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Blood amino acid levels are maintained in a narrow physiological range. The pancreatic α cells have emerged as the primary aminoacidemia regulator through glucagon secretion to promote hepatic amino acid catabolism. Interruption of glucagon signaling disrupts the liver-α cells axis leading to hyperaminoacidemia, which triggers a compensatory rise in glucagon secretion and α cell hyperplasia. The mechanisms of hyperaminoacidemia-induced α cell hyperplasia remain incompletely understood. Using a mouse α cell line and in vivo studies in zebrafish and mice, we found that hyperaminoacidemia-induced α cell hyperplasia requires ErbB3 signaling. In addition to mechanistic target of rapamycin complex 1, another ErbB3 downstream effector signal transducer and activator of transcription 3 also plays a role in α cell hyperplasia. Mechanistically, ErbB3 may partner with ErbB2 to stimulate cyclin D2 and suppress p27 via mechanistic target of rapamycin complex 1 and signal transducer and activator of transcription 3. Our study identifies ErbB3 as a new regulator for hyperaminoacidemia-induced α cell proliferation and a critical component of the liver-α cells axis that regulates aminoacidemia.
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Mitochondria play an integral role in cell death, autophagy, immunity, and inflammation. We previously showed that Nur77, an orphan nuclear receptor, induces apoptosis by targeting mitochondria. Here, we report that celastrol, a potent anti-inflammatory pentacyclic triterpene, binds Nur77 to inhibit inflammation and induce autophagy in a Nur77-dependent manner. Celastrol promotes Nur77 translocation from the nucleus to mitochondria, where it interacts with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase important for inflammatory signaling. The interaction is mediated by an LxxLL motif in TRAF2 and results not only in the inhibition of TRAF2 ubiquitination but also in Lys63-linked Nur77 ubiquitination. Under inflammatory conditions, ubiquitinated Nur77 resides at mitochondria, rendering them sensitive to autophagy, an event involving Nur77 interaction with p62/SQSTM1. Together, our results identify Nur77 as a critical intracellular target for celastrol and unravel a mechanism of Nur77-dependent clearance of inflamed mitochondria to alleviate inflammation.
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Antiinflamatorios/farmacología , Autofagia/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Mitocondrias Hepáticas/efectos de los fármacos , Mitofagia/efectos de los fármacos , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Factor 2 Asociado a Receptor de TNF/metabolismo , Triterpenos/farmacología , Ubiquitinación/efectos de los fármacos , Transporte Activo de Núcleo Celular , Animales , Antiinflamatorios/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Modelos Animales de Enfermedad , Femenino , Genotipo , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Ligandos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias Hepáticas/metabolismo , Mitocondrias Hepáticas/patología , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/deficiencia , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Triterpenos Pentacíclicos , Fenotipo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Interferencia de ARN , Proteína Sequestosoma-1/genética , Proteína Sequestosoma-1/metabolismo , Transducción de Señal/efectos de los fármacos , Factor 2 Asociado a Receptor de TNF/genética , Transfección , Triterpenos/metabolismoRESUMEN
Objectives: Accumulating evidence indicates that the expression and/or variants of several genes play an essential role in the progress of colorectal cancer (CRC). The current study is a meta-analysis undertaken to estimate the prognosis and survival associated with CTNNB1/ß-catenin, APC, Wnt, SMAD3/4, TP53, and Cyclin D1 genes among CRC patients. Methods: The authors searched PubMed, EMBASE, and Science Direct for relevant reports published between 2000 and 2020 and analyzed them to determine any relationship between the (immunohistochemically/sequencing-detected) gene expression and variants of the selected genes and the survival of CRC patients. Results: The analysis included 34,074 patients from 64 studies. To evaluate association, hazard ratios (HRs) were estimated for overall survival (OS) or disease-free survival (DFS), with a 95% confidence interval (CIs). Pooled results showed that ß-catenin overexpression, APC mutation, SMAD-3 or 4 loss of expression, TP53 mutations, and Cyclin D1 expression were associated with shorter OS. ß-Catenin overexpression (HR: 0.137 (95% CI: 0.131-0.406)), loss of expression of SMAD3 or 4 (HR: 0.449 (95% CI: 0.146-0.753)), the mutations of TP53 (HR: 0.179 (95% CI: 0.126-0.485)), and Cyclin D1 expression (HR: 0.485 (95% CI: 0.772-0.198)) also presented risk for shorter DFS. Conclusions: The present meta-analysis indicates that overexpression or underexpression and variants of CTNNB1/ß-catenin, APC, SMAD3/4, TP53, and Cyclin D1 genes potentially acted as unfavorable biomarkers for the prognosis of CRC. The Wnt gene was not associated with prognosis.
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Neoplasias Colorrectales , beta Catenina , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Genes bcl-1 , Humanos , Pronóstico , Proteína smad3/genética , Proteína smad3/metabolismo , Proteína p53 Supresora de Tumor/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
In the present study, a new series of chalcone adamantly arotinoids (chalcone AdArs) derived from RAR antagonist MX781, are synthesized, characterized, and evaluated for the biological activities in vitro. The studies of antiproliferative activity and RXRα-binding affinity of target compounds result in the discovery of a lead candidate (WA15), which is a good RXRα binder (Kd = 2.89 × 10-6 M) with potent antiproliferative activity against human cancer cell lines (IC50 ≈ 10 µM) and low toxic to normal LO2 and MRC-5 cells (IC50 > 50 µM). Different from MX781, WA15 eliminates RARα antagonist activity but inhibits 9-cis-RA-induced RXRα transactivation activity in a dose-dependent manner. Compound WA15 is found to be a good apoptosis inducer in various cancer cells and promotes cell apoptosis in an RXRα-independent manner. Besides, WA15 shows the induction of proteasome-dependent RXRα degradation which might enhance the WA15-induced apoptosis. Finally, the immunoblotting indicates that WA15 can inhibit the TNFα-induced IKK activation and IκBα degradation, suggesting that the anticancer activity of WA15 might be related to the inhibition of IKK/NF-κB signal pathway.
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Antineoplásicos/farmacología , Chalonas/farmacología , Descubrimiento de Drogas , Receptor alfa X Retinoide/antagonistas & inhibidores , Retinoides/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Chalonas/síntesis química , Chalonas/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Receptor alfa X Retinoide/metabolismo , Retinoides/síntesis química , Retinoides/química , Relación Estructura-ActividadRESUMEN
OBJECTIVE: The present study aimed to investigate the molecular events in alisol B 23-acetate (ABA) cytotoxic activity against a liver cancer cell line. METHODS: First, we employed a quantitative proteomics approach based on stable isotope labeling by amino acids in cell culture (SILAC) to identify the different proteins expressed in HepG2 liver cancer cells upon exposure to ABA. Next, bioinformatics analyses through DAVID and STRING on-line tools were used to predict the pathways involved. Finally, we applied functional validation including cell cycle analysis and Western blotting for apoptosis and mTOR pathway-related proteins to confirm the bioinformatics predictions. RESULTS: We identified 330 different proteins with the SILAC-based quantitative proteomics approach. The bioinformatics analysis and the functional validation revealed that the mTOR pathway, ribosome biogenesis, cell cycle, and apoptosis pathways were differentially regulated by ABA. G1 cell cycle arrest, apoptosis and mTOR inhibition were confirmed. CONCLUSIONS: ABA, a potential mTOR inhibitor, induces the disruption of ribosomal biogenesis. It also affects the mTOR-MRP axis to cause G1 cell cycle arrest and finally leads to cancer cell apoptosis.
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Tubeimoside-1 (TBMS1) exerts its anticancer effects by inducing G2/M arrest and apoptosis of cancer cells. However, the precise molecular mechanism of its anti-tumor effects has not been fully elucidated, especially the signaling pathways involved in the early stage of TBMS1 stimulation. In this study, we employed stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomics approach and identified 439 proteins that exhibit significant differential expressions in NCI-H460 lung cancer cells upon exposure to TBMS1. Gene ontology and network analysis using DAVID and STRING on-line tools revealed that several nucleolar stress (ribosomal biogenesis) response proteins were differentially regulated by TBMS1. Functional validation demonstrated that TBMS1-induced NCI-H460 cell cytotoxicity involved nucleolar stress-induced p53/murine double minute clone 2 (MDM2), mTOR, and NF-κB signaling pathways.
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Neoplasias Pulmonares/tratamiento farmacológico , Proteómica , Proteínas Proto-Oncogénicas c-mdm2/genética , Saponinas/administración & dosificación , Triterpenos/administración & dosificación , Proteína p53 Supresora de Tumor/genética , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Nucléolo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , FN-kappa B/genética , Proteínas Ribosómicas/biosíntesis , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Nur77, an immediate-early response gene, participates in a wide range of biological functions. Its human homologue, NUR77, is known by several names and has the HGNC-approved gene symbol NR4A1. However, the role of Nur77 in inflammatory bowel disease (IBD) and its underlying mechanisms remain elusive. Here, using public data from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) on the most recent genome-wide association studies (GWAS) for ulcerative colitis (UC) and Crohn's disease (CD), we found that genetic variants of the NUR77 gene are associated with increased risk for both UC and CD. Accordingly, Nur77 expression was significantly reduced in colon tissues from patients with UC or CD and mice treated with DSS. Nur77 deficiency increased the susceptibility of mice to DSS-induced experimental colitis and prevented intestinal recovery, whereas treatment with cytosporone B (Csn-B), an agonist for Nur77, significantly attenuated excessive inflammatory response in the DSS-induced colitis mouse model. Mechanistically, NUR77 acts as a negative regulator of TLR-IL-1R signalling by interacting with TRAF6. This interaction prevented auto-ubiquitination and oligomerization of TRAF6 and subsequently inhibited NF-κB activation and pro-inflammatory cytokine production. Taken together, our GWAS-based analysis and in vitro and in vivo studies have demonstrated that Nur77 is an important regulator of TRAF6/TLR-IL-1R-initiated inflammatory signalling, and loss of Nur77 may contribute to the development of IBD, suggesting Nur77 as a potential target for the prevention and treatment of IBD.
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Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Receptores de Interleucina-1/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Receptores Toll-Like/metabolismo , Adulto , Anciano , Animales , Colon/metabolismo , Sulfato de Dextran/farmacología , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Ratones , Persona de Mediana Edad , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/antagonistas & inhibidores , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/deficiencia , Fenilacetatos/farmacología , Estudios Prospectivos , Transducción de Señal/fisiologíaRESUMEN
Sperm-associated antigen 9(SPAG9), as a well-recognized oncogene protein, has a critical effect on renal cell carcinoma (RCC) progression. Our study tried to explore the mediator of miR-200a-3p, a tumor suppressing miRNA on SPAG9 expression and renal cell proliferation and apoptosis. We found the expression of miR-200a-3p was significantly lower in RCC specimens. Based on in vitro assays, we found miR-200a-3p significantly inhibit cancer cell proliferation by inducing apoptosis. In addition, our study uncovered that miR-200a-3p directly regulates oncogenic SPAG9 in 786-O and ACHN cells. Silencing of SPAG9 resulted in significantly decreased in the growth and the cell cycle of the renal cancer cell lines. Understanding of oncogenic SPAG9 regulated by miR-200a-3p might be beneficial to reveal new therapeutic targets for RCC.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , MicroARNs/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Apoptosis , Carcinoma de Células Renales/genética , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Renales/genética , MicroARNs/genéticaRESUMEN
In order to find new natural products with anti-inflammatory activity, chemical investigation of a 3000-meter deep-sea sediment derived bacteria Bacillus subtilis B5 was carried out. A new macrolactin derivative was isolated and identified as 7,13-epoxyl-macrolactin A (1). Owing to the existence of the epoxy ring, 1 exhibited a significant inhibitory effect on the expression of inducible nitric oxide and cytokines, compared with previously isolated known macrolactins (2-5). Real-time Polymerase Chain Reaction (PCR) analysis showed that the new compound significantly inhibited the mRNA expressions of inducible nitric oxide synthase (iNOS), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Reverse transcription-PCR analysis demonstrated that the new compound reduced the mRNA expression level of IL-1ß in a concentration-dependent manner.
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Bacillus subtilis/metabolismo , Productos Biológicos/farmacología , Citocinas/antagonistas & inhibidores , Éteres Cíclicos/farmacología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Línea Celular , Citocinas/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Óxido Nítrico Sintasa de Tipo II/metabolismo , ARN Mensajero/metabolismoRESUMEN
OBJECTIVE: To explore the effect of negative emotions on serum levels of adrenocorticotropic hormone (ACTH) and neuropeptide Y (NYP) in hepatitis B liver cirrhosis (HBLC) patients. METHODS: Totally 617 HBLC patients were assigned to the negative emotion group (415 cases) and the non-negative emotion group (202 cases) judged by negative emotions. Case numbers of various grading Child-Pugh were recorded in the two groups. Their liver functions were compared between the two groups. Serum levels of ACTH and NPY were detected using double antibody sandwich enzyme-linked immunosorbent assay (ELISA) in the two groups. RESULTS: There was no statistical difference in Child-Pugh grading between the two groups (χ2 = 0.65, P = 0.72). Compared with the non-negative emotional group, serum ACTH levels decreased significantly in the negative emotion group with statistical difference (P < 0.05). There was no statistical difference in serum ACTH levels between the two groups (P > 0.05). CONCLUSION: The negative emotion of HBLC patients was not related to the serum ACTH level, but to relatively lower-concentration serum NPY levels.
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Hormona Adrenocorticotrópica/sangre , Emociones , Hepatitis B/sangre , Cirrosis Hepática/sangre , Hepatitis B/psicología , Humanos , Cirrosis Hepática/psicología , Neuropéptido Y , SueroRESUMEN
Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.
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Neoplasias Colorrectales , Interleucina-6 , Humanos , Carcinogénesis/metabolismo , Transformación Celular Neoplásica/metabolismo , Neoplasias Colorrectales/patología , Histonas/metabolismo , Interleucina-6/metabolismo , Lactatos/metabolismo , Macrófagos/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Microambiente TumoralRESUMEN
The orphan nuclear receptor Nur77 is an immediate-early response gene whose expression is rapidly induced by various extracellular stimuli. The aims of this study were to study the role of Nur77 expression in the growth and survival of colon cancer cells and the mechanism by which Nur77 expression was regulated. We showed that levels of Nur77 were elevated in a majority of human colon tumors (9/12) compared to their nontumorous tissues and that Nur77 expression could be strongly induced by different colonic carcinogens including deoxycholic acid (DCA). DCA-induced Nur77 expression resulted in up-regulation of antiapoptotic BRE and angiogenic VEGF, and it enhanced the growth, colony formation, and migration of colon cancer cells. In studying the mechanism by which Nur77 was regulated in colon cancer cells, we found that ß-catenin was involved in induction of Nur77 expression through its activation of the transcriptional activity of AP-1 (c-Fos/c-Jun) that bound to and transactivated the Nur77 promoter. Together, our results demonstrate that Nur77 acts to promote the growth and survival of colon cancer cells and serves as an important mediator of the Wnt/ß-catenin and AP-1 signaling pathways.
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Proliferación Celular , Neoplasias del Colon/metabolismo , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , beta Catenina/metabolismo , Animales , Western Blotting , Supervivencia Celular , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Ácido Desoxicólico/toxicidad , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Humanos , Inmunohistoquímica , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Ratones , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Factor de Transcripción AP-1/metabolismo , beta Catenina/genéticaRESUMEN
BACKGROUND: Stomach adenocarcinomas (STAD) are the most common malignancy of the human digestive system and represent the fourth leading cause of cancer-related deaths. As early-stage STAD are generally mild or asymptomatic, patients with advanced STAD have short overall survival. Early diagnosis of STAD has a considerable influence on clinical outcomes. METHODS: The mRNA expression data and clinical indicators of STAD and normal tissues were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The gene expression differences were analyzed by R packages, and gene function enrichment analysis was performed. Kaplan-Meier method and univariate Cox proportional risk regression analysis were used to screen differential expressed genes (DEGs) related to survival of STAD patients. Multivariate Cox proportional risk regression analysis was used to further screen and determine the prognostic DEGs in STAD patients, and to construct a multigene prognostic prediction signature. The accuracy of predictive signature was tested by receiver operating characteristic (ROC) curve software package, and the nomogram of patients with STAD was drawn. Cox regression was used to investigate the correlation between multigene prognostic signature and clinical factors. The predictive performance of this model was compared with two other models proposed in previous studies using KM survival analysis, ROC curve analysis, Harrell consistency index and decision curve analysis (DCA). qRT-PCR and Western blot were used to verify the expression levels of prognostic genes. The pathways and functions of possible involvement of features were predicted using the GSEA method. RESULTS: A total of 569 early-stage specific DEGs were retrieved from TCGA-STAD dataset, including 229 up-regulated genes and 340 down-regulated genes. Enrichment analysis showed that the early-stage specific DEGs were associated with cytokine-cytokine receptor interaction, neuroactive ligand-receptor interaction, and calcium signaling pathway. Multiple Cox regression algorithm was used to identify 10 early-stage specific DEGs associated with overall survival (P < 0.01) of STAD patients, and a multi-mRNA prognosis signature was established. The patients were divided into high-risk group and low-risk group according to the risk score. In the training set, the prognostic signature was positively correlated with tumor size and stage (P < 0.05), survival curve (P < 0.001) and time-dependent ROC (AUC = 0.625). In the training dataset and test dataset, the both signatures had good predictive efficiencies. Cox regression and DCA analysis revealed that the prognostic signature was an independent factor and had a better predict effect than the conventional TNM stage classification method and the earlier published biomarkers on the prognosis of STAD patients. CONCLUSION: In this study, based on the early-stage specifically expressed genes, the prognostic signature constructed through TCGA and GEO datasets may become an indicator for clinical prognosis assessment of STAD and a new strategy for targeted therapy in the future.
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Adenocarcinoma , Biomarcadores de Tumor , Neoplasias Gástricas , Humanos , Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Citocinas , Ligandos , Pronóstico , Receptores de Citocinas , ARN Mensajero/genética , Estómago/patología , Neoplasias Gástricas/genéticaRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease that may progress to nonalcoholic steatohepatitis (NASH), hepatic tissue fibrosis, liver cirrhosis, and hepatocellular carcinoma. In this study, we investigated the effects of Pien Tze Huang (PTH), a well-known traditional Chinese herbal formula with liver protective effect, in methionine-choline deficient diet (MCD)- and high-fat diet (HFD)-induced NASH mouse models. Our results showed that PTH could exert hepatoprotective effects by improving liver weight and steatosis and reducing the fibrosis and serum levels of alanine transaminase (ALT) and aspartate transaminase (AST) in both animal models. The effects of PTH was accompanied with the reduction of infiltrated macrophages, the inhibition of the expression of cytokines, and the induction of adiponectin expression. Mechanistically, we found that PTH could inhibit the activation of proinflammatory transcription factor nuclear factor-κB (NF-κB) by preventing the degradation of inhibitor of κBα (IκBα). These results demonstrate that PTH can improve NAFLD largely due to its suppression of the NF-κB inflammatory pathway.
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Medicamentos Herbarios Chinos , Enfermedad del Hígado Graso no Alcohólico , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Fibrosis , Hígado , Cirrosis Hepática/metabolismo , Metionina/farmacología , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
Nanodrugs have attracted increasing interest in drug delivery and disease treatment. However, the cumbersome preparation process and the poor biocompatibility of nanodrugs obstruct their clinical translation. In this study, we utilized a self-assembly strategy to develop a low-toxicity, long-lasting nanodrug for the effective treatment and real-time monitoring of bladder tumors. The accurate self-assembly of compatible raw materials allowed for an encapsulation rate of 43.7% for insoluble erdafitinib. Interestingly, robust therapeutic effects and reduced side effects could be realized simultaneously using this nanodrug, enabling broader scenarios for the clinical application of erdafitinib. Furthermore, the nanodrug exhibited a significantly prolonged in vivo half-life (14.4 h) and increased bioavailability (8.0 µg/mL·h), which were 8.3 times and 5.0 times higher than those of its nonformulated counterpart. Also, it is worth mentioning that the introduction of a fluorescent protein module into the nanodrug brought up a novel possibility for real-time feedback on the therapeutic response. In conclusion, this research revealed a versatile technique for developing low-toxicity, long-acting, and multifunctional nanoformulations, paving the way for multidimensional therapy of malignant tumors.
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Cancer treatment has become one of the biggest challenges in modern medicine. Recently, many efforts have been devoted to treat tumors by surgical resection, radiotherapy, or chemotherapy. In comparison to these methods, photo-thermal therapy (PTT) with noninvasive, controllable, direct, and precise characteristics has received tremendous attention in eliminating tumor cells over the past decades. In particular, PTT based on biomacromolecule-based photo-thermal agents (PTAs) outperforms other systems with high photo-thermal efficiency, simple coating, and low immunogenicity. Considering the unique advantages of biomacromolecule-based PTAs in tumor treatment, it is necessary to summarize the recent progress in the field of biomacromolecule-based PTAs for tumor treatment. Herein, this minireview outlines recent progress in the fabrication and applications of biomacromolecule-based PTAs. Within this framework, various types of biomacromolecule-based PTAs are highlighted, including cell-based agents, protein-based agents, nucleotide-based agents, and polysaccharide-based PTAs. In each section, the functional design, photo-thermal effects, and potential clinical applications of each type of PTA are discussed. Finally, a brief perspective for the development of biomacromolecule-based PTAs is presented.
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Antineoplásicos/uso terapéutico , Materiales Biocompatibles/uso terapéutico , Neoplasias/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Antineoplásicos/química , Materiales Biocompatibles/química , Humanos , Ensayo de Materiales , Neoplasias/patología , Fármacos Fotosensibilizantes/químicaRESUMEN
Striatin-4 (STRN4 or Zinedin) is a scaffolding protein belonging to the mammalian STRN family of proteins and consists of multiple functional signaling domains. Due to its numerous signaling complexes, STRN4 has been reported to be involved in the tumorigenesis of various cancer types, including colon cancer, liver cancer and prostate cancer. However, few studies on STRN4 have been conducted in bladder cancer, and its prognostic role in bladder cancer remains unknown. The present study aimed to investigate the expression levels of STRN4 in bladder transitional cell carcinoma and evaluate the prognostic role of STRN4. STRN4 expression in clinical specimens was analyzed using immunohistochemistry and reverse transcription-quantitative PCR. It was demonstrated that STRN4 expression was significantly associated with clinical parameters such as tumor size, muscle invasion depth and pathological tumor grade. Abnormal STRN4 expression was typically associated with worse overall survival time and outcome when compared with the low STRN4 expression group. Using multivariate analysis, it was reported that STRN4 was an independent prognostic biomarker for survival time in bladder transitional cell carcinoma. Although the specific biological mechanisms of STRN4 in bladder cancer still remain to be elucidated, STRN4 expression could be a prognostic indicator in bladder cancer.
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OBJECTIVE: We aimed to explore the diagnostic value of microRNA-192 expression in urinary sediment combined with B-ultrasound in the diagnosis of bladder cancer. METHODS: A total of 118 patients with bladder cancer and 120 patients with benign urinary system diseases were selected for collection of urinary sediment. Real-time quantitative polymerase chain reaction was applied to detect the microRNA-192 expression (normalized to U6 level) in urinary sediment. Besides, the relationship between microRNA-192 expression and clinicopathological characteristics was analyzed. Furthermore, receiver operating characteristic curve was performed to analyze clinical value of microRNA-192 expression alone and microRNA-192 expression in urinary sediment combined with B-ultrasound in the diagnosis of bladder cancer. RESULTS: MicroRNA-192 expression was significantly downregulated in urinary sediment of patients with bladder cancer, which was related to tumor stage and tumor size (P < .05). The results of receiver operating characteristic curve analysis showed that the best critical value of microRNA-192 expression in urinary sediment for the diagnosis of bladder cancer was 0.785 with the sensitivity and specificity of 76.7% and 78.0%, respectively. The sensitivity and specificity of microRNA-192 expression in urinary sediment combined with B-ultrasound in the diagnosis of bladder cancer were 93.2% and 76.7%, respectively. The sensitivity of combined diagnosis (93.2%) was not significantly different from that of cystoscopy (93.2%; P > 0.05). There were significant differences between the expression of microRNA-192 in urinary sediment and the sensitivity of B-ultrasound examination alone with cystoscopy (P < .05). CONCLUSION: The downregulation of microRNA-192 expression in urinary sediment of patients with bladder cancer may be related to tumor progression. The microRNA-192 expression in urinary sediment is valuable in the diagnosis of bladder cancer, which shows high sensitivity in diagnosis of bladder cancer when combined with B-ultrasound.
Asunto(s)
Biomarcadores de Tumor/genética , Cistoscopía/métodos , MicroARNs/genética , Ultrasonografía/métodos , Neoplasias de la Vejiga Urinaria/diagnóstico , Adulto , Anciano , Biomarcadores de Tumor/orina , Estudios de Casos y Controles , Femenino , Humanos , Masculino , MicroARNs/orina , Persona de Mediana Edad , Curva ROC , Neoplasias de la Vejiga Urinaria/diagnóstico por imagen , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/orinaRESUMEN
Appendiceal intussusception caused by mucocele of the appendix is extremely rare. In the current study, a 32-year-old woman was admitted to the department of general surgery of our hospital, complaining of persistent right, lower quadrant pain without an obvious cause for 17 hours. Physical examination indicated significant pain and tenderness in the right, lower abdominal quadrant. Blood analysis indicated that leukocyte count, the percentage of neutrophils and the serum C-reactive protein were increased. Abdominal and pelvic computed tomography revealed a well-encapsulated cystic mass surrounded by the caecum and intussusception. The appendiceal intussusception caused by mucocele of the appendix was revealed during the laparoscopic exploration. Appendectomy and partial cecectomy were conducted using the laparoscopic approach. Postoperative pathological examinations showed ileocecal intussusception and chronic inflammation, appendiceal mucocele and acute suppurative appendicitis. The patient showed satisfactory recovery that was observed during 15-months of follow-ups. This case highlights that laparoscopic appendectomy and partial cecectomy may be a beneficial, minimally invasive approach for appendiceal intussusception caused by mucocele of the appendix.
RESUMEN
Recently, the fabrication of nanotechnology-based co-delivery systems has garnered enormous interest for efficacious cancer therapy. However, these systems still face certain challenges such as codelivery of drugs with different chemistries, inadequate loading efficiency, immune rejection resulting in rapid clearance and substantially poor bioavailability in vivo. To address the challenges, we have developed a biomimetic and stable design based on bovine serum albumin (BSA) nanoparticles that are encapsulated with a hydrophilic photothermal agent, indocyanine green (ICG), as well as a hydrophobic agent, gambogic acid (GA), via the desolvation method. Furthermore, these nanoconstructs have been coated with the red blood cell membranes (RBCm), which exhibit pronounced long-term circulation in addition to avoiding premature leakage of drugs. RBCm-coated BSA nanoparticles show a higher affinity towards both GA and ICG (RmGIB NPs), resulting in high loading efficiencies of 24.3⯱â¯1.2 % and 25.0⯱â¯1.2 %, respectively. Moreover, the bio-efficacy investigations of these biomimetic constructs (RmGIB NPs) in cells in vitro as well as in tumor-bearing mice in vivo confirm augmented inhibition, demonstrating potential synergistic chemo-photothermal therapeutic efficacy. Altogether, we provide an efficient delivery platform for designing and constructing BSA nanovehicles toward synergistic and effective co-delivery of therapeutics.