. These findings offer new avenues for comprehending the development of adrenal diseases mediated by gut microbiota.
Asunto(s)
Microbioma Gastrointestinal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Humanos , Microbioma Gastrointestinal/genética , Enfermedades de las Glándulas Suprarrenales/microbiología , Enfermedades de las Glándulas Suprarrenales/genética , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Hiperaldosteronismo/genética , Hiperaldosteronismo/microbiología , Síndrome de Cushing/microbiología , Síndrome de Cushing/genética , Insuficiencia Suprarrenal/microbiologíaRESUMEN
Cancer cells can evade immune elimination by activating immunosuppressive signaling pathways in the tumor microenvironment (TME). Targeting immunosuppressive signaling pathways to promote antitumor immunity has become an attractive strategy for cancer therapy. Aurora-A is a well-known oncoprotein that plays a critical role in tumor progression, and its inhibition is considered a promising strategy for treating cancers. However, targeting Aurora-A has not yet got a breakthrough in clinical trials. Recent reports have indicated that inhibition of oncoproteins may reduce antitumor immunity, but the role of tumor-intrinsic Aurora-A in regulating antitumor immunity remains unclear. In this study, we demonstrated that in tumors with high lymphocyte infiltration (hot tumors), higher tumor-intrinsic Aurora-A expression is associated with a better prognosis in CRC patients. Mechanically, tumor-intrinsic Aurora-A promotes the cytotoxic activity of CD8+ T cells in immune hot CRC via negatively regulating interleukin-16 (IL-16), and the upregulation of IL-16 may impair the therapeutic effect of Aurora-A inhibition. Consequently, combination treatment with IL-16 neutralization improves the therapeutic response to Aurora-A inhibitors in immune hot CRC tumors. Our study provides evidence that tumor-intrinsic Aurora-A contributes to anti-tumor immunity depending on the status of lymphocyte infiltration, highlighting the importance of considering this aspect in cancer therapy targeting Aurora-A. Importantly, our results suggest that combining Aurora-A inhibitors with IL-16-neutralizing antibodies may represent a novel and effective approach for cancer therapy, particularly in tumors with high levels of lymphocyte infiltration.
Asunto(s)
Antineoplásicos , Neoplasias Colorrectales , Humanos , Linfocitos T CD8-positivos , Interleucina-16 , Transducción de Señal , Inmunosupresores , Neoplasias Colorrectales/patología , Microambiente TumoralRESUMEN
The nucleolar 58-kDa microspherule protein (MSP58) protein is a candidate oncogene implicated in modulating cellular proliferation and malignant transformation. In this study, we show that knocking down MSP58 expression caused aneuploidy and led to apoptosis, whereas ectopic expression of MSP58 regulated cell proliferation in a context-dependent manner. Specifically, ectopic expression of MSP58 in normal human IMR90 and Hs68 diploid fibroblasts, the H184B5F5/M10 mammary epithelial cell line, HT1080 fibrosarcoma cells, primary mouse embryonic fibroblasts, and immortalized NIH3T3 fibroblasts resulted in induction of premature senescence, an enlarged and flattened cellular morphology, and increased senescence-associated ß-galactosidase activity. MSP58-driven senescence was strictly dependent on the presence of functional p53 as revealed by the fact that normal cells with p53 knockdown by specific shRNA or cells with a mutated or functionally impaired p53 pathway were effective in bypassing MSP58-induced senescence. At least two senescence mechanisms are induced by MSP58. First, MSP58 activates the DNA damage response and p53/p21 signaling pathways. Second, MSP58, p53, and the SWI/SNF chromatin-remodeling subunit Brahma-related gene 1 (BRG1) form a ternary complex on the p21 promoter and collaborate to activate p21. Additionally, MSP58 protein levels increased in cells undergoing replicative senescence and stress-induced senescence. Notably, the results of analyzing expression levels of MSP58 between tumors and matched normal tissues showed significant changes (both up- and down-regulation) in its expression in various types of tumors. Our findings highlight new aspects of MSP58 in modulating cellular senescence and suggest that MSP58 has both oncogenic and tumor-suppressive properties.
Asunto(s)
Senescencia Celular/fisiología , ADN Helicasas/metabolismo , Proteínas Nucleares/metabolismo , Proteína Oncogénica p21(ras)/metabolismo , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis/fisiología , División Celular/fisiología , Línea Celular Transformada , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Daño del ADN/fisiología , ADN Helicasas/genética , Fibrosarcoma , Regulación Neoplásica de la Expresión Génica/fisiología , Técnicas de Silenciamiento del Gen , Humanos , Glándulas Mamarias Humanas/citología , Glándulas Mamarias Humanas/fisiología , Ratones , Células 3T3 NIH , Proteínas Nucleares/genética , Proteínas de Unión al ARN/genética , Transducción de Señal/fisiología , Estrés Fisiológico/fisiología , Factores de Transcripción/genéticaRESUMEN
BACKGROUND & AIMS: Constitutive activation of NF-κB is an important event involved in chronic inflammation in hepatocellular carcinoma (HCC). CPAP, which plays important roles in centrosomal functions, was previously identified as the transcriptional co-activator of NF-κB. However, the molecular mechanism is unclear. The goal of this study was to investigate the role of CPAP in activating the NF-κB pathway in HCC. METHODS: SK-Hep1, HuH7, HepG2, HepG2X, Hep3B, and Hep3BX cells with CPAP overexpression or CPAP siRNA were used to evaluate activation of NF-κB under TNF-α stimulation by reporter assay, RT-PCR, Q-PCR, and Western blot analysis. In vivo SUMO modification of CPAP was demonstrated by an in situ PLA assay. Human HCC tissues were used to perform Q-PCR, Western blot, and IHC. RESULTS: CPAP siRNA abolished the interaction between IKKß and NF-κB, whereas overexpression of CPAP enhanced this interaction and finally led to augmented NF-κB activation by increasing the phosphorylation of NF-κB. CPAP could enter nuclei by associating with NF-κB. Furthermore, CPAP was SUMO-1 modified upon TNF-α stimulus, and this is essential for its NF-κB co-activator activity. SUMO-1-deficient CPAP mutant lost its NF-κB co-activator activity and failed to enter nuclei. Importantly, SUMOylated CPAP could synergistically increase the HBx-induced NF-κB activity. CONCLUSIONS: CPAP is essential for the recruitment of the IKK complex to inactivated NF-κB upon TNF-α treatment. Expression of CPAP was positively correlated with a poor prognosis in HBV-HCC. CPAP has the potential to serve as a therapeutic target for inflammation and inflammation-related diseases.
Asunto(s)
Carcinoma Hepatocelular/etiología , Quinasa I-kappa B/fisiología , Neoplasias Hepáticas/etiología , Proteínas Asociadas a Microtúbulos/fisiología , FN-kappa B/fisiología , Transducción de Señal/fisiología , Sumoilación , Transactivadores/fisiología , Carcinoma Hepatocelular/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Neoplasias Hepáticas/metabolismo , Inhibidor NF-kappaB alfa , Fosforilación , Proteína SUMO-1/fisiología , Factor de Necrosis Tumoral alfa/farmacología , Proteínas Reguladoras y Accesorias ViralesRESUMEN
Sour bamboo shoot is a traditional Chinese fermented vegetable food. The traditional pickling method of sour bamboo shoots has the disadvantages of being time-consuming, inhomogeneous, and difficult to control. Pulsed vacuum pressure pickling (PVPP) technology uses pulsed vacuum pressure to enhance the pickling efficiency significantly. To demonstrate the effects of salt content and PVPP technical parameters on the fermentation of bamboo shoots, the sample salinity, pH value, color, crunchiness and chewiness, nitrite content, and lactic acid bacteria content during the pickling process were investigated. The salt content inside the bamboo shoots gradually increased to the equilibrium point during the pickling process. The pickling efficiency of bamboo shoots under PVPP technology increased by 34.1% compared to the traditional control groups. Meanwhile, the uniform salt distribution under PVPP technology also obtained better performance in comparison with the traditional groups. The pH value declined slowly from 5.96 to 3.70 with the extension of pickling time and sour flavor accumulated progressively. No significant differences were found in the color values (L *, a *, and b *) and the crunchiness of the bamboo shoot under different salt solution concentrations, vacuum pressure, and pulsation frequency ratio conditions. Colony-forming unit of lactic acid bacteria (CFU of LAB) decreased, to begin with, and then increased until the 6th day, followed by a declining trend in volatility. The nitrate content of bamboo shoots samples under PVPP treatments did not exceed the safety standard (<20 mg/kg) during the whole fermentation process, which proves the safety of PVPP technology. In conclusion, PVPP technology can safely replace the traditional method with better quality performance. The optimal PVPP processing conditions (vacuum pressure 60 kPa, 10 min vacuum pressure time vs. 4 min atmospheric pressure time, salt solution concentration 6%) have been recommended for pickling bamboo shoots with high product quality.
RESUMEN
Osteoporosis is a clinically prevalent comorbidity in patients with hemophilia. A preventive effect of kefir peptides (KPs) on postmenopausal osteoporosis has been proved. The aim of this study was to evaluate the therapeutic effect of KPs for the treatment of osteoporosis in coagulation factor VIII (FVIII) gene knockout mice (F8KO), a model of hemophilia A. In this study, male F8KO mice at 20 weeks of age were orally administered different doses of KPs for 8 weeks. The therapeutic effects of KPs were shown in the femoral trabeculae and the 4th lumbar vertebrae, which increased the trabecular bone mineral density (BMD), bone volume (Tb.BV/TV), and trabecular number (Tb.N) and decreased the trabecular separation (Tb.Sp), and they were also observed in the femoral cortical bones, in which the mechanical properties were enhanced in a dose-dependent manner. Characterization of receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and interleukin 6 (IL-6) demonstrated that the serum RANKL/OPG ratio and IL-6 levels were significantly decreased in the F8KO mice after the KP treatment. Tartrate-resistant acid phosphatase (TRAP) staining of mature osteoclasts indicated that the therapeutic effect of KPs in F8KO mice was associated with the functions of KPs to inhibit RANKL-induced osteoclastogenesis by reducing serum RANKL/OPG ratio and IL-6 secretion. The present study is the first to address the potentials of KPs for the treatment of hemophilia-induced osteoporosis in mice and it also provides useful information for the application of KPs as a complementary therapy for the treatment of osteoporosis in hemophilic patients.
RESUMEN
Chronic and persistent inflammation is a well-known carcinogenesis promoter. Hepatocellular carcinoma (HCC) is one of the most common inflammation-associated cancers; most HCCs arise in the setting of chronic inflammation and hepatic injury. Both NF-κB and STAT3 are important regulators of inflammation. Centrosomal P4.1-associated protein (CPAP), a centrosomal protein that participates primarily in centrosome functions, is overexpressed in HCC and can increase TNF-α-mediated NF-κB activation and IL-6-induced STAT3 activation. A transgenic (Tg) mouse model with hepatocyte-specific CPAP expression was established to investigate the physiological role of CPAP in hepatocarcinogenesis. Obvious inflammatory cell accumulation and fatty change were observed in the livers of CPAP Tg mice. The alanine aminotransferase (ALT) level and the expression levels of inflammatory genes, such as IL-6, IL-1ß and TNF-α, were higher in CPAP Tg mice than in wild type (WT) mice. High-dose/short-term treatment with diethylnitrosamine (DEN) increased the ALT level, proinflammatory gene expression levels, and STAT3 and NF-κB activation in CPAP Tg mice; low-dose/long-term DEN treatment induced more severe liver tumor formation in CPAP Tg mice than in WT mice. CPAP can increase the expression of chemokine (C-C motif) ligand 16 (CCL-16), an important chemotactic cytokine, in human hepatocytes. CCL-16 expression is positively correlated with CPAP and TNF-α mRNA expression in the peritumoral part of HCC. In summary, these results suggest that CPAP may promote hepatocarcinogenesis through enhancing the inflammation pathway via increasing the expression of CCL-16.
Asunto(s)
Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/fisiopatología , Hepatocitos/inmunología , Inflamación/etiología , Neoplasias Hepáticas/etiología , Proteínas Asociadas a Microtúbulos/efectos adversos , Animales , Enfermedad Crónica , Humanos , Inflamación/fisiopatología , Neoplasias Hepáticas/fisiopatología , RatonesRESUMEN
The Atlantic sea nettle ( Chrysaora quinquecirrha) has an important evolutionary position due to its high ecological value. However, due to limited sequencing technologies and complex jellyfish genomic sequences, the current C. quinquecirrha genome assembly is highly fragmented. Here, we used the most advanced high-throughput chromosome conformation capture (Hi-C) technology to obtain high-coverage sequencing data of the C. quinquecirrha genome. We then anchored these data to the previously published contig-level assembly to improve the genome. Finally, a high-continuity genome sequence of C. quinquecirrha was successfully assembled, which contained 1 882 scaffolds with a N50 length of 3.83 Mb. The N50 length of the genome assembly was 5.23 times longer than the previously released one, and additional analysis revealed that it had a high degree of genomic continuity and accuracy. Acquisition of the high-continuity genome sequence of C. quinquecirrha not only provides a basis for the study of jellyfish evolution through comparative genomics but also provides an important resource for studies on jellyfish growth and development.
Asunto(s)
Genoma , Escifozoos/genética , Animales , Evolución Biológica , Análisis de Secuencia de ADN/métodosRESUMEN
Abnormal expression of Aurora-A and epidermal growth factor receptor (EGFR) is observed in different kinds of cancer and associated with poor prognosis in cancer patients. However, the relationship between Aurora-A and EGFR in tumour development was not clear. In previous reports, we found that EGFR translocates to nucleus to activate Aurora-A expression after EGF treatment in EGFR-overexpressed cells. However, we also observed that not all the EGFR-overexpressed cells have the nuclear EGFR pathway to mediate the Aurora-A expression. In this study, we demonstrated that EGF signalling increased the Aurora-A protein expression in EGFR-overexpressed colorectal cancer cell lines via increasing the translational efficiency. In addition, the overexpression of EGFR was also associated with higher expression of Aurora-A in clinical colorectal samples. Activation of the PI3K/Akt/mTOR and MEK/ERK pathways mediated the effect of EGF-induced translational up-regulation. Besides, only the splicing variants containing exon 2 of Aurora-A mRNA showed increased interaction with the translational complex to synthesize Aurora-A protein under EGF stimulus. Besides, the exon 2 containing splicing variants were the major Aurora-A splicing forms expressed in human colorectal cancers. Taken together, our results propose a novel regulatory mechanism for the abnormal expression of Aurora-A in EGFR-overexpressed cancers, and highlight the importance of alternative 5'-UTR splicing variants in regulating Aurora-A expression. Furthermore, the specific expression of exon 2 containing splicing variants in cancer tissues may serve as a potential target for cancer therapy in the future.
Asunto(s)
Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Receptores ErbB/metabolismo , Biosíntesis de Proteínas , Proteínas Serina-Treonina Quinasas/genética , Regulación hacia Arriba/genética , Regiones no Traducidas 5'/genética , Empalme Alternativo/genética , Aurora Quinasas , Línea Celular Tumoral , Neoplasias Colorrectales/patología , Activación Enzimática/efectos de los fármacos , Factor de Crecimiento Epidérmico/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ribosomas/efectos de los fármacos , Ribosomas/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Centrosomal P4.1-associated protein (CPAP) is overexpressed in hepatocellular carcinoma (HCC) and positively correlated with recurrence and vascular invasion. Here, we found that CPAP plays an important role in HCC malignancies. Functional characterization indicated that CPAP overexpression increases tumor growth, angiogenesis, and metastasis ex vivo and in vivo. In addition, overexpressed CPAP contributes to sorafenib resistance. Mechanical investigation showed that the expression level of CPAP is positively correlated with activated STAT3 in HCC. CPAP acts as a transcriptional coactivator of STAT3 by directly binding with STAT3. Interrupting the interaction between CPAP and STAT3 attenuates STAT3-mediated tumor growth and angiogenesis. Overexpression of CPAP upregulates several STAT3 target genes such as IL-8 and CD44 that are involved in angiogenesis, and CPAP mRNA expression is positively correlated with the levels of both mRNAs in HCC. Knocked-down expression of CPAP impairs IL-6-mediated STAT3 activation, target gene expression, cell migration, and invasion abilities. IL-6/STAT3-mediated angiogenesis is significantly increased by CPAP overexpression and can be blocked by decreased expression of IL-8. Our findings not only shed light on the importance of CPAP in HCC malignancies, but also provide potential therapeutic strategies for inhibiting the angiogenesis pathway and treating metastatic HCC.
Asunto(s)
Carcinoma Hepatocelular/irrigación sanguínea , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Neovascularización Patológica/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Receptores de Hialuranos/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Neoplasias Hepáticas/patología , Ratones Endogámicos NOD , Ratones SCID , Metástasis de la Neoplasia , Neovascularización Patológica/genética , Factor de Transcripción STAT3/química , Transducción de Señal , Dominios Homologos srcRESUMEN
Many Aurora-A inhibitors have been developed for cancer therapy; however, the specificity and safety of Aurora-A inhibitors remain uncertain. The Aurora-A mRNA yields nine different 5'-UTR isoforms, which result from mRNA alternative splicing. Interestingly, we found that the exon 2-containing Aurora-A mRNA isoforms are predominantly expressed in cancer cell lines as well as human colorectal cancer tissues, making the Aurora-A mRNA exon 2 a promising treatment target in Aurora-A-overexpressing cancers. In this study, a selective siRNA, siRNA-2, which targets Aurora-A mRNA exon 2, was designed to translationally inhibit the expression of Aurora-A in cancer cells but not normal cells; locked nucleic acid (LNA)-modified siRNA-2 showed improved efficacy in inhibiting Aurora-A mRNA translation and tumor growth. Xenograft animal models combined with noninvasion in vivo imaging system (IVIS) analysis further confirmed the anticancer effect of LNA-siRNA-2 with improved efficiency and safety and reduced side effects. Mice orthotopically injected with colorectal cancer cells, LNA-siRNA-2 treatment not only inhibited the tumor growth but also blocked liver and lung metastasis. The results of our study suggest that LNA-siRNA-2 has the potential to be a novel therapeutic agent for cancer treatment.
Asunto(s)
Aurora Quinasa A/genética , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Isoformas de Proteínas/genética , Regiones no Traducidas 5'/efectos de los fármacos , Empalme Alternativo/genética , Animales , Aurora Quinasa A/antagonistas & inhibidores , Neoplasias Colorrectales/patología , Células HCT116 , Humanos , Ratones , Metástasis de la Neoplasia , Oligonucleótidos/farmacología , Isoformas de Proteínas/antagonistas & inhibidores , ARN Mensajero/genética , ARN Interferente Pequeño/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND AND PURPOSE: Atherosclerosis, resulting from lipid dysregulation and vascular inflammation, causes atherosclerotic cardiovascular disease (ASCVD), which contributes to morbidity and mortality worldwide. Chalcone and its derivatives possess beneficial properties, including anti-inflammatory, antioxidant and antitumour activity with unknown cardioprotective effects. We aimed to develop an effective chalcone derivative with antiatherogenic potential. EXPERIMENTAL APPROACH: Human THP-1 cells and HUVECs were used as in vitro models. Western blots and real-time PCRs were performed to quantify protein, mRNA and miRNA expressions. The cholesterol efflux capacity was assayed by 3 H labelling of cholesterol. LDL receptor knockout (Ldlr-/- ) mice fed a high-fat diet were used as an in vivo atherogenesis model. Haematoxylin and eosin and oil red O staining were used to analyse plaque formation. KEY RESULTS: Using ATP-binding cassette transporter A1 (ABCA1) expression we identified the chalcone derivative, 1m-6, which enhances ABCA1 expression and promotes cholesterol efflux in THP-1 macrophages. Moreover, 1m-6 stabilizes ABCA1 mRNA and suppresses the expression of potential ABCA1-regulating miRNAs through nuclear factor erythroid 2-related factor 2 (Nrf2)/haem oxygenase-1 (HO-1) signalling. Additionally, 1m-6 significantly inhibits TNF-α-induced expression of adhesion molecules, vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), plus production of proinflammatory cytokines via inhibition of JAK/STAT3 activation and the modulation of Nrf2/HO-1 signalling in HUVECs. In atherosclerosis-prone mice, 1m-6 significantly reduces lipid accumulation and atherosclerotic plaque formation. CONCLUSION AND IMPLICATIONS: Our study demonstrates that 1m-6 produces promising atheroprotective effects by enhancing cholesterol efflux and suppressing inflammation-induced endothelial dysfunction, which opens a new avenue for treating ASCVD. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.
Asunto(s)
Aterosclerosis , Chalcona , Chalconas , Transportador 1 de Casete de Unión a ATP/genética , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Chalcona/farmacología , Chalconas/farmacología , Colesterol , Inflamación/tratamiento farmacológico , Ratones , Ratones NoqueadosRESUMEN
Background: Pancreatic adenocarcinoma (PAAD) is an aggressive and invasive tumor with poor prognosis. Identifying prognostic biomarkers of PAAD will provide crucial information for developing treatment plans. Methods: In this analysis, a gene-expression dataset, containing RNA-sequencing data recalculated into transcripts per million, was obtained from the UCSC Xena platform. Three thousand nine hundred and seventy six differentially expressed genes were obtained with analysis of variance. Using these data a co-expression network was constructed using weighted gene co-expression network analysis, from which we obtained eight modules. Results: The blue module included 497 genes and demonstrated significant negative correlation with overall survival. Furthermore, pathway analyses demonstrated the involvement of many of these genes in the tight junction pathway, which plays a critical role in PAAD. In addition, we identified six genes in common (i.e., ANXA2 [annexin A2], EPHA2 [erythropoietin-producing hepatocellular class A2], ITGB4 [integrin beta 4], KRT19 [keratin type I cytoskeletal 19], LGALS3 [galectin-3], and S100A14 [S100 calcium binding protein A14]) between the protein-protein interaction and gene co-expression networks that may have critical functions in PAAD. These hub genes were not only highly expressed at the RNA level but also exhibited high expression in the immunohistological data in the Human Protein Atlas Database. Conclusion: Thus, this research clarified the framework of co-expressed gene modules in PAAD and highlighted potential prognostic biomarkers for the clinical diagnosis of PAAD.
Asunto(s)
Neoplasias Pancreáticas/genética , Uniones Estrechas/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Humanos , Neoplasias Pancreáticas/metabolismo , Pronóstico , ARN/genética , Uniones Estrechas/metabolismo , Transcriptoma/genética , Neoplasias PancreáticasRESUMEN
BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive malignant cancer in the adrenal cortex with poor prognosis. Though previous research has attempted to elucidate the progression of ACC, its molecular mechanism remains poorly understood. METHODS: Gene transcripts per million (TPM) data were downloaded from the UCSC Xena database, which included ACC (The Cancer Genome Atlas, n = 77) and normal samples (Genotype Tissue Expression, n = 128). We used weighted gene co-expression network analysis to identify gene connections. Overall survival (OS) was determined using the univariate Cox model. A protein-protein interaction (PPI) network was constructed by the search tool for the retrieval of interacting genes. RESULTS: To determine the critical genes involved in ACC progression, we obtained 2,953 significantly differentially expressed genes and nine modules. Among them, the blue module demonstrated significant correlation with the "Stage" of ACC. Enrichment analysis revealed that genes in the blue module were mainly enriched in cell division, cell cycle, and DNA replication. Combined with the PPI and co-expression networks, we identified four hub genes (i.e., TOP2A, TTK, CHEK1, and CENPA) that were highly expressed in ACC and negatively correlated with OS. Thus, these identified genes may play important roles in the progression of ACC and serve as potential biomarkers for future diagnosis.
RESUMEN
We report citrate-capped platinum nanoparticles (Pt NPs) as oxidase mimetics for effectively catalyzing the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB), 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid), dopamine, and methylene blue in the presence of O2. To confirm oxidase-like activity of citrate-capped Pt NPs, their activity toward oxygen reduction reaction was studied using cyclic voltammetry and rotating ring-disk electrode method. The results obtained showed that Pt NP NPs can catalyze the oxidation of organic substrates to the colored product and the reduction of oxygen to water through a four-electron exchange process. Because the aggregation of Pt NPs can inhibit their oxidase-like activity and protamine can recognize heparin, we prepared the protamine-modified Pt NPs through direct adsorption on the surface of citrate-capped Pt NPs. The electrostatic attraction between heparin and protamine-stabilized Pt NPs induced nanoparticle aggregation, inhibiting their catalytic activity. Therefore, the lowest detectable heparin concentrations through UV-vis absorption and by the naked eye were estimated to be 0.3 and 60nM, respectively. Moreover, the proposed system enabled the determination of the therapeutic heparin concentration in a single drop of blood.
Asunto(s)
Anticoagulantes/sangre , Ácido Cítrico/química , Colorimetría/métodos , Heparina/sangre , Nanopartículas del Metal/química , Platino (Metal)/química , Adulto , Bencidinas/química , Materiales Biomiméticos/química , Técnicas Biosensibles/métodos , Catálisis , Humanos , Límite de Detección , Masculino , Nanopartículas del Metal/ultraestructura , Oxidación-Reducción , Oxidorreductasas/química , Oxígeno/química , Protaminas/química , Adulto JovenRESUMEN
Most of the previously reported studies have focused on the change in the size, morphology, and composition of metal nanocatalysts for improving their catalytic activity. Herein, we report poly(diallyldimethylammonium chloride) [PDDA]-stabilized nanoparticles (NPs) of platinum (Pt) and palladium (Pd) as highly active and efficient catalysts for hydrogenation of 4-nitrophenol (4-NP) in the presence of NaBH4. PDDA-stabilized Pt and Pd NPs possessed similar particle size and same facet with citrate-capped Pt and Pd NPs, making this study to investigate the inter-relationship between catalytic activity and surface ligand without the consideration of the effects of particle size and facet. Compared to citrate-capped Pt and Pd NPs, PDDA-stabilized Pt and Pd NPs exhibited excellent pH and salt stability. PDDA could serve as an electron acceptor for metal NPs to produce the net positive charges on the metal surface, which provide strong electrostatic attraction with negatively charged nitrophenolate and borohydride ions. The activity parameter and rate constant of PDDA-stabilized metal NPs were higher than those of citrate-capped metal NPs. Compared to the previously reported Pd nanomaterials for the catalysis of NaBH4-mediated reduction of 4-NP, PDDA-stabilized Pd NPs exhibited the extremely high activity parameter (195s-1g-1) and provided excellent scalability and reusability.
RESUMEN
The objective of this research was to investigate the effects of different modified casings and storage time on the quality attributes of cooked sausages using principal component analysis (PCA) and discriminant analysis. The effects of modifying different casing treatments on sausages' color (L* , a* , b* ), pH, and texture (hardness, springiness, cohesion, gumminess, chewiness) after 36-d storage were estimated by PCA. According to the PCA, lightness at day 36 was correlated to sample stuffed in casing with treatment 2 (T2; soy lecithin concentration: 1:27.5, soy oil concentration: 1.25%, lactic acid concentration: 19.5 mL/kg NaCl [solid], residence time: 75 min). T2 sample can be distinguished from control sample at days 1, 8, 15, and 36 according to electronic nose system. DA was performed to determine possible different sample groups according to selected variables. Results showed that chewiness was the best discriminator for differentiating sausages stored for 15 d from other days. Chewiness and gumminess were able to discriminate sausages stuffed in casing with T2 from control sample. The relationships between modified concentrations and quality attributes of cooked sausages after 36-d storage were also established.