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1.
Photochem Photobiol Sci ; 23(6): 1031-1039, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38839721

RESUMEN

A novel cyclic chalcone fluorescent probe C-PN was synthesized to detect ONOO-. After reaction with peroxynitrite, the double bond of C-PN in the cyclic chalcone structure was disconnected, which caused the change of intramolecular charge transfer (ICT) effect, emitting blue fluorescence and quenching orange red fluorescence. Visible to the naked eye, the color of the probe solution changed. The probe showed low sensitivity (detection limit = 20.2 nm), short response time (less than 60 s) at low concentration of ONOO-, good visibility, and good selectivity and stability for ONOO-.

2.
Zhongguo Zhong Yao Za Zhi ; 49(3): 587-595, 2024 Feb.
Artículo en Zh | MEDLINE | ID: mdl-38621862

RESUMEN

A method for material classification of traditional Chinese medicines based on the physical properties of powder has been established by our research group. This method involves pre-treatment of traditional Chinese medicine decoction pieces, powder preparation, and determination of physical properties, being cumbersome. In this study, the word segmentation logic of semantic analysis was adopted to establish the thesaurus and local standardized semantic word segmentation database with the macroscopic and microscopic characteristics of 36 model traditional Chinese medicines as the basic data. The physical properties of these medicines have been determined and the classification of these medicines is clear in the cluster analysis. A total of 55 keywords for powdery, fibrous, sugary, oily, and brittle materials were screened by association rules and the set inclusion and exclusion criteria, and the weights of the keywords were calculated. Furthermore, the algorithms of the keyword matching scores and the computation rules of the single or multiple material classification were established for building the intelligent model of semantic analysis for the material classification. The semantic classification results of the other 35 TCMs except Pseudostellariae Radix(multi-material medicine) agreed with the clustering results based on the physical properties of the powder, with an agreement rate of 97.22%. In model validation, the prediction results of semantic classification of traditional Chinese medicines were consistent with the clustering results based on the physical properties of powder, with an agreement rate of 83.33%. The results showed that the method of material classification based on semantic analysis was feasible, which laid a foundation for the development of intelligent decision-making technology for personalized traditional Chinese medicine preparations.


Asunto(s)
Medicamentos Herbarios Chinos , Medicina Tradicional China , Polvos , Semántica , Raíces de Plantas
3.
Hepatology ; 75(4): 831-846, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34543483

RESUMEN

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is aggressive and has high rates of relapse, conferring poor long-term survival after curative resection. Little is known about the genomic evolution that occurs during ICC relapse. APPROACH AND RESULTS: We conducted whole-exome sequencing of 30 paired primary and relapsed tumors from 10 patients with ICC who received curative resection. We sought to identify frequently altered genes, infer tumor subclonal architectures, and track genomic evolution from primary to relapsed tumors. We examined functional effects and the mechanism of action of SLIT2, a gene specifically mutated in relapsed tumors, on tumor growth and metastasis and the tumor microenvironment. Our results indicated that relapsed ICCs were genetically derived from intrahepatic dissemination of primary tumors. However, they acquired additional mutations while maintaining most drivers, such as TP53 and IDH1. Multiregion sequencing suggested polyclonal seeding of ICC dissemination. Four of 10 relapsed ICCs acquired SLIT2 mutations that were not present in the corresponding primary tumors. Validation in an expanded sample revealed SLIT2 mutations in 2.3% (1/44) of primary ICCs and 29.5% (13/44) of relapsed ICCs. Biofunctional investigations revealed that inactivating mutation of SLIT2 resulted in activation of PI3K-Akt signaling in ICC cells, directly enhanced neutrophil chemotaxis, mediated tumor-associated neutrophil infiltration, and contributed to ICC growth and metastasis. CONCLUSIONS: We characterized genomic evolution during ICC relapse and identified SLIT2 as a driver of tumor dissemination and tumor-associated neutrophil infiltration.


Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Péptidos y Proteínas de Señalización Intercelular , Proteínas del Tejido Nervioso , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Evolución Molecular , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Mutación , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Proteínas del Tejido Nervioso/genética , Fosfatidilinositol 3-Quinasas , Pronóstico , Microambiente Tumoral/genética
4.
Chem Biodivers ; 20(8): e202300754, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37401658

RESUMEN

Magnolol and Honokiol are the primary active components that have been identified and extracted from Magnolia officinalis, and several investigations have demonstrated that they have significant pharmacological effects. Despite their therapeutic benefits for a wide range of illnesses, research on and the implementation of these compounds have been hindered by their poor water solubility and low bioavailability. Researchers are continually using chemical methods to alter their structures to make them more effective in treating and preventing diseases. Researchers are also continuously developing derivative drugs with high efficacy and few adverse effects. This article summarizes and analyzes derivatives with significant biological activities reported in recent research obtained by structural modification. The modification sites have mainly focused on the phenolic hydroxy groups, benzene rings, and diene bonds. Changes to the allyl bisphenol structure will result in unexpected benefits, including high activity, low toxicity, and good bioavailability. Furthermore, alongside earlier experimental research in our laboratory, the structure-activity relationships of magnolol and honokiol were preliminarily summarized, providing experimental evidence for improving their development and utilization.


Asunto(s)
Lignanos , Magnolia , Lignanos/farmacología , Lignanos/química , Compuestos de Bifenilo/química , Relación Estructura-Actividad , Magnolia/química
5.
Cancer Sci ; 113(2): 423-431, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34779545

RESUMEN

Infiltrating immune cells in the tumor microenvironment (TME) influence tumor progression and patient prognosis, making them attractive therapeutic targets for immunotherapy research. A deeper understanding of immune cell distributions in the TME in hepatocellular carcinoma (HCC) is needed to identify interactions among different immune cell types that might impact the effectiveness of potential immunotherapies. We performed multiplex immunohistochemistry using a tissue microarray of samples from 302 patients with HCC to elucidate the spatial distributions of immune cell subpopulations (CD3+ , CD4+ , CD8+ , CD66b+ , and CD68+ ) in HCC and normal liver tissues. We analyzed the associations between different immune subpopulations using Pearson's correlation. G(r) functions, K(r) functions and Euclidean distance were applied to characterize the bivariate distribution patterns among the immune cell types. Cox regression and Kaplan-Meier analysis were used to evaluate the associations between tumor infiltration by different immune cells and patient outcomes after curative surgery. We also analyzed the relationship between the spatial distribution of different immune cell subpopulations with HCC patient prognosis. We found that the immune cell spatial distribution in the HCC TME is heterogeneous. Our study provides a theoretical basis for HCC immunotherapy.


Asunto(s)
Carcinoma Hepatocelular/inmunología , Neoplasias Hepáticas/inmunología , Antígenos CD/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Femenino , Humanos , Inmunohistoquímica , Inmunoterapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Persona de Mediana Edad , Infiltración Neutrófila , Pronóstico , Microambiente Tumoral/inmunología
6.
Anal Bioanal Chem ; 414(23): 6779-6789, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35879424

RESUMEN

An intramolecular charge transfer (ICT)-based fluorescent probe P-ONOO- was synthesized to detect ONOO-. After responding to peroxynitrite, the dicyano-vinyl group of P-ONOO- generates the aldehyde group, emitting strong green fluorescence accompanied by quenching of the yellow fluorescence. According to the calculated Fukui function, the modification of the alkoxy group can enhance the f+ of P-ONOO-, which can enhance the probe's nucleophilic addition reactivity with ONOO-. It has been experimentally verified that P-ONOO- shows fast response (within 30 s), excellent sensitivity (the detection limit = 10.4 nM), and good selectivity towards ONOO-. Additionally, the probe P-ONOO- has high membrane permeability and good biocompatibility, which can image endogenous ONOO- and exogenous ONOO- in HeLa cells.


Asunto(s)
Colorantes Fluorescentes , Ácido Peroxinitroso , Alcoholes , Células HeLa , Humanos , Espectrometría de Fluorescencia/métodos
7.
Cancer Immunol Immunother ; 70(2): 377-389, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32761426

RESUMEN

Recent studies suggested that the immune microenvironment and mutational landscape are associated with the response to immune-based therapy in several types of cancer. The roles of those factors in Chinese HCC remain largely unknown. In this study, we obtained 182 FFPE samples of HCC cohort that were previously subjected to NGS (49 WGS, 18 WES, and 115 targeted sequencing). We performed immunohistochemistry to detect CD3, CD4, CD8, CD57, Foxp3, CD68, CD66b, and PD-L1 expression in the samples. We identified diverse associations between the mutational landscape and the immune microenvironment in the HCC samples. High mutational burden and an aristolochic acid-dominated mutational signature were both correlated with elevated tumoral PD-L1 expression and CD3+ T-cell infiltration and high numbers of CD68+ TAMs and CD66b+ TANs. CD4+ and CD8+ T cells exhibited lower infiltration levels in tumors with mutations in AXIN1/CTNNB1 and in tumors with aflatoxin-dominant mutational signatures. Moreover, tumors with TP53 mutations had less CD8+ T-cell infiltration and more Foxp3+ Treg-cell infiltration than those without TP53 mutations. Kaplan-Meier survival analysis revealed that the presence of CD8+, Foxp3+, CD66b+, or CD68+ immune cells; tumoral PD-L1 expression alone; or the presence of CD8+ or Foxp3+ cells combined with TP53 mutation were predictive of recurrence and poor overall survival after curative resection. In conclusion, the association between the mutational landscape and the immune microenvironment warrants further analysis to determine its impact on patient outcomes to guide personalized immune-based therapy for Chinese patients with HCC.


Asunto(s)
Carcinoma Hepatocelular/epidemiología , Neoplasias Hepáticas/epidemiología , Microambiente Tumoral/inmunología , Secuenciación Completa del Genoma/métodos , Pueblo Asiatico , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/mortalidad , Femenino , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/mortalidad , Masculino , Análisis de Supervivencia
8.
PLoS Pathog ; 15(6): e1007879, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31199852

RESUMEN

Burkholderia pseudomallei is a gram-negative, facultative intracellular bacterium, which causes a disease known as melioidosis. Professional phagocytes represent a crucial first line of innate defense against invading pathogens. Uptake of pathogens by these cells involves the formation of a phagosome that matures by fusing with early and late endocytic vesicles, resulting in killing of ingested microbes. Host Rab GTPases are central regulators of vesicular trafficking following pathogen phagocytosis. However, it is unclear how Rab GTPases interact with B. pseudomallei to regulate the transport and maturation of bacterial-containing phagosomes. Here, we showed that the host Rab32 plays an important role in mediating antimicrobial activity by promoting phagosome maturation at an early phase of infection with B. pseudomallei. And we demonstrated that the expression level of Rab32 is increased through the downregulation of the synthesis of miR-30b/30c in B. pseudomallei infected macrophages. Subsequently, we showed that B. pseudomallei resides temporarily in Rab32-positive compartments with late endocytic features. And Rab32 enhances phagosome acidification and promotes the fusion of B. pseudomallei-containing phagosomes with lysosomes to activate cathepsin D, resulting in restricted intracellular growth of B. pseudomallei. Additionally, Rab32 mediates phagosome maturation depending on its guanosine triphosphate/guanosine diphosphate (GTP/GDP) binding state. Finally, we report the previously unrecognized role of miR-30b/30c in regulating B. pseudomallei-containing phagosome maturation by targeting Rab32 in macrophages. Altogether, we provide a novel insight into the host immune-regulated cellular pathway against B. pseudomallei infection is partially dependent on Rab32 trafficking pathway, which regulates phagosome maturation and enhances the killing of this bacterium in macrophages.


Asunto(s)
Burkholderia pseudomallei/inmunología , Melioidosis/inmunología , MicroARNs/inmunología , Fagosomas/inmunología , Proteínas de Unión al GTP rab/inmunología , Animales , Burkholderia pseudomallei/patogenicidad , Melioidosis/patología , Ratones , Viabilidad Microbiana/inmunología , Fagosomas/microbiología , Fagosomas/patología , Células RAW 264.7
9.
Hepatology ; 72(3): 906-922, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-31838741

RESUMEN

BACKGROUND AND AIMS: There is growing evidence that single-stranded, circular RNA (circRNA) plays a key role in the development of certain cancers, including hepatocellular carcinoma (HCC). It is less clear, however, what role circRNA plays in HCC metastasis. APPROACH AND RESULTS: In this study, through circRNA sequencing, we identified a circRNA: circASAP1 (a circRNA derived from exons 2 and 3 of the ASAP1 gene, hsa_circ_0085616), which is associated with pulmonary metastasis after curative resection in patients with HCC. CircASAP1 was overexpressed in HCC cell lines with high metastatic potential and in metastatic HCCs. In vitro, circASAP1 promoted cell proliferation, colony formation, migration, and invasion, and in vivo, it enhanced tumor growth and pulmonary metastasis. Mechanism studies showed that circASAP1 acts as a competing endogenous RNA for microRNA 326 (miR-326) and microRNA 532-5p (miR-532-5p), both of which are tumor suppressors in HCC. We found that mitogen-activated protein kinase (MAPK) 1 and colony stimulating factor (CSF)-1 were direct common targets for microRNA 326 (miR-326) and microRNA 532-5p (miR-532-5p), which were regulated by circASAP1. CircASAP1 promotes HCC cell proliferation and invasion by regulating miR-326/miR-532-5p-MAPK1 signaling and, furthermore, mediates tumor-associated macrophage infiltration by regulating the miR-326/miR-532-5p-CSF-1 pathway. Clinical HCC samples exhibited a positive correlation between circASAP1 expression and levels of CSF-1, MAPK1, and CD68+ tumor-associated macrophages, all of which were predictive of patient outcomes. CONCLUSION: We identified circASAP1 as a key regulator of HCC metastasis that acts on miR-326/miR-532-5p-MAPK1/CSF-1 signaling and serves as a prognostic predictor in patients with HCC.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Pulmonares , Factor Estimulante de Colonias de Macrófagos/metabolismo , MicroARNs/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Metástasis de la Neoplasia/genética , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Femenino , Hepatectomía/efectos adversos , Hepatectomía/métodos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Masculino , Ratones , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , ARN Circular/metabolismo
10.
Microb Pathog ; 158: 104969, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34044047

RESUMEN

Burkholderia pseudomallei is the etiological agent of melioidosis, which is an emerging infectious disease endemic to many tropical regions. Autophagy is an intrinsic cellular process that degrades cytoplasmic components and plays an important role in protecting the host against pathogens. Like many intracellular pathogens, B. pseudomallei can evade the autophagy-dependent cellular clearance. However, the underlying mechanism remains unclear. In this study, we applied a combination of multiple assays to monitor autophagy processes and found that B. pseudomallei induced an incomplete autophagic flux and eliminate autophagy clearance in macrophages by blocking autophagosome-lysosome fusion. Based on a high-throughput microarray screening, we found that LIPA (lysosomal acid LIPAse A) was downregulated during B. pseudomallei infection. MiR-146a was then identified to be specifically upregulated upon infection with B. pseudomallei and further regulated LIPA expression by interacting with 3'UTR of LIPA. Furthermore, overexpression of miR-146a contributed to the defect of autophagic flux caused by B. pseudomallei and was beneficial for the survival of B. pseudomallei in macrophages. Therefore, our findings suggest that miR-146a inhibits autophagy via posttranscriptional suppression of LIPA expression to maintain B. pseudomallei survival in macrophages.


Asunto(s)
Burkholderia pseudomallei , Macrófagos/microbiología , Melioidosis , MicroARNs , Esterol Esterasa , Animales , Autofagia , Burkholderia pseudomallei/genética , Células HEK293 , Humanos , Ratones , MicroARNs/genética , Células RAW 264.7
11.
Zhongguo Zhong Yao Za Zhi ; 46(15): 3772-3779, 2021 Aug.
Artículo en Zh | MEDLINE | ID: mdl-34472249

RESUMEN

To explore the correlation between concentrate viscosity and molding quality of personalized traditional Chinese medicine(TCM) condensed water pill, this study established a concentrate viscosity characterization method with rotational rheometry. Seven model prescriptions were respectively concentrated to different degrees and the viscosity of each concentrate was determined. The pre-sence of 'viscosity jump' in the middle stage of 'flag hanging' of all the model prescriptions implied that there might be an ideal viscosity range in the preparation of condensed water pill. The further study of 22 model prescriptions demonstrated that the optimum viscosity range of concentrate was 5-15 Pa·s(25 ℃) for approximately 82% of the prescriptions. About 18% of the prescriptions had a wide range, which might be caused by the high proportions of mineral and crustacean drugs in the crushing part and sugar and fibrous drugs in the decocting part. This study clarified the optimum viscosity range for concentrates of personalized TCM condensed water pills and achieved a preparation technology without any excipient, laying a foundation for the on-line control of the preparation.


Asunto(s)
Medicamentos Herbarios Chinos , Medicina Tradicional China , Excipientes , Viscosidad , Agua
12.
Hepatology ; 70(4): 1214-1230, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30933361

RESUMEN

Tumor-associated neutrophils (TANs) play a crucial role in tumor development and progression in the cancer microenvironment. Despite increased understanding of TAN contributions to hepatocellular carcinoma (HCC) progression and prognosis, the direct interaction between TANs and HCC cells is not fully understood. In this study, we tested the effect of TANs on HCC cells in vitro and in vivo and investigated the mechanism of interaction between them. Our results showed that TANs secreted bone morphogenetic protein 2 and transforming growth factor beta 2 and triggered microRNA 301b-3p (miR-301-3p) expression in HCC cells, subsequently suppressed gene expression of limbic system-associated membrane protein (LSAMP) and CYLD lysine 63 deubiquitinase (CYLD), and increased stem cell characteristics in HCC cells. These TAN-induced HCC stem-like cells were hyperactive in nuclear factor kappa B signaling, secreted higher levels of chemokine (C-X-C motif) ligand 5 (CXCL5), and recruited more TAN infiltration, suggesting a positive feedback loop. In clinical HCC samples, increased TANs correlated with elevated miR-301b-3p, decreased LSAMP and CYLD expression, and increased nuclear p65 accumulation and CXCL5 expression, all of which predicted patient outcome. Conclusion: Our work identified a positive feedback loop governing cancer stem-like cells and TANs in HCC that controls tumor progression and patient outcome.


Asunto(s)
Carcinoma Hepatocelular/genética , Quimiocina CXCL5/genética , Progresión de la Enfermedad , Neoplasias Hepáticas/genética , Neutrófilos/metabolismo , Animales , Biopsia con Aguja , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Supervivencia Celular/genética , Retroalimentación , Humanos , Inmunohistoquímica , Técnicas In Vitro , Neoplasias Hepáticas/patología , Ratones , Ratones SCID , MicroARNs/genética , Células Madre Neoplásicas/metabolismo , Pronóstico , Transducción de Señal/genética , Microambiente Tumoral
13.
Cancer Cell Int ; 20(1): 582, 2020 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-33292317

RESUMEN

BACKGROUND: Plasmacytoid dendritic cells (pDCs) are present in various primary and metastatic human neoplasms; however, their clinical significance in intrahepatic cholangiocarcinoma is not clear. METHODS: To evaluate pDCs' distributions in and around tumors as well as their potential function and predictive value for prognosis in patients undergoing curative resection, we performed immunohistochemistry to examine the expression of pDC marker BDCA2, and CD3, CD4, CD8 and Foxp3 in intratumoral and peritumoral tissues from 359 patients with intrahepatic cholangiocarcinoma and compared with prognostic and clinicopathologic factors. RESULTS: Results showed that patients with high numbers of BDCA2+ pDCs in peritumoral tissues were more likely to have elevated levels of carbohydrate antigen 19-9 and gamma-glutamyl transferase, larger and more tumors, advanced tumor-node-metastasis staging, more vascular/bile duct invasion, and lymphatic metastasis in association with greater chance of recurrence and shorter overall survival. Peritumoral tissues with larger numbers of pDCs also showed increased Foxp3+ regulatory T cell infiltration, both of which were found to be independent factors for predicting time to recurrence and overall survival. By contrast, patient outcomes were not associated with the presence of intratumoral pDCs. CONCLUSIONS: Peritumoral pDC infiltration may indicate an immune tolerogenic peritumor microenvironment and can be used to predict a poor prognosis for patients undergoing curative resection for intrahepatic cholangiocarcinoma.

14.
Anal Bioanal Chem ; 412(11): 2687-2696, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32072211

RESUMEN

Biothiols, including cysteine (Cys), homocysteine (Hcy), and glutathione (GSH), play key roles in biological processes, and detecting such thiols selectively is critical for understanding functions of biothiols. In this work, a pyridazine annelated perylene-based fluorescent probe PAPC is synthesized for highly selective detection of Cys. PAPC exhibits strong blue emission in PBS, while the red emission at 605 nm can be observed in the presence of Cys. The probe PAPC shows ratiometric fluorescence (I605/I460) detection of Cys with wide linear range of 1-120 µM and low detection limit of 0.19 µM. Super large Stokes shift (170 nm) and ratiometric fluorescence endow the probe low background signal. The discrimination of Cys over Hcy and GSH can be achieved through the difference of the ratiometric fluorescence. In addition, the probe has been proven to track Cys in real samples such as urine and HeLa cells. Therefore, PAPC probe is a promising candidate for detecting Cys in practical application. Graphical abstract.


Asunto(s)
Cisteína/análisis , Colorantes Fluorescentes/química , Perileno/análogos & derivados , Células HeLa , Humanos , Modelos Moleculares , Imagen Óptica , Perileno/química , Espectrometría de Fluorescencia
15.
J Cell Biochem ; 120(4): 6035-6045, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30368883

RESUMEN

BACKGROUND: Prognosis of hepatocellular carcinoma (HCC) remains poor due to high recurrence rate and ineffective treatment options, highlighting the need to better understand the mechanism of recurrence and metastasis in HCC. METHODS: We first collected messenger RNA (mRNA) expression data from 442 cases of HCC patients from The Cancer Genome Atlas (TCGA) database as well as 251 HCC patients from Zhongshan Hospital during 2009 and 2010 to analyze the expression pattern from tissue microarray (TMA) of baculoviral IAP repeat containing 3 (BIRC3). Then, we used BIRC3 gain-of-function (overexpression) and loss-of-function (knockdown) studies to examine the effect of BIRC3 on HCC cell proliferation and invasion. In addition, we also investigated the undying mechanism by which BIRC3 contributes to HCC tumor progression. Functionally, we also used a BIRC3-specific inhibitor AT-406 in HCC xenograft model to explore the potential therapeutic benefit of targeting BIRC3 in liver cancer. RESULTS: BIRC3 serves as a novel prognostic indicator for HCC patients undergoing curative resection. BIRC3 promotes HCC epithelial-mesenchymal transition (EMT), cell migration, and metastasis via upregulating MAP3K7, therefore, inducing ERK1/2 phosphorylation. The specific BIRC3 inhibitor AT-406 can inhibit HCC cell proliferation and reduce pulmonary metastases. CONCLUSION: BIRC3 induces tumor proliferation and metastasis in vitro and in vivo. BIRC3 may serve as a novel therapeutic target for liver cancer.


Asunto(s)
Proteína 3 que Contiene Repeticiones IAP de Baculovirus/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Animales , Proteína 3 que Contiene Repeticiones IAP de Baculovirus/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Línea Celular Tumoral , Movimiento Celular/genética , Movimiento Celular/fisiología , Proliferación Celular/genética , Proliferación Celular/fisiología , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Matrices Tisulares
16.
J Hepatol ; 71(6): 1152-1163, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31349001

RESUMEN

BACKGROUND & AIMS: Early recurrence of hepatocellular carcinoma (HCC) after curative resection is common. However, the association between genetic mechanisms and early HCC recurrence, especially in Chinese patients, remains largely unknown. METHODS: We performed whole-genome sequencing (49 cases), whole-exome sequencing (18 cases), and deep targeted sequencing (115 cases) on 182 primary HCC samples. Focusing on WNK2, we used Sanger sequencing and qPCR to evaluate all the coding exons and copy numbers of that gene in an additional 554 HCC samples. We also explored the functional effect and mechanism of WNK2 on tumor growth and metastasis. RESULTS: We identified 5 genes (WNK2, RUNX1T1, CTNNB1, TSC1, and TP53) harboring somatic mutations that correlated with early tumor recurrence after curative resection in 182 primary HCC samples. Focusing on WNK2, the overall somatic mutation and copy number loss occurred in 5.3% (39/736) and 27.2% (200/736), respectively, of the total 736 HCC samples. Both types of variation were associated with lower WNK2 protein levels, higher rates of early tumor recurrence, and shorter overall survival. Biofunctional investigations revealed a tumor-suppressor role of WNK2: its inactivation led to ERK1/2 signaling activation in HCC cells, tumor-associated macrophage infiltration, and tumor growth and metastasis. CONCLUSIONS: Our results delineate genomic events that characterize Chinese HCCs and identify WNK2 as a driver of early HCC recurrence after curative resection. LAY SUMMARY: We applied next-generation sequencing and conducted an in-depth genomic analysis of hepatocellular carcinomas from a Chinese patient cohort. The results delineate the genomic events that characterize hepatocellular carcinomas in Chinese patients and identify WNK2 as a driver associated with early tumor recurrence after curative resection.


Asunto(s)
Carcinoma Hepatocelular , Hepatectomía , Neoplasias Hepáticas , Recurrencia Local de Neoplasia/genética , Proteínas Serina-Treonina Quinasas/genética , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , China , Femenino , Genes Supresores de Tumor , Predisposición Genética a la Enfermedad , Hepatectomía/efectos adversos , Hepatectomía/métodos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/patología , Proteína 1 Compañera de Translocación de RUNX1/genética , Transducción de Señal , Secuenciación del Exoma , beta Catenina/genética
17.
Biochem Biophys Res Commun ; 514(1): 51-57, 2019 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-31018905

RESUMEN

Krüppel-like factors (KLFs) are zinc-finger transcriptional factors that regulate target gene expression. Recent studies have shown that KLFs play essential roles in cancer development, whereas the function of KLF7 in glioma remains unclear. In this study, we showed that KLF7 was up-regulated in glioma tissues and its expression was inversely correlated with the patients' survival. Functional experiments demonstrated that KLF7 promoted the proliferation, migration and tumorigenesis of glioma cells. Mechanistically, KLF7 transcriptionally activated argininosuccinate lyase (ASL), which was observed highly expressed in glioma tissues. The biosynthesis of polyamine, a urea cycle metabolite, was enhanced by KLF7 in glioma cells. In addition, ASL contributed to the growth of glioma cells triggered by KLF7. Our findings demonstrate KLF7 as an oncogene and link KLF7 to ASL-mediated polyamine metabolism in glioma.


Asunto(s)
Argininosuccinatoliasa/genética , Neoplasias Encefálicas/genética , Glioma/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Poliaminas/metabolismo , Animales , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Glioma/metabolismo , Glioma/patología , Humanos , Masculino , Ratones Endogámicos BALB C , Activación Transcripcional
18.
Cancer Immunol Immunother ; 68(8): 1223-1233, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31201473

RESUMEN

Plasmacytoid dendritic cells (pDCs) are present in various primary and metastatic human neoplasms; however, their clinical significance in hepatocellular carcinoma (HCC) is unclear. In this study, we investigated the distribution, prognostic value, and potential function of pDCs in HCC patients undergoing curative resection. We performed immunohistochemical analyses of whole tumor sections from 224 patients to assess the expression of BDCA2, CD3, CD4, CD8, Foxp3, granzyme B, IL-17, and CD34. The findings were validated using tissue microarrays from another two independent cohorts totaling 841 HCC patients undergoing curative resection. Our results demonstrated that high numbers of BDCA2+ pDCs within tumors correlated with high alpha-fetoprotein levels, greater vascular invasion, advanced tumor-node-metastasis stage, shorter overall survival, and a higher recurrence rate. However, patient outcomes were not associated with pDCs in peritumoral stromal or nontumor tissues. Furthermore, an increase in intratumoral pDCs was associated with increased intratumoral infiltration of Foxp3+ regulatory T cells and IL-17-producing cells and correlated with tumor vascular density. Univariate and multivariate analyses revealed that the presence of intratumoral pDCs alone or in combination with regulatory T and/or IL-17-producing cells was an independent predictor of time to recurrence and overall survival. In conclusion, our study demonstrated that intratumoral infiltration by pDCs is a novel indicator for poor prognosis in patients with HCC, possibly through the induction of an immune tolerogenic and inflammatory tumor microenvironment comprising regulatory T and IL-17-producing cells. An assessment of the combination of these cells represents a superior predictor of patient outcome.


Asunto(s)
Carcinoma Hepatocelular/diagnóstico , Células Dendríticas/inmunología , Interleucina-17/metabolismo , Neoplasias Hepáticas/diagnóstico , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/mortalidad , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Factores de Transcripción Forkhead/metabolismo , Hepatectomía , Humanos , Lectinas Tipo C/metabolismo , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/mortalidad , Masculino , Glicoproteínas de Membrana/metabolismo , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Receptores Inmunológicos/metabolismo , Análisis de Supervivencia , alfa-Fetoproteínas/metabolismo
19.
Zhongguo Zhong Yao Za Zhi ; 44(1): 28-33, 2019 Jan.
Artículo en Zh | MEDLINE | ID: mdl-30868808

RESUMEN

Temporary prescription preparation is the preparation processed into different dosage forms by relevant pharmacist according to the temporary preparation requirement and the personalized prescription made by the doctor in accordance with the syndrome differentiation and drug performance.It is an important part in personalized pharmaceutical services.Rational design of process route,production equipment and quality control method for the temporary prescription preparation,and establishment of technology research strategy and mode in accordance with the characteristics of traditional Chinese medicine temporary prescription preparations play an important role in promoting the development of the temporary prescription preparations.To promote the normalization,standardization and intelligent development of temporary prescription preparations,we would comprehensively summarize the significance,policy,technology characteristics,technology research status quo and existing problems in this paper,and put forward the research direction of temporary prescription preparation technology based on the physical properties of raw materials,equipment research strategy,and intelligent manufacturing technology.Thus it will push the inheritance and innovation of temporary prescription preparation.


Asunto(s)
Medicina Tradicional China , Prescripciones/normas , Proyectos de Investigación , Control de Calidad
20.
Future Oncol ; 14(12): 1177-1186, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29316827

RESUMEN

AIM: The MAGE family member H1 (MAGEH1) belongs to melanoma-associated antigen (MAGE) superfamily. The role of MAGEH1 in hepatocellular carcinoma (HCC) is largely undefined. MATERIALS & METHODS: We used quantitative reverse transcription PCR and immunohistochemistry to detect MAGEH1 expression in HCC tissues. CCK-8 assay, wound healing migration assay and Transwell Matrigel invasion assay were used to measure HCC cell proliferation, migration and invasion ability. RESULTS:  MAGEH1 expression was downregulated in HCC tumor tissues compared with adjacent normal liver tissues and in samples from patients with tumor recurrence. MAGEH1 reduced HCC cell proliferation, migration and invasion ability. Low MAGEH1 expression was significantly correlated with poor prognosis in HCC patients. CONCLUSION:  MAGEH1 may serve as a potential biomarker and a new prognostic factor for HCC.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas de Neoplasias/metabolismo , Recurrencia Local de Neoplasia/diagnóstico , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/cirugía , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación hacia Abajo , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Hígado/patología , Hígado/cirugía , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/cirugía , Masculino , Proteínas Asociadas a Microtúbulos/genética , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Recurrencia Local de Neoplasia/epidemiología , Pronóstico , Tasa de Supervivencia
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