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In vertebrates, the earliest hematopoietic stem and progenitor cells (HSPCs) are derived from a subset of specialized endothelial cells, hemogenic endothelial cells, in the aorta-gonad-mesonephros region through endothelial-to-hematopoietic transition. HSPC generation is efficiently and accurately regulated by a variety of factors and signals; however, the precise control of these signals remains incompletely understood. Post-transcriptional regulation is crucial for gene expression, as the transcripts are usually bound by RNA-binding proteins (RBPs) to regulate RNA metabolism. Here, we report that the RBP protein Csde1-mediated translational control is essential for HSPC generation during zebrafish early development. Genetic mutants and morphants demonstrated that depletion of csde1 impaired HSPC production in zebrafish embryos. Mechanistically, Csde1 regulates HSPC generation through modulating Wnt/ß-catenin signaling activity. We demonstrate that Csde1 binds to ctnnb1 mRNAs (encoding ß-catenin, an effector of Wnt signaling) and regulates translation but not stability of ctnnb1 mRNA, which further enhances ß-catenin protein level and Wnt signal transduction activities. Together, we identify Csde1 as an important post-transcriptional regulator and provide new insights into how Wnt/ß-catenin signaling is precisely regulated at the post-transcriptional level.
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Hemangioblastos , Pez Cebra , Animales , Pez Cebra/genética , Pez Cebra/metabolismo , beta Catenina/metabolismo , Vía de Señalización Wnt/genética , Células Madre Hematopoyéticas/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Hemangioblastos/metabolismoRESUMEN
BACKGROUND: Phytophthora infestans causes late blight, threatening potato production. The tropane alkaloid scopolamine from some industrial plants (Datura, Atropa, etc.) has a broad-spectrum bacteriostatic effect, but its effect on P. infestans is unknown. RESULTS: In the present study, scopolamine inhibited the mycelial growth of phytopathogenic oomycete P. infestans, and the half-maximal inhibitory concentration (IC50 ) was 4.25 g L-1 . The sporangia germination rates were 61.43%, 16.16%, and 3.99% at concentrations of zero (control), 0.5 IC50 , and IC50 , respectively. The sporangia viability of P. infestans was significantly reduced after scopolamine treatment through propidium iodide and fluorescein diacetate staining, speculating that scopolamine destroyed cell membrane integrity. The detached potato tuber experiment demonstrated that scopolamine lessened the pathogenicity of P. infestans in potato tubers. Under stress conditions, scopolamine showed good inhibition of P. infestans, indicating that scopolamine could be used in multiple adverse conditions. The combination effect of scopolamine and the chemical pesticide Infinito on P. infestans was more effective than the use of scopolamine or Infinito alone. Moreover, transcriptome analysis suggested that scopolamine leaded to a downregulation of most P. infestans genes, functioning in cell growth, cell metabolism, and pathogenicity. CONCLUSION: To our knowledge, this is the first study to detect scopolamine inhibitory activity against P. infestans. Also, our findings highlight the potential of scopolamine as an eco-friendly option for controlling late blight in the future. © 2023 Society of Chemical Industry.
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BACKGROUND: Rapidly growing genome-wide ChIP-seq data have provided unprecedented opportunities to explore transcription factor (TF) binding under various cellular conditions. Despite the rich resources, development of analytical methods for studying the interaction among TFs in gene regulation still lags behind. RESULTS: In order to address cooperative TF binding and detect TF clusters with coordinative functions, we have developed novel computational methods based on clustering the sample paths of nonhomogeneous Poisson processes. Simulation studies demonstrated the capability of these methods to accurately detect TF clusters and uncover the hierarchy of TF interactions. A further application to the multiple-TF ChIP-seq data in mouse embryonic stem cells (ESCs) showed that our methods identified the cluster of core ESC regulators reported in the literature and provided new insights on functional implications of transcrisptional regulatory modules. CONCLUSIONS: Effective analytical tools are essential for studying protein-DNA relations. Information derived from this research will help us better understand the orchestration of transcription factors in gene regulation processes.
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Genoma , Factores de Transcripción , Animales , Ratones , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Unión Proteica/genética , Análisis por Conglomerados , Regulación de la Expresión Génica , Sitios de UniónRESUMEN
Vibrio collagenases of the M9A subfamily are closely related to Vibrio pathogenesis for their role in collagen degradation during host invasion. Although some Vibrio collagenases have been characterized, the collagen degradation mechanism of Vibrio collagenase is still largely unknown. Here, an M9A collagenase, VP397, from marine Vibrio pomeroyi strain 12613 was characterized, and its fragmentation pattern on insoluble type I collagen fibers was studied. VP397 is a typical Vibrio collagenase composed of a catalytic module featuring a peptidase M9N domain and a peptidase M9 domain and two accessory bacterial prepeptidase C-terminal domains (PPC domains). It can hydrolyze various collagenous substrates, including fish collagen, mammalian collagens of types I to V, triple-helical peptide [(POG)10]3, gelatin, and 4-phenylazobenzyloxycarbonyl-Pro-Leu-Gly-Pro-o-Arg (Pz-peptide). Atomic force microscopy (AFM) observation and biochemical analyses revealed that VP397 first assaults the C-telopeptide region to dismantle the compact structure of collagen and dissociate tropocollagen fragments, which are further digested into peptides and amino acids by VP397 mainly at the Y-Gly bonds in the repeating Gly-X-Y triplets. In addition, domain deletion mutagenesis showed that the catalytic module of VP397 alone is capable of hydrolyzing type I collagen fibers and that its C-terminal PPC2 domain functions as a collagen-binding domain during collagenolysis. Based on our results, a model for the collagenolytic mechanism of VP397 is proposed. This study sheds light on the mechanism of collagen degradation by Vibrio collagenase, offering a better understanding of the pathogenesis of Vibrio and helping in developing the potential applications of Vibrio collagenase in industrial and medical areas. IMPORTANCE Many Vibrio species are pathogens and cause serious diseases in humans and aquatic animals. The collagenases produced by pathogenic Vibrio species have been regarded as important virulence factors, which occasionally exhibit direct pathogenicity to the infected host or facilitate other toxins' diffusion through the digestion of host collagen. However, our knowledge concerning the collagen degradation mechanism of Vibrio collagenase is still limited. This study reveals the degradation strategy of Vibrio collagenase VP397 on type I collagen. VP397 binds on collagen fibrils via its C-terminal PPC2 domain, and its catalytic module first assaults the C-telopeptide region and then attacks the Y-Gly bonds in the dissociated tropocollagen fragments to release peptides and amino acids. This study offers new knowledge regarding the collagenolytic mechanism of Vibrio collagenase, which is helpful for better understanding the role of collagenase in Vibrio pathogenesis and for developing its industrial and medical applications.
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Colágeno Tipo I , Vibrio , Secuencia de Aminoácidos , Aminoácidos , Animales , Colágeno/metabolismo , Colágeno Tipo I/genética , Colagenasas/genética , Colagenasas/metabolismo , Mamíferos , Péptidos/metabolismo , Tropocolágeno , Vibrio/metabolismoRESUMEN
Bovine bone is rich in collagen and is a good material for collagen peptide preparation. Although thermolysin-like proteases (TLPs) have been applied in different fields, the potential of TLPs in preparing bioactive collagen peptides has rarely been evaluated. Here, we characterized a thermophilic TLP, A69, from a hydrothermal bacterium Anoxybacillus caldiproteolyticus 1A02591, and evaluated its potential in preparing bioactive collagen peptides. A69 showed the highest activity at 60 °C and pH 7.0. We optimized the conditions for bovine bone collagen hydrolysis and set up a process with high hydrolysis efficiency (99.4%) to prepare bovine bone collagen peptides, in which bovine bone collagen was hydrolyzed at 60 °C for 2 h with an enzyme-substrate ratio of 25 U/g. The hydrolysate contained 96.5% peptides that have a broad molecular weight distribution below 10000 Da. The hydrolysate showed good moisture-retention ability and a high hydroxyl radical (â¢OH) scavenging ratio of 73.2%, suggesting that the prepared collagen peptides have good antioxidative activity. Altogether, these results indicate that the thermophilic TLP A69 has promising potential in the preparation of bioactive collagen peptides, which may have potentials in cosmetics, food and pharmaceutical industries. This study lays a foundation for the high-valued utilization of bovine bone collagen.
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Anoxybacillus , Antioxidantes/farmacología , Colágeno/farmacología , Metaloendopeptidasas/química , Péptidos/farmacología , Animales , Antioxidantes/química , Bovinos , Colágeno/química , Péptidos/químicaRESUMEN
Parkinson's disease (PD) is one of the most common nervous system degenerative diseases. However, the etiology of this disease remains elusive. Here, a proteasome inhibitor (PSI)-induced undifferentiated SH-SY5Y PD model was established to analyze protein alterations through proteomic study. METHODS: Cultured undifferentiated SH-SY5Y cells were divided into a control group and a group treated with 2.5 µM PSI (PSI-treated group). An methyl thiazolyl tetrazolium (MTT) assay was applied to detect cell viability. Acridine orange/ethidium bromide (AO/EB), α-synuclein immunofluorescence and hematoxylin and eosin (H&E) staining were applied to evaluate apoptosis and cytoplasmic inclusions, respectively. The protein spots that were significantly changed were separated, analyzed by 2D gel electrophoresis and DIGE De Cyder software, and subsequently identified by MALDI-TOF mass spectrometry and database searching. RESULTS: The results of the MTT assay showed that there was a time and dose dependent change in cell viability following incubation with PSI. After 24 h incubation, PSI resulted in early apoptosis, and cytoplasmic inclusions were found in the PSI-treated group through H&E staining and α-synuclein immunofluorescence. Thus, undifferentiated SH-SY5Y cells could be used as PD model following PSI-induced inhibition of proteasomal function. In total, 18 proteins were differentially expressed between the groups, 7 of which were up-regulated and 11 of which were down-regulated. Among them, 5 protein spots were identified as being involved in the ubiquitin proteasome pathway-induced PD process. CONCLUSIONS: Mitochondrial heat shock protein 75 (MTHSP75), phosphoglycerate dehydrogenase (PHGDH), laminin binding protein (LBP), tyrosine 3/tryptophan 5-monooxygenase activation protein (14-3-3ε) and YWHAZ protein (14-3-3ζ) are involved in mitochondrial dysfunction, serine synthesis, amyloid clearance, apoptosis process and neuroprotection. These findings may provide new clues to deepen our understanding of PD pathogenesis.
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Enfermedad de Parkinson/metabolismo , Inhibidores de Proteasoma/farmacología , Proteómica , Proteínas 14-3-3/metabolismo , Apoptosis/efectos de los fármacos , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo , Proteínas de Choque Térmico/metabolismo , Humanos , Cuerpos de Inclusión/efectos de los fármacos , Laminina/metabolismo , Enfermedad de Parkinson Secundaria/metabolismo , Fosfoglicerato-Deshidrogenasa/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismoRESUMEN
An optical fiber displacement sensor based on the microwave photonics interferometric (MWPI) method is proposed and experimented, which provides an ideal solution for large range displacement measurement with high resolution. The sensor used a Michelson microwave photonics interferometer to sense the displacement with one sensing arm and a length-adjusted reference arm. The displacement variation would change the period of the microwave response function of the interferometer. According to the principle that the phase difference in one free spectral range (FSR) of the microwave response function is 360°, the displacement can be retrieved by the microwave response function by means of a vector network analyzer (VNA). A programmable path-switching true time delay line was used in the reference arm to decrease the microwave bandwidth. The measurement results show that the displacement sensing range is larger than 3 m and the measurement resolution is 31 µm. Finally, the measurement stability is tested, and the factors affecting the measurement resolution of this method and the main source of errors are investigated in detail.
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Albumin-bilirubin (ALBI) grade was first described in 2015 as an indicator of liver dysfunction in patients with hepatocellular carcinoma. ALBI grade has been reported to have prognostic value in several malignancies including non-small cell lung cancer (NSCLC). The present study aimed to explore the prognostic impact of ALBI grade in patients with small cell lung cancer (SCLC). It retrospectively analyzed 135 patients with SCLC treated at Hebei General Hospital between April 2015 and August 2021. Patients were divided into two groups according to the cutoff point of ALBI grade determined by the receiver operating characteristic (ROC) curve: Group 1 with pre-treatment ALBI grade ≤-2.55 for an improved hepatic reserve and group 2 with ALBI grade >-2.55. Kaplan-Meier and Cox regression analysis were performed to assess the potential prognostic factors associated with progression free survival (PFS) and overall survival (OS). Propensity score matching (PSM) was applied to eliminate the influence of confounding factors. PFS and OS (P<0.001) were significantly improved in group 1 compared with in group 2. Multivariate analysis revealed that sex (P=0.024), surgery (P=0.050), lactate dehydrogenase (LDH; P=0.038), chemotherapy (P=0.038) and ALBI grade (P=0.028) are independent risk factors for PFS and that surgery (P=0.013), LDH (P=0.039), chemotherapy (P=0.009) and ALBI grade (P=0.013) are independent risk factors for OS. After PSM, ALBI grade is an independent prognostic factor of PFS (P=0.039) and OS (P=0.007). It was concluded that ALBI grade was an independent prognostic factor in SCLC.
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The incidence of Hepatocellular carcinoma (HCC) and HCC-related deaths have remarkably increased over the recent decades. It has been reported that ß-catenin activation can be frequently observed in HCC cases. This study identified the integrin-linked kinase-associated phosphatase (ILKAP) as a novel ß-catenin-interacting protein. ILKAP is localized both in the nucleus and cytoplasm and regulates the WNT pathway in different ways. First, it is demonstrated that ILKAP activates the WNT pathway in HCC cells by increasing the protein level of ß-catenin and other proteins associated with the WNT signaling, such as c-Myc and CyclinD1. Next, it is shown that ILKAP promotes the metastasis of HCC both in vitro and in vivo in a zebrafish xenograft model. It is also found that ILKAP dephosphorylates the GSK3ß and CK1, contributing to the reduced ubiquitination of ß-catenin. Furthermore, it is identified that ILKAP functions by mediating binding between TCF4 and ß-catenin to enhance expression of WNT target genes. Taken together, the study demonstrates a critical function of ILKAP in metastasis of HCC, since ILKAP is crucial for the activation of the WNT pathway via stabilization of ß-catenin and increased binding between TCF4 and ß-catenin.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Fosfoproteínas Fosfatasas , Vía de Señalización Wnt , beta Catenina , Animales , Humanos , beta Catenina/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Metástasis de la Neoplasia , Factor de Transcripción 4/metabolismo , Factor de Transcripción 4/genética , Vía de Señalización Wnt/fisiología , Pez Cebra , Fosfoproteínas Fosfatasas/genética , Fosfoproteínas Fosfatasas/metabolismoRESUMEN
Aim: To assess the potential factors with predictive value for survival in small-cell lung cancer (SCLC) patients and to develop a nomogram prediction model. Patients & methods: We retrospectively screened and analyzed patients with pathologically confirmed SCLC from April 2015 to December 2021. Results: A total of 167 patients with SCLC were included. According to the Memorial Sloan-Kettering prognostic score (MPS), patients were divided into three groups: group 0 (n = 65), group 1 (n = 69) and group 2 (n = 33). The multivariate analysis showed that MPS was an independent prognostic factor for progression-free and overall survival in SCLC patients (p < 0.05). The nomogram showed that MPS was the most influential factor for overall survival. Conclusion: MPS is an independent prognostic factor for overall and progression-free survival in SCLC patients and performed better than other indicators used in this study.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Pronóstico , Neoplasias Pulmonares/diagnóstico , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , NomogramasRESUMEN
BACKGROUND: Colorectal cancer (CRC), the fourth of the world's major common malignancy, poses a serious threat to the physical and mental health of the population. Nevertheless, the prognosis of CRC patients remains unsatisfactory. Consequently, it is still imperative to continuously discover the CRC mechanisms. METHODS: The expression profiles of mRNAs were recognized by whole transcriptome sequencing to identity differentially expressed mRNA (DE-mRNA). TCGA COAD cohort, PPOGgene and Kaplan-Meier Plotter databases were utilized to validate RNF114 relevance to CRC prognosis. The effect of RNF114 on the malignant biological behavior of CRC was explored in CRC cells and subcutaneous tumor models and lung metastasis model after exogenous regulation of RNF114. RESULTS: A total of 1358 DE-mRNAs were identified, including 617 up-regulated and 741 down-regulated DE-mRNAs, and they were mainly involved in the term of receptor ligand activity, Wnt signaling pathway and pathway in cancer. Notably, RNF114 was hyper-expressed in tissues and cell of CRC, and significantly correlated with tumor invasion depth and TNM stage of CRC patients. RNF114 expression were significantly associated with overall survival, and had superior diagnostic value in CRC. In vitro, knockdown of RNF114 statistically diminished the proliferation, stemness, invasion and wound healing of CRC cells and facilitated their apoptosis, and the opposite result was observed for overexpression of RNF114. In vivo, knockdown of RNF114 effectively diminished the mass and volume of tumors, and lung metastasis in animal model. CONCLUSIONS: In summary, we identified DE-mRNAs in CRC, and elucidated that RNF114 facilitates CRC process. The discovery will contribute to theoretical foundation for RNF114 as a potential therapeutic target and biomarker, and offer new perspectives for CRC research.
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Neoplasias Colorrectales , Vía de Señalización Wnt , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , ARN MensajeroRESUMEN
Hematopoietic stem and progenitor cells (HSPCs) are considered as a heterogeneous population, but precisely when, where and how HSPC heterogeneity arises remain largely unclear. Here, using a combination of single-cell multi-omics, lineage tracing and functional assays, we show that embryonic HSPCs originate from heterogeneous hemogenic endothelial cells (HECs) during zebrafish embryogenesis. Integrated single-cell transcriptome and chromatin accessibility analysis demonstrates transcriptional heterogeneity and regulatory programs that prime lymphoid/myeloid fates at the HEC level. Importantly, spi2+ HECs give rise to lymphoid/myeloid-primed HSPCs (L/M-HSPCs) and display a stress-responsive function under acute inflammation. Moreover, we uncover that Spi2 is required for the formation of L/M-HSPCs through tightly controlling the endothelial-to-hematopoietic transition program. Finally, single-cell transcriptional comparison of zebrafish and human HECs and human induced pluripotent stem cell-based hematopoietic differentiation results support the evolutionary conservation of L/M-HECs and a conserved role of SPI1 (spi2 homolog in mammals) in humans. These results unveil the lineage origin, biological function and molecular determinant of HSPC heterogeneity and lay the foundation for new strategies for induction of transplantable lineage-primed HSPCs in vitro.
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Hemangioblastos , Células Madre Pluripotentes Inducidas , Animales , Humanos , Pez Cebra , Hematopoyesis/fisiología , Células Madre Hematopoyéticas , Diferenciación Celular , Linaje de la Célula , MamíferosRESUMEN
BACKGROUND: Previous studies showed that local vibration stimulation therapy was effective in relieving fatigue, and the effects of different modes of vibration stimulation therapy were further investigated. OBJECTIVE: This study aimed to examine the effects of different vibration stimulation modes on relieving acute exercise fatigue based on the multiphysiological indicators such as heart rate variability (HRV), skin conductance level (SCL), and ratings of perceived exertion (RPE) subjective scale. METHODS: Sixty participants selected from the dragon boat team of the Shanghai University of Traditional Chinese Medicine were divided into acupoint stimulation group (20 participants), muscle stimulation group (20 participants), and control group (20 participants) by complete randomization. RESULTS: (1) RPE: both stimulation groups showed a significant increase compared to the control group. (2) Heart rate values: the difference between muscle stimulation group and control group was statistically significant; (3) SCL: the two stimulation groups had significantly higher and statistically significant differences in SCL (max) and SCL (mean) values compared to the control group; the muscle stimulation group had statistically significant differences in SCL (min) compared to the control group, and the acupoint stimulation group had statistically significant differences in SCL (v) compared to the control group; (4) HRV (hf): The difference between the acupoint stimulation group and the muscle stimulation group was statistically significant. CONCLUSION: (1) Both stimulation groups are part of vibration therapy, which can relieve sympathetic tension and regulate the vegetative nervous system's relaxation effect. (2) The meridian-vessel theory may be related to the acupoint stimulation group. The low-level visceral regulation centers in the spinal nerve segment region, where the acupoints are located, trigger changes in autonomic tone and enhance parasympathetic nerve activity to relieve acute motor fatigue. (3) The muscle stimulation group may be due to the 30-Hz vibration frequency's ability to raise muscle epidermal temperature, which increases blood flow and reflexively inhibits sympathetic excitation.
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Modalidades de Fisioterapia , Vibración , Humanos , Vibración/uso terapéutico , China , Frecuencia Cardíaca/fisiología , Resultado del Tratamiento , Ejercicio FísicoRESUMEN
The Wnt/ß-catenin signaling is usually abnormally activated in hepatocellular carcinoma (HCC), and pituitary tumor-transforming gene 1 (PTTG1) has been found to be highly expressed in HCC. However, the specific mechanism of PTTG1 pathogenesis remains poorly understood. Here, we found that PTTG1 is a bona fide ß-catenin binding protein. PTTG1 positively regulates Wnt/ß-catenin signaling by inhibiting the destruction complex assembly, promoting ß-catenin stabilization and subsequent nuclear localization. Moreover, the subcellular distribution of PTTG1 was regulated by its phosphorylation status. Among them, PP2A induced PTTG1 dephosphorylation at Ser165/171 residues and prevented PTTG1 translocation into the nucleus, but these effects were effectively reversed by PP2A inhibitor okadaic acid (OA). Interestingly, we found that PTTG1 decreased Ser9 phosphorylation-inactivation of GSK3ß by competitively binding to PP2A with GSK3ß, indirectly leading to cytoplasmic ß-catenin stabilization. Finally, PTTG1 was highly expressed in HCC and associated with poor patient prognosis. PTTG1 could promote the proliferative and metastasis of HCC cells. Overall, our results indicated that PTTG1 plays a crucial role in stabilizing ß-catenin and facilitating its nuclear accumulation, leading to aberrant activation of Wnt/ß-catenin signaling and providing a feasible therapeutic target for human HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Línea Celular , Vía de Señalización Wnt/genética , Línea Celular TumoralRESUMEN
Abnormal activation of Wnt/ß-catenin-mediated transcription is closely associated with the malignancy of pancreatic cancer. Family with sequence similarity 83 member A (FAM83A) was shown recently to have oncogenic effects in a variety of cancer types, but the biological roles and molecular mechanisms of FAM83A in pancreatic cancer need further investigation. Here, we newly discovered that FAM83A binds directly to ß-catenin and inhibits the assembly of the cytoplasmic destruction complex thus inhibiting the subsequent phosphorylation and degradation. FAM83A is mainly phosphorylated by the SRC non-receptor kinase family member BLK (B-lymphoid tyrosine kinase) at tyrosine 138 residue within the DUF1669 domain that mediates the FAM83A-ß-catenin interaction. Moreover, FAM83A tyrosine 138 phosphorylation enhances oncogenic Wnt/ß-catenin-mediated transcription through promoting ß-catenin-TCF4 interaction and showed an elevated nucleus translocation, which inhibits the recruitment of histone deacetylases by TCF4. We also showed that FAM83A is a direct downstream target of Wnt/ß-catenin signaling and correlates with the levels of Wnt target genes in human clinical pancreatic cancer tissues. Notably, the inhibitory peptides that target the FAM83A-ß-catenin interaction significantly suppressed pancreatic cancer growth and metastasis in vitro and in vivo. Our results revealed that blocking the FAM83A cascade signaling defines a therapeutic target in human pancreatic cancer.
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Proteínas de Neoplasias , Neoplasias Pancreáticas , beta Catenina , Familia-src Quinasas , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Carcinogénesis/genética , Transformación Celular Neoplásica/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/genética , Fosforilación/genética , Tirosina/metabolismo , Vía de Señalización Wnt/genética , Familia-src Quinasas/genética , Familia-src Quinasas/metabolismo , Neoplasias PancreáticasRESUMEN
Autophagy serves as a pro-survival mechanism for a cell or a whole organism to cope with nutrient stress. Our understanding of the molecular regulation of this fusion event remains incomplete. Here, we identified RUNDC1 as a novel ATG14-interacting protein, which is highly conserved across vertebrates, including zebrafish and humans. By gain and loss of function studies, we demonstrate that RUNDC1 negatively modulates autophagy by blocking fusion between autophagosomes and lysosomes via inhibiting the assembly of the STX17-SNAP29-VAMP8 complex both in human cells and the zebrafish model. Moreover, RUNDC1 clasps the ATG14-STX17-SNAP29 complex via stimulating ATG14 homo-oligomerization to inhibit ATG14 dissociation. This also prevents VAMP8 from binding to STX17-SNAP29. We further identified that phosphorylation of RUNDC1 Ser379 is crucial to inhibit the assembly of the STX17-SNAP29-VAMP8 complex via promoting ATG14 homo-oligomerization. In line with our findings, RunDC1 is crucial for zebrafish in their response to nutrient-deficient conditions. Taken together, our findings demonstrate that RUNDC1 is a negative regulator of autophagy that restricts autophagosome fusion with lysosomes by clasping the ATG14-STX17-SNAP29 complex to hinder VAMP8 binding.
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The epidemiologic pictures of Kawasaki disease (KD) in Jilin Province of China is still not clear. We sent a questionnaire form and diagnostic guidelines for KD to the province's 32 hospitals above the county and city level with pediatric in-patients. All patients with KD diagnosed during January 1999 through December 2008 were recruited in this survey. The incidence of KD was 1.39 to 11.07 (5.26 ± 3.97) per 100,000 children under the age of 5 years between 1999 and 2008. The ratio of male to female was 1.96 to 1. Ages at onset ranged from 58 days to 14 years. Patients under 5 years of age accounted of 88.73%. The disease occurred throughout the year, but it occurred more frequently in May to July and November. The most common cardiac abnormality was coronary artery dilatation (49.5%). Age at onset and hypoalbuminemia (<30 g/l) were selected for multivariate logistic regression equation. In conclusion, incidences of KD increased in Jilin Province. Age and gender distribution shared similarities with previous reports, and the seasonal distribution was different. Age and lower serum albumin were the most important risk factors of coronary arterial lesions (CAL) in KD. In addition, patients treated with steroids also had a possible heightened risk of contracting CAL.
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Síndrome Mucocutáneo Linfonodular/epidemiología , Adolescente , Edad de Inicio , Niño , Preescolar , China/epidemiología , Enfermedad de la Arteria Coronaria/epidemiología , Femenino , Encuestas Epidemiológicas , Humanos , Incidencia , Lactante , Masculino , Síndrome Mucocutáneo Linfonodular/diagnóstico , Factores de Riesgo , Estaciones del AñoRESUMEN
Background: The routine clinical nutritional and inflammatory indicators such as serum albumin, total cholesterol and lymphocytes have been widely investigated in the prognosis of small cell lung cancer (SCLC). The Naples prognostic score (NPS), based on nutritional and inflammatory status, has been identified as a prognostic impactor in several malignancies. However, the prognostic role of NPS in SCLC has not been elucidated. This study aims to evaluate the prognostic effect of NPS in SCLC patients. Patients and Methods: Patients with SCLC were recruited at Hebei General Hospital between April 2015 and August 2021. Pretreatment clinical and laboratory data were obtained. Participants were assigned into three groups according to NPS (group 0: NPS=0, group 1: NPS=1 or 2, group 2: NPS=3 or 4). Kaplan-Meier and Cox regression analysis were performed to assess the prognostic significance of NPS. The RMS package in R software was used to draw the nomogram predictive model. Results: A total of 128 patients were enrolled. The median progression-free survival (PFS) and overall survival (OS) was 7.2 and 12.3 months, respectively. The median PFS and OS was 12.3 vs 19.8 months, 7.6 vs 14.1 months and 6.0 vs 8.45 months for the three groups respectively. There were significant differences in both OS and FPS among the three groups. Survival analysis showed that NPS was significantly correlated with both OS and PFS (P<0.05). Lower NPS is associated with longer OS and PFS. Multivariate analysis showed that NPS has an independent prognostic impact on OS (P<0.05). The nomogram predictive model showed that NPS has good predictive power for survival rates. Conclusion: NPS is an independent prognostic factor for OS in SCLC patients. Low NPS may predict longer OS. Therefore NPS plays a vital role in the nomogram predictive model of survival rates in SCLC patients.
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A new near-infrared (NIR) probe based on a coumarinyl ligand (CL) was designed and synthesized. The probe CL can be used for simultaneous fluorescent turn-on and colorimetric detection of Hg2+ and Ag+ in ethanol/water medium. Colorless solution of probe CL changed to light yellow or dark yellow after addition of Hg2+ or Ag+ ions. Meanwhile the maximum absorption band shifted from 379 nm to 404 nm and the intensity increased enormously (for Hg2+) or moderately (for Ag+). Probe CL displayed an extraordinarily large Stokes shift of 316 nm and addition of Hg2+ or Ag+ to probe CL induced enhancement in the intensity of fluorescence emission at 695 nm by 15 or 8 fold. The detection limit of CL for Hg2+ and Ag+ ions is 0.83 and 8.8 µM, respectively. The applicable pH for sensing Hg2+ by probe CL is in a broad range of 2-12. Application of probe CL for in vitro U87MG cell imaging to detect Hg2+ ions was confirmed.
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Colorantes Fluorescentes , Mercurio , Colorimetría , Colorantes Fluorescentes/química , Iones , Espectroscopía Infrarroja CortaRESUMEN
Background: Ketamine is famous for its dissociative anesthetic properties. It is also analgesic, anti-inflammatory and anti-depressant, and even has a cerebral protective effect. We searched the evidence of the correlation between ketamine target and clinical efficacy and utilized network pharmacology to gather information about the multi-target mechanism of ketamine against cerebral ischemia (CI). We found that ketamine's clinical significance may be more extensive than previously thought. Methods: The drug target of ketamine and CI-related genes were predicted by SwissTargetPrediction, DrugBank, PubChem, GeneCards and DisGeNET databases. The intersection of ketamine's drug-targets and CI-related genes was analyzed by using GO and KEGG. We predicted the molecular docking between the potential target and ketamine. Results: The results indicated that the effect of ketamine on CI was primarily associated with the target of α-synuclein (SNCA), muscarinic acetylcholine receptor M1 (CHRM1) and nitric oxide synthase 1 (NOS1). It principally regulates the signal pathways of circadian transmission, calcium signaling pathway, dopaminergic synapse, cholinergic synapse and glutamatergic synapse. Molecular docking analysis exhibited that hydrogen bond and Pi-Pi interaction were the predominant modes of interaction. Conclusion: There are protein targets affected by ketamine in the treatment of CI. Three pivotal targets involving 298 proteins, SNCA, CHRM1 and NOS1, have emerged as multi-target mechanisms for ketamine in CI therapy. Similarly, this study also provides a new idea for introducing network pharmacology into the evaluation of multi-targeted drugs for CI and cerebral protection.